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  • Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-17
    Sean G Rudd; Nikolaos Tsesmetzis; Kumar Sanjiv; Cynthia BJ Paulin; Lakshmi Sandhow; Juliane Kutzner; Ida Hed Myrberg; Sarah S Bunten; Hanna Axelsson; Si Min Zhang; Azita Rasti; Petri Mäkelä; Si'Ana A Coggins; Sijia Tao; Sharda Suman; Rui M Branca; Georgios Mermelekas; Elisée Wiita; Sun Lee; Julian Walfridsson; Raymond F Schinazi; Baek Kim; Janne Lehtiö; Georgios Z Rassidakis; Katja Pokrovskaja Tamm; Ulrika Warpman‐Berglund; Mats Heyman; Dan Grandér; Sören Lehmann; Thomas Lundbäck; Hong Qian; Jan‐Inge Henter; Torsten Schaller; Thomas Helleday; Nikolas Herold

    The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

    更新日期:2020-01-17
  • Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-17
    Annerieke Sierksma; Ashley Lu; Renzo Mancuso; Nicola Fattorelli; Nicola Thrupp; Evgenia Salta; Jesus Zoco; David Blum; Luc Buée; Bart De Strooper; Mark Fiers

    Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome‐wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

    更新日期:2020-01-17
  • Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-14
    Eva M Buhl; Sonja Djudjaj; Barbara M Klinkhammer; Katja Ermert; Victor G Puelles; Maja T Lindenmeyer; Clemens D Cohen; Chaoyong He; Erawan Borkham‐Kamphorst; Ralf Weiskirchen; Bernd Denecke; Panuwat Trairatphisan; Julio Saez‐Rodriguez; Tobias B Huber; Lorin E Olson; Jürgen Floege; Peter Boor

    Kidney fibrosis is characterized by expansion and activation of platelet‐derived growth factor receptor‐β (PDGFR‐β)‐positive mesenchymal cells. To study the consequences of PDGFR‐β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR‐β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR‐β activation resembled those found in patients. In conclusion, PDGFR‐β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.

    更新日期:2020-01-14
  • Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-13
    Sophia G Liva; Yu‐Chou Tseng; Anees M Dauki; Michael G Sovic; Trang Vu; Sally E Henderson; Yi‐Chiu Kuo; Jason A Benedict; Xiaoli Zhang; Bryan C Remaily; Samuel K Kulp; Moray Campbell; Tanios Bekaii‐Saab; Mitchell A Phelps; Ching‐Shih Chen; Christopher C Coss

    No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

    更新日期:2020-01-13
  • Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-13
    Jie‐hong Wu; Ya‐nan Li; An‐qi Chen; Can‐dong Hong; Chun‐lin Zhang; Hai‐ling Wang; Yi‐fan Zhou; Peng‐Cheng Li; Yong Wang; Ling Mao; Yuan‐peng Xia; Quan‐wei He; Hui‐juan Jin; Zhen‐yu Yue; Bo Hu

    Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR.

    更新日期:2020-01-13
  • Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-13
    Ewa Wilcz‐Villega; Edward Carter; Alastair Ironside; Ruoyan Xu; Isabella Mataloni; Julie Holdsworth; William Jones; Rocío Moreno Béjar; Lukas Uhlik; Robert B Bentham; Susana A Godinho; Jesmond Dalli; Richard Grose; Gyorgy Szabadkai; Louise Jones; Kairbaan Hodivala‐Dilke; Katiuscia Bianchi

    During obesity, macrophages infiltrate the breast tissue leading to low‐grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKε and its downstream target—the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA‐approved drug targeting IKKε and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high‐fat diet‐induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation–IKKε and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity‐driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity.

    更新日期:2020-01-13
  • Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-13
    Ewelina Szymańska; Paulina Nowak; Krzysztof Kolmus; Magdalena Cybulska; Krzysztof Goryca; Edyta Derezińska‐Wołek; Anna Szumera‐Ciećkiewicz; Marta Brewińska‐Olchowik; Aleksandra Grochowska; Katarzyna Piwocka; Monika Prochorec‐Sobieszek; Michał Mikula; Marta Miączyńska

    Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers.

    更新日期:2020-01-13
  • Funding community collaboration to develop effective therapies for neurofibromatosis type 1 tumors
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-02
    Salvatore La Rosa; Vidya Browder; Annette C Bakker; Jaishri O Blakeley; Sharad K Verma; Ling M Wong; Jill Morris; Naba Bora

    The time from identifying a drug target to a new drug approval is often measured in decades and can take even longer for therapies to treat rare diseases. In fact, 95% of rare diseases do not have a specific therapy approved at all. Coordinated efforts to augment the drug development pipeline along with long‐term and comprehensive support that enable scientific breakthroughs for rare diseases are possible, but it requires integration across multiple stakeholders. This article analyzes the coordinated funding efforts of four federal and philanthropic organizations to advance drug development for neurofibromatosis type 1‐associated tumors and discusses how these organizations have been collaborating and evolved practices to optimize funding and research support.

    更新日期:2020-01-09
  • Live vaccines—a short‐cut to cancer viro‐immunotherapy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-20
    Thomas C Wirth; Julia Niemann; Florian Kühnel

    Tumour immunotherapies have been a breakthrough in clinical oncology but only a few patients benefit from this progress. Additional interventions that sensitize immunologically cold tumours for the administration of checkpoint modifiers are urgently needed. In this issue of EMBO Molecular Medicine, Aznar et al present the already approved yellow fever vaccine 17D as an oncolytic agent for tumour immunoactivation. In tumour‐bearing mice, they demonstrated a convincing synergy of the vaccine with CD137 agonistic antibodies resulting in significantly improved survival.

    更新日期:2020-01-09
  • Repurposing the yellow fever vaccine for intratumoral immunotherapy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-19
    Maria Angela Aznar; Carmen Molina; Alvaro Teijeira; Inmaculada Rodriguez; Arantza Azpilikueta; Saray Garasa; Alfonso R Sanchez‐Paulete; Luna Cordeiro; Iñaki Etxeberria; Maite Alvarez; Sergio Rius‐Rocabert; Estanislao Nistal‐Villan; Pedro Berraondo; Ignacio Melero
    更新日期:2020-01-09
  • Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-11
    Jinbeom Heo; Byeong‐Joo Noh; Seungun Lee; Hye‐Yeon Lee; YongHwan Kim; Jisun Lim; Hyein Ju; Hwan Yeul Yu; Chae‐Min Ryu; Peter CW Lee; Hwangkyo Jeong; Yumi Oh; Kyunggon Kim; Sang‐Yeob Kim; Jaekyoung Son; Bumsik Hong; Jong Soo Kim; Yong Mee Cho; Dong‐Myung Shin
    更新日期:2020-01-09
  • Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-28
    Mingzhi Han; Shuai Wang; Ning Yang; Xu Wang; Wenbo Zhao; Halala Sdik Saed; Thomas Daubon; Bin Huang; Anjing Chen; Gang Li; Hrvoje Miletic; Frits Thorsen; Rolf Bjerkvig; Xingang Li; Jian Wang
    更新日期:2020-01-09
  • Neutrophils suppress tumor‐infiltrating T cells in colon cancer via matrix metalloproteinase‐mediated activation of TGFβ
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-02
    Markus Germann; Nadine Zangger; Marc‐Olivier Sauvain; Christine Sempoux; Amber D Bowler; Pratyaksha Wirapati; Lana E Kandalaft; Mauro Delorenzi; Sabine Tejpar; George Coukos; Freddy Radtke
    更新日期:2020-01-09
  • Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-29
    Yue‐qing Zhou; Yun Shi; Ling Yang; Yu‐fen Sun; Yu‐fei Han; Zi‐xian Zhao; Yu‐jia Wang; Ying Liu; Yu Ma; Ting Zhang; Tao Ren; Tina P Dale; Nicholas R Forsyth; Fa‐guang Jin; Jie‐ming Qu; Wei Zuo; Jin‐fu Xu
    更新日期:2020-01-09
  • Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-02
    Pamela Bella; Andrea Farini; Stefania Banfi; Daniele Parolini; Noemi Tonna; Mirella Meregalli; Marzia Belicchi; Silvia Erratico; Pasqualina D'Ursi; Fabio Bianco; Mariella Legato; Chiara Ruocco; Clementina Sitzia; Simone Sangiorgi; Chiara Villa; Giuseppe D'Antona; Luciano Milanesi; Enzo Nisoli; PierLuigi Mauri; Yvan Torrente
    更新日期:2020-01-09
  • Glutathione peroxidase 8 negatively regulates caspase‐4/11 to protect against colitis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-29
    Jye‐Lin Hsu; Jen‐Wei Chou; Tzu‐Fan Chen; Jeh‐Ting Hsu; Fang‐Yi Su; Joung‐Liang Lan; Po‐Chang Wu; Chun‐Mei Hu; Eva Y‐HP Lee; Wen‐Hwa Lee
    更新日期:2020-01-09
  • Myopathy reversion in mice after restauration of mitochondrial complex I
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-09
    Claudia V Pereira; Susana Peralta; Tania Arguello; Sandra R Bacman; Francisca Diaz; Carlos T Moraes

    Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15‐day‐old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time. rAAV9‐Ndufs3 delivered systemically into 15‐ to 18‐day‐old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9‐mediated gene replacement to revert muscle function after disease onset, we also treated post‐symptomatic, 2‐month‐old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2 months. These findings have far‐reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.

    更新日期:2020-01-09
  • Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-09
    Lise Van Wyngene; Tineke Vanderhaeghen; Steven Timmermans; Jolien Vandewalle; Kelly Van Looveren; Jolien Souffriau; Charlotte Wallaeys; Melanie Eggermont; Sam Ernst; Evelien Van Hamme; Amanda Gonçalves; Guy Eelen; Anneleen Remmerie; Charlotte L Scott; Caroline Rombouts; Lynn Vanhaecke; Liesbet De Bus; Johan Decruyenaere; Peter Carmeliet; Claude Libert

    Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.

    更新日期:2020-01-09
  • “Designer cytokines” targeting the tumor vasculature—think global and act local
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-09
    Thomas Kammertoens; Josephine Kemna; Matthias Leisegang

    Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide‐induced serum factor that causes necrosis of tumors (Carswell et al, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler et al, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti‐tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe et al (2020) describing novel “designer cytokines” (TNF and interferon‐γ) that increase local activity by targeting the CD13‐positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off‐target effects on normal cells.

    更新日期:2020-01-09
  • Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-08
    Yann Ehinger; Julie Bruyère; Nicolas Panayotis; Yah‐Se Abada; Emilie Borloz; Valérie Matagne; Chiara Scaramuzzino; Hélène Vitet; Benoit Delatour; Lydia Saidi; Laurent Villard; Frédéric Saudou; Jean‐Christophe Roux

    Mutations in the X‐linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain‐derived neurotrophic factor (BDNF) levels, but non‐specific overexpression of BDNF only partially improves the phenotype of Mecp2‐deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF‐containing vesicles, and is under‐expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho‐mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.

    更新日期:2020-01-08
  • Safe eradication of large established tumors using neovasculature‐targeted tumor necrosis factor‐based therapies
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-08
    Leander Huyghe; Alexander Van Parys; Anje Cauwels; Sandra Van Lint; Stijn De Munter; Jennyfer Bultinck; Lennart Zabeau; Jeroen Hostens; An Goethals; Nele Vanderroost; Annick Verhee; Gilles Uzé; Niko Kley; Frank Peelman; Bart Vandekerckhove; Peter Brouckaert; Jan Tavernier

    Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity‐on‐Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF‐based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T‐cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8‐targeted type I interferon AcTakine. Co‐treatment with a CD13‐targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible.

    更新日期:2020-01-08
  • Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-20
    Qihui Zhou; Nikola Mareljic; Meike Michaelsen; Samira Parhizkar; Steffanie Heindl; Brigitte Nuscher; Daniel Farny; Mareike Czuppa; Carina Schludi; Alexander Graf; Stefan Krebs; Helmut Blum; Regina Feederle; Stefan Roth; Christian Haass; Thomas Arzberger; Arthur Liesz; Dieter Edbauer

    The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.

    更新日期:2019-12-20
  • “Splitting the matrix”: intussusceptive angiogenesis meets MT1‐MMP
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-20
    Gabriela D'Amico; José M Muñoz‐Félix; Ana Rita Pedrosa; Kairbaan M Hodivala‐Dilke

    Pathological angiogenesis contributes to tumour progression as well as to chronic inflammatory diseases. In this issue of EMBO Molecular Medicine, Esteban and co‐workers identify endothelial cell MT1‐MMP as a key regulator of intussusceptive angiogenesis (IA) in inflammatory colitis. Thrombospondin 1 (TSP1) cleavage by MT1‐MMP results in the binding of the c‐terminal fragment of TSP1 to αvβ3 integrin, which induces nitric oxide (NO) production, vasodilation and further initiation of IA. This novel control mechanism of inflammatory IA points towards promising new therapeutic targets for inflammatory bowel disease.

    更新日期:2019-12-20
  • The challenges of translation
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-18
    Helmut R Salih; Gundram Jung

    Cancer immunotherapy is a highly active area in translational medicine where the challenges and rewards of developing new drugs “from bench to bedside” become particularly visible. Here, we comment on both, the scientific and non‐scientific hurdles of this translational process using the example of bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells, two closely related strategies for antibody‐guided recruitment of T cells against cancer. Both exert impressive therapeutic activity and were recently approved for treatment of B‐cell malignancies. We discuss how the efficacy of these auspicious therapeutic tools may be further improved, in particular against solid tumors, but we also address another critical issue: Since both approaches were already introduced in the 1980s, why did it take almost thirty years until they became clinically available?

    更新日期:2019-12-06
  • In search of the next super models
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-18
    Alexander Goedel; Niels Grote Beverborg; Makoto Sahara; Kenneth R Chien

    The advent of pluripotent stem cell biology and facile genetic manipulation via CRISPR technology has ushered in a new era of human disease models for drug discovery and development. While these precision “super models” hold great promise for tailoring personalized therapy, their full potential and in vivo validation have remained elusive.

    更新日期:2019-12-06
  • Looking beyond the usual suspects: sulfide stress in schizophrenia pathophysiology
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-29
    Michel Simonneau

    Schizophrenia is a complex, multifactorial disease that displays heterogeneous behavioral and cognitive syndrome (Lieberman & First, 2018). The origin of schizophrenia appears to lie in genetic and/or environmental disruption of brain development (Owen et al, 2016). In spite of current treatment that largely consists in antipsychotic drugs combined with psychological therapies, social support, and rehabilitation, developing more effective therapeutic interventions is an essential issue.

    更新日期:2019-12-06
  • Targeting senescent cells in translational medicine
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-19
    Marta Paez‐Ribes; Estela González‐Gualda; Gary J Doherty; Daniel Muñoz‐Espín

    Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.

    更新日期:2019-12-06
  • Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-03
    Maksymilian Prondzynski; Marc D Lemoine; Antonia TL Zech; András Horváth; Vittoria Di Mauro; Jussi T Koivumäki; Nico Kresin; Josefine Busch; Tobias Krause; Elisabeth Krämer; Saskia Schlossarek; Michael Spohn; Felix W Friedrich; Julia Münch; Sandra D Laufer; Charles Redwood; Alexander E Volk; Arne Hansen; Giulia Mearini; Daniele Catalucci; Christian Meyer; Torsten Christ; Monica Patten; Thomas Eschenhagen; Lucie Carrier
    更新日期:2019-12-06
  • Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-28
    Masayuki Ide; Tetsuo Ohnishi; Manabu Toyoshima; Shabeesh Balan; Motoko Maekawa; Chie Shimamoto‐Mitsuyama; Yoshimi Iwayama; Hisako Ohba; Akiko Watanabe; Takashi Ishii; Norihiro Shibuya; Yuka Kimura; Yasuko Hisano; Yui Murata; Tomonori Hara; Momo Morikawa; Kenji Hashimoto; Yayoi Nozaki; Tomoko Toyota; Yuina Wada; Yosuke Tanaka; Tadafumi Kato; Akinori Nishi; Shigeyoshi Fujisawa; Hideyuki Okano; Masanari Itokawa; Nobutaka Hirokawa; Yasuto Kunii; Akiyoshi Kakita; Hirooki Yabe; Kazuya Iwamoto; Kohji Meno; Takuya Katagiri; Brian Dean; Kazuhiko Uchida; Hideo Kimura; Takeo Yoshikawa
    更新日期:2019-12-06
  • 4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-29
    Suh Young Jeong; Penelope Hogarth; Andrew Placzek; Allison M Gregory; Rachel Fox; Dolly Zhen; Jeffrey Hamada; Marianne van der Zwaag; Roald Lambrechts; Haihong Jin; Aaron Nilsen; Jared Cobb; Thao Pham; Nora Gray; Martina Ralle; Megan Duffy; Leila Schwanemann; Puneet Rai; Alison Freed; Katrina Wakeman; Randall L Woltjer; Ody CM Sibon; Susan J Hayflick
    更新日期:2019-12-06
  • CoA‐dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-07
    Roald A Lambrechts; Hein Schepers; Yi Yu; Marianne van der Zwaag; Kaija J Autio; Marcel A Vieira‐Lara; Barbara M Bakker; Marina A Tijssen; Susan J Hayflick; Nicola A Grzeschik; Ody CM Sibon
    更新日期:2019-12-06
  • Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-11
    Sebastian Palmqvist; Philip S Insel; Erik Stomrud; Shorena Janelidze; Henrik Zetterberg; Britta Brix; Udo Eichenlaub; Jeffrey L Dage; Xiyun Chai; Kaj Blennow; Niklas Mattsson; Oskar Hansson
    更新日期:2019-12-06
  • Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK‐rearranged lung cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-21
    Mi Ran Yun; Hun Mi Choi; You Won Lee; Hyeong Seok Joo; Chae Won Park; Jae Woo Choi; Dong Hwi Kim; Han Na Kang; Kyoung‐Ho Pyo; Eun Joo Shin; Hyo Sup Shim; Ross A Soo; James Chih‐Hsin Yang; Sung Sook Lee; Hyun Chang; Min Hwan Kim; Min Hee Hong; Hye Ryun Kim; Byoung Chul Cho
    更新日期:2019-12-06
  • The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-21
    Shengchen Lin; Chongbiao Huang; Jianwei Sun; Oana Bollt; Xiuchao Wang; Eric Martine; Jiaxin Kang; Matthew D Taylor; Bin Fang; Pankaj K Singh; John Koomen; Jihui Hao; Shengyu Yang
    更新日期:2019-12-06
  • Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-28
    Liping Ye; Chuyong Lin; Xi Wang; Qiji Li; Yue Li; Meng Wang; Zekun Zhao; Xianqiu Wu; Dongni Shi; Yunyun Xiao; Liangliang Ren; Yunting Jian; Meisongzhu Yang; Ruizhang Ou; Guangzheng Deng; Ying Ouyang; Xiangfu Chen; Jun Li; Libing Song
    更新日期:2019-12-06
  • Immune‐mediated ECM depletion improves tumour perfusion and payload delivery
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-11
    Yen Ling Yeow; Venkata Ramana Kotamraju; Xiao Wang; Meenu Chopra; Nasibah Azme; Jiansha Wu; Tobias D Schoep; Derek S Delaney; Kirk Feindel; Ji Li; Kelsey M Kennedy; Wes M Allen; Brendan F Kennedy; Irma Larma; David D Sampson; Lisa M Mahakian; Brett Z Fite; Hua Zhang; Tomas Friman; Aman P Mann; Farah A Aziz; M Priyanthi Kumarasinghe; Mikael Johansson; Hooi C Ee; George Yeoh; Lingjun Mou; Katherine W Ferrara; Hector Billiran; Ruth Ganss; Erkki Ruoslahti; Juliana Hamzah
    更新日期:2019-12-06
  • Therapeutic targeting of circ‐CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-11
    Huanhuan Li; Feng Yang; Anpei Hu; Xiaojing Wang; Erhu Fang; Yajun Chen; Dan Li; Huajie Song; Jianqun Wang; Yanhua Guo; Yang Liu; Hongjun Li; Kai Huang; Liduan Zheng; Qiangsong Tong
    更新日期:2019-12-06
  • Cobalt protoporphyrin IX increases endogenous G‐CSF and mobilizes HSC and granulocytes to the blood
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-11-11
    Agata Szade; Krzysztof Szade; Witold N Nowak; Karolina Bukowska‐Strakova; Lucie Muchova; Monika Gońka; Monika Żukowska; Maciej Cieśla; Neli Kachamakova‐Trojanowska; Marzena Rams‐Baron; Alicja Ratuszna; Józef Dulak; Alicja Józkowicz
    更新日期:2019-12-06
  • Regulation of liver regeneration by growth factors and cytokines
    EMBO Mol. Med. (IF 10.624) Pub Date : 2010-07-22
    Friederike Böhm; Ulrike A. Köhler; Tobias Speicher; Sabine Werner

    The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver regeneration. In particular, the availability of genetically modified mice and their use in liver regeneration studies has unraveled novel and often unexpected functions of growth factors, cytokines and their downstream signalling targets in liver regeneration. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ.

    更新日期:2019-12-04
  • Endothelial MT1‐MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-12-03
    Sergio Esteban; Cristina Clemente; Agnieszka Koziol; Pilar Gonzalo; Cristina Rius; Fernando Martínez; Pablo M Linares; María Chaparro; Ana Urzainqui; Vicente Andrés; Motoharu Seiki; Javier P Gisbert; Alicia G Arroyo
    更新日期:2019-12-03
  • The amyloid hypothesis of Alzheimer's disease at 25 years
    EMBO Mol. Med. (IF 10.624) Pub Date : 2016-03-29
    Dennis J Selkoe; John Hardy

    Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

    更新日期:2019-11-18
  • Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts
    EMBO Mol. Med. (IF 10.624) Pub Date : 2017-08-01
    Jessica Hartmann; Martina Schüßler‐Lenz; Attilio Bondanza; Christian J Buchholz

    Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B‐cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19‐specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.

    更新日期:2019-11-18
  • Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-06-06
    Tenagne D Challa; Stephan Wueest; Fabrizio C Lucchini; Mara Dedual; Salvatore Modica; Marcela Borsigova; Christian Wolfrum; Matthias Blüher; Daniel Konrad
    更新日期:2019-11-18
  • Multiple cancer pathways regulate telomere protection
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-06-13
    Leire Bejarano; Giuseppe Bosso; Jessica Louzame; Rosa Serrano; Elena Gómez‐Casero; Jorge Martínez‐Torrecuadrada; Sonia Martínez; Carmen Blanco‐Aparicio; Joaquín Pastor; Maria A Blasco
    更新日期:2019-11-18
  • 4 Ds in health research—working together toward rapid precision medicine
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-18
    Ellen Niederberger; Michael J Parnham; Jochen Maas; Gerd Geisslinger

    Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre‐existing disease condition. Therapy remains predominantly symptom‐based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.

    更新日期:2019-11-07
  • Toward personalized TGFβ inhibition for pancreatic cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-22
    Ryan M Carr; Martin E Fernandez‐Zapico

    Cancer can be conceptualized as arising from somatic mutations resulting in a single renegade cell escaping from the constraints of multicellularity. Thus, the era of precision medicine has led to intense focus on the cancer cell to target these mutations that result in oncogenic signaling and sustain malignancy. However, in pancreatic ductal adenocarcinoma (PDAC) there are only four abundantly common driver mutations (KRAS, CDKN2A, TP53, and SMAD4), which are not currently actionable. Thus, precision therapy for PDAC must look beyond the cancer cell. In fact, PDAC is more than a collection of renegade cells, instead representing an extensive, supportive ecosystem, having developed over several years, and consisting of numerous interactions between the cancer cells, normal mesenchymal cells, immune cells, and the dense extracellular matrix. In this issue, Huang and colleagues demonstrate how elucidation of these complex relationships within the tumor microenvironment (TME) can be exploited for therapeutic intervention in PDAC. They identify in a subset of PDAC with mutations in TGFβ signaling, that a paracrine signaling axis can be abrogated to modulate the TME and improve outcomes.

    更新日期:2019-11-07
  • Targeting cardiac hypertrophy through a nuclear co‐repressor
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-17
    Andrea Grund; Joerg Heineke

    Heart failure entails the inability of the heart to pump blood to vital organs. One of the main risk factors for heart failure is the development of pathological hypertrophy. In this issue of EMBO Molecular Medicine, Li and coworkers show that NCoR1, a co‐repressor of transcription factors, inhibits the transcriptional activity of MEF2 by stabilizing its complex with class II HDACs. By this mechanism, NCoR1 was identified as potent inhibitor of pathological cardiac hypertrophy and dysfunction.

    更新日期:2019-11-07
  • Plasma Proteome Profiling to detect and avoid sample‐related biases in biomarker studies
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-30
    Philipp E Geyer; Eugenia Voytik; Peter V Treit; Sophia Doll; Alisa Kleinhempel; Lili Niu; Johannes B Müller; Marie‐Luise Buchholtz; Jakob M Bader; Daniel Teupser; Lesca M Holdt; Matthias Mann
    更新日期:2019-11-07
  • Targeting TGFβR2‐mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-14
    Huocong Huang; Yuqing Zhang; Valerie Gallegos; Noah Sorrelle; Mohamed Medhat Zaid; Jason Toombs; Wenting Du; Steven Wright; Moriah Hagopian; Zhaoning Wang; Abdel Nasser Hosein; Adwait Amod Sathe; Chao Xing; Eugene J Koay; Kyla E Driscoll; Rolf A Brekken
    更新日期:2019-11-07
  • The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-26
    Yuqian Yan; Jian Ma; Dejie Wang; Dong Lin; Xiaodong Pang; Shangqian Wang; Yu Zhao; Lei Shi; Hui Xue; Yunqian Pan; Jun Zhang; Claes Wahlestedt; Francis J Giles; Yu Chen; Martin E Gleave; Collin C Collins; Dingwei Ye; Yuzhuo Wang; Haojie Huang
    更新日期:2019-11-07
  • Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-10
    Hao Wu; Yijie Han; Yasmina Rodriguez Sillke; Hongzhang Deng; Sophiya Siddiqui; Christoph Treese; Franziska Schmidt; Marie Friedrich; Jacqueline Keye; Jiajia Wan; Yue Qin; Anja A Kühl; Zhihai Qin; Britta Siegmund; Rainer Glauben
    更新日期:2019-11-07
  • 3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-14
    Guo Chen; Wei Xie; Jihoon Nah; Allan Sauvat; Peng Liu; Federico Pietrocola; Valentina Sica; Didac Carmona‐Gutierrez; Andreas Zimmermann; Tobias Pendl; Jelena Tadic; Martina Bergmann; Sebastian J Hofer; Lana Domuz; Sylvie Lachkar; Maria Markaki; Nektarios Tavernarakis; Junichi Sadoshima; Frank Madeo; Oliver Kepp; Guido Kroemer
    更新日期:2019-11-07
  • Nuclear receptor corepressor 1 represses cardiac hypertrophy
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-18
    Chao Li; Xue‐Nan Sun; Bo‐Yan Chen; Meng‐Ru Zeng; Lin‐Juan Du; Ting Liu; Hui‐Hui Gu; Yuan Liu; Yu‐Lin Li; Lu‐Jun Zhou; Xiao‐Jun Zheng; Yu‐Yao Zhang; Wu‐Chang Zhang; Yan Liu; Chaoji Shi; Shuai Shao; Xue‐Rui Shi; Yi Yi; Xu Liu; Jun Wang; Johan Auwerx; Zhao V Wang; Feng Jia; Ruo‐Gu Li; Sheng‐Zhong Duan
    更新日期:2019-11-07
  • Role of bulge epidermal stem cells and TSLP signaling in psoriasis
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-26
    Nuria Gago‐Lopez; Liliana F Mellor; Diego Megías; Guillermo Martín‐Serrano; Ander Izeta; Francisco Jimenez; Erwin F Wagner
    更新日期:2019-11-07
  • Disruption of Sema3A/Plexin‐A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-09-30
    Fabien Binamé; Lucas D Pham‐Van; Caroline Spenlé; Valérie Jolivel; Dafni Birmpili; Lionel A Meyer; Laurent Jacob; Laurence Meyer; Ayikoé G Mensah‐Nyagan; Chrystelle Po; Michaël Van der Heyden; Guy Roussel; Dominique Bagnard
    更新日期:2019-11-07
  • Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-07
    Flora Magnotti; Lucie Lefeuvre; Sarah Benezech; Tiphaine Malsot; Louis Waeckel; Amandine Martin; Sébastien Kerever; Daria Chirita; Marine Desjonqueres; Agnès Duquesne; Mathieu Gerfaud‐Valentin; Audrey Laurent; Pascal Sève; Michel‐Robert Popoff; Thierry Walzer; Alexandre Belot; Yvan Jamilloux; Thomas Henry
    更新日期:2019-11-07
  • MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review
    EMBO Mol. Med. (IF 10.624) Pub Date : 2012-02-20
    Marilena V. Iorio; Carlo M. Croce

    Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA‐based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

    更新日期:2019-11-06
  • Inflammasomes in neuroinflammatory and neurodegenerative diseases
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-04-23
    Sofie Voet; Sahana Srinivasan; Mohamed Lamkanfi; Geert van Loo
    更新日期:2019-11-06
  • Peroxisome proliferator-activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
    EMBO Mol. Med. (IF 10.624) Pub Date : 2017-03-10
    Oren Pleniceanu,Racheli Shukrun,Dorit Omer,Einav Vax,Itamar Kanter,Klaudyna Dziedzic,Naomi Pode-Shakked,Michal Mark-Daniei,Sara Pri-Chen,Yehudit Gnatek,Hadas Alfandary,Nira Varda-Bloom,Dekel D Bar-Lev,Naomi Bollag,Rachel Shtainfeld,Leah Armon,Achia Urbach,Tomer Kalisky,Arnon Nagler,Orit Harari-Steinberg,Jack L Arbiser,Benjamin Dekel

    Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of in vivo models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growth in vivo to involve robust PPARγ-pathway activation. Similarly, immunostaining revealed strong PPARγ expression in human AML specimens. Accordingly, we demonstrate that while PPARγ agonism accelerates AML growth, PPARγ antagonism is inhibitory, strongly suppressing AML proliferation and tumor-initiating capacity, via a TGFB-mediated inhibition of PDGFB and CTGF. Finally, we show striking similarity between AML cell lines and mesenchymal stem cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establish the first in vivo human AML model, which provides evidence that AML may originate in a PPARγ-activated renal MSC lineage that is skewed toward adipocytes and smooth muscle and away from osteoblasts, and uncover PPARγ as a regulator of AML growth, which could serve as an attractive therapeutic target.

    更新日期:2019-11-01
  • An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2019-10-09
    Archita Mishra,Ashalatha S Mamidi,Raju S Rajmani,Ananya Ray,Rajanya Roy,Avadhesha Surolia

    更新日期:2019-11-01
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