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  • Inhibition of double‐strand DNA‐sensing cGAS ameliorates brain injury after ischemic stroke
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-04-01
    Qian Li; Yuze Cao; Chun Dang; Bin Han; Ranran Han; Heping Ma; Junwei Hao; Lihua Wang

    Cytosolic double‐stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid‐sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP‐AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that

  • Resolving mechanisms of immune‐mediated disease in primary CD4 T cells
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-04-01
    Christophe Bourges; Abigail F Groff; Oliver S Burren; Chiara Gerhardinger; Kaia Mattioli; Anna Hutchinson; Theodore Hu; Tanmay Anand; Madeline W Epping; Chris Wallace; Kenneth GC Smith; John L Rinn; James C Lee

    Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is

  • Towards the optical cochlear implant: optogenetic approaches for hearing restoration
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-30
    Alexander Dieter; Daniel Keppeler; Tobias Moser

    Cochlear implants (CIs) are considered the most successful neuroprosthesis as they enable speech comprehension in the majority of half a million CI users suffering from sensorineural hearing loss. By electrically stimulating the auditory nerve, CIs constitute an interface re‐connecting the brain and the auditory scene, providing the patient with information regarding the latter. However, since electric

  • Cancer‐associated fibroblasts: activin A adds another string to their bow
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-26
    Remi Samain; Victoria Sanz‐Moreno

    Non‐melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer‐associated fibroblasts (CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear

  • Antithrombin inhibition using nanobodies to correct bleeding in hemophilia
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-25
    Jamie M O'Sullivan; James S O'Donnell

    In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous studies that used RNA interference (RNAi) therapy to reduce AT levels (Sehgal et al, 2015; Pasi et al, 2017), the authors utilized llama‐derived single‐domain

  • Endothelial Notch signaling controls insulin transport in muscle
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-18
    Sana S Hasan; Markus Jabs; Jacqueline Taylor; Lena Wiedmann; Thomas Leibing; Viola Nordström; Giuseppina Federico; Leticia P Roma; Christopher Carlein; Gretchen Wolff; Bilgen Ekim‐Üstünel; Maik Brune; Iris Moll; Fabian Tetzlaff; Hermann‐Josef Gröne; Thomas Fleming; Cyrill Géraud; Stephan Herzig; Peter P Nawroth; Andreas Fischer

    The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ‐specific manner. Insulin flux across the endothelium to muscle cells is a rate‐limiting process influencing insulin‐mediated lowering of blood glucose. Here, we demonstrate

  • Sepsis therapies: learning from 30 years of failure of translational research to propose new leads
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-16
    Jean‐Marc Cavaillon; Mervyn Singer; Tomasz Skirecki

    Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient

  • Adeno‐associated virus‐vectored influenza vaccine elicits neutralizing and Fcγ receptor‐activating antibodies
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-12
    Daniel E Demminger; Lisa Walz; Kristina Dietert; Helen Hoffmann; Oliver Planz; Achim D Gruber; Veronika von Messling; Thorsten Wolff

    The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has propelled research on distinct antigens and delivery methods to efficiently induce broad

  • Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-11
    Elena Barbon; Gabriel Ayme; Amel Mohamadi; Jean‐François Ottavi; Charlotte Kawecki; Caterina Casari; Sebastien Verhenne; Solenne Marmier; Laetitia van Wittenberghe; Severine Charles; Fanny Collaud; Cecile V Denis; Olivier D Christophe; Federico Mingozzi; Peter J Lenting

    Novel therapies for hemophilia, including non‐factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama‐derived single‐domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant

  • Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-10
    Kai Schlepckow; Kathryn M Monroe; Gernot Kleinberger; Ludovico Cantuti‐Castelvetri; Samira Parhizkar; Dan Xia; Michael Willem; Georg Werner; Nadine Pettkus; Bettina Brunner; Alice Sülzen; Brigitte Nuscher; Heike Hampel; Xianyuan Xiang; Regina Feederle; Sabina Tahirovic; Joshua I Park; Rachel Prorok; Cathal Mahon; Chun‐Chi Liang; Ju Shi; Do Jin Kim; Hanna Sabelström; Fen Huang; Gilbert Di Paolo; Mikael

    Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies

  • Targeting the pregnane X receptor using microbial metabolite mimicry
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-10
    Zdeněk Dvořák; Felix Kopp; Cait M Costello; Jazmin S Kemp; Hao Li; Aneta Vrzalová; Martina Štěpánková; Iveta Bartoňková; Eva Jiskrová; Karolína Poulíková; Barbora Vyhlídalová; Lars U Nordstroem; Chamini V Karunaratne; Harmit S Ranhotra; Kyu Shik Mun; Anjaparavanda P Naren; Iain A Murray; Gary H Perdew; Julius Brtko; Lucia Toporova; Arne Schön; William G Wallace; William G Walton; Matthew R Redinbo;

    The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously

  • A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-09
    Michael Cangkrama; Mateusz Wietecha; Nicolas Mathis; Rin Okumura; Luca Ferrarese; Dunja Al‐Nuaimi; Maria Antsiferova; Reinhard Dummer; Metello Innocenti; Sabine Werner

    Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces

  • Genomic data sharing in Europe is Stumbling-Could a code of conduct prevent its fall?
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-18
    Fruzsina Molnár-Gábor,Jan O Korbel

    Genomic data sharing is becoming more important as scientists join forces across borders in biomedical research for the benefit of patients and society. The EU's General Data Protection Regulation (GDPR) helps simplify sharing of such data at the European and international level. However, initial optimism has dried up as EU member states go their own ways in implementing the GDPR into national laws

  • Google's Project Nightingale highlights the necessity of data science ethics review.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-17
    Christophe Olivier Schneble,Bernice Simone Elger,David Martin Shaw

    On November 14 last year, the British Guardian published an account from an anonymous whistleblower at Google, accusing the company of misconduct in regard to handling sensitive health data. The whistleblower works for Project Nightingale, an attempt by Google to get into the lucrative US healthcare market, by storing and processing the personal medical data of up to 50 million customers of Ascension

  • PDGFR-β and kidney fibrosis.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-18
    Alberto Ortiz

    Chronic kidney disease (CKD) is one of the fastest growing global causes of death, estimated to rank among the top five by 2040 (Foreman et al, 2018). This illustrates current pitfalls in diagnosis and management of CKD. Advanced CKD requires renal function replacement by dialysis or transplantation. However, earlier CKD stages, even when renal function is still normal, are already associated with

  • A CINful way to overcome addiction: how chromosomal instability enables cancer to overcome its oncogene addiction.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-18
    Daniel Bronder,Samuel F Bakhoum

    Oncogene-addicted tumors present a valuable target for therapeutic intervention and an opportunity to achieve a wide therapeutic window. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Chromosomal instability, a defining feature of human cancer, has been linked to targeted therapy resistance, but

  • Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-24
    Jarred M Griffin,Frank Bradke

    The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies

  • 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

  • Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-31
    Xinyu Mei,Dashi Qi,Ting Zhang,Ying Zhao,Li Jin,Junli Hou,Jianhua Wang,Yan Lin,Yu Xue,Pingping Zhu,Zexian Liu,Lei Huang,Ji Nie,Wen Si,Jingyi Ma,Jianhong Ye,Richard H Finnell,Hexige Saiyin,Hongyan Wang,Jianyuan Zhao,Shimin Zhao,Wei Xu

    Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy

  • 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

  • MicroRNA exporter HuR clears the internalized pathogens by promoting pro-inflammatory response in infected macrophages.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-07
    Avijit Goswami,Kamalika Mukherjee,Anup Mazumder,Satarupa Ganguly,Ishita Mukherjee,Saikat Chakrabarti,Syamal Roy,Shyam Sundar,Krishnananda Chattopadhyay,Suvendra N Bhattacharyya

    HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles-mediated export of miRNAs, ensures robust derepression of miRNA-repressed cytokines essential for strong pro-inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of

  • Predicting antimicrobial resistance in Pseudomonas aeruginosa with machine learning-enabled molecular diagnostics.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-12
    Ariane Khaledi,Aaron Weimann,Monika Schniederjans,Ehsaneddin Asgari,Tzu-Hao Kuo,Antonio Oliver,Gabriel Cabot,Axel Kola,Petra Gastmeier,Michael Hogardt,Daniel Jonas,Mohammad Rk Mofrad,Andreas Bremges,Alice C McHardy,Susanne Häussler

    Limited therapy options due to antibiotic resistance underscore the need for optimization of current diagnostics. In some bacterial species, antimicrobial resistance can be unambiguously predicted based on their genome sequence. In this study, we sequenced the genomes and transcriptomes of 414 drug-resistant clinical Pseudomonas aeruginosa isolates. By training machine learning classifiers on information

  • 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

    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

  • Acquisition of chromosome instability is a mechanism to evade oncogene addiction.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-06
    Lorena Salgueiro,Christopher Buccitelli,Konstantina Rowald,Kalman Somogyi,Sridhar Kandala,Jan O Korbel,Rocio Sotillo

    Chromosome instability (CIN) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras-driven breast cancer, we demonstrate that aneuploid tumours acquire genetic modifications that facilitate the development of resistance to

  • Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-14
    Helen Parker,Stuart M Ellison,Rebecca J Holley,Claire O'Leary,Aiyin Liao,Jalal Asadi,Emily Glover,Arunabha Ghosh,Simon Jones,Fiona L Wilkinson,David Brough,Emmanuel Pinteaux,Hervé Boutin,Brian W Bigger

    Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)-1β and interleukin-1 receptor antagonist (IL-1Ra) expression were significantly increased

  • Metabolic effects of bezafibrate in mitochondrial disease.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-02-28
    Hannah Steele,Aurora Gomez-Duran,Angela Pyle,Sila Hopton,Jane Newman,Renae J Stefanetti,Sarah J Charman,Jehill D Parikh,Langping He,Carlo Viscomi,Djordje G Jakovljevic,Kieren G Hollingsworth,Alan J Robinson,Robert W Taylor,Leonardo Bottolo,Rita Horvath,Patrick F Chinnery

    Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of

  • Follistatin is a novel therapeutic target and biomarker in FLT3/ITD acute myeloid leukemia
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-05
    Bai‐Liang He; Ning Yang; Cheuk Him Man; Nelson Ka‐Lam Ng; Chae‐Yin Cher; Ho‐Ching Leung; Leo Lai‐Hok Kan; Bowie Yik‐Ling Cheng; Stephen Sze‐Yuen Lam; Michelle Lu‐Lu Wang; Chun‐Xiao Zhang; Hin Kwok; Grace Cheng; Rakesh Sharma; Alvin Chun‐Hang Ma; Chi‐Wai Eric So; Yok‐Lam Kwong; Anskar Yu‐Hung Leung

    Internal tandem duplication of Fms‐like tyrosine kinase 3 (FLT3/ITD) occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor response to conventional treatment and adverse outcome. Here, we reported that human FLT3/ITD expression led to axis duplication and dorsalization in about 50% of zebrafish embryos. The morphologic phenotype was accompanied by ectopic expression of a morphogen

  • Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-04
    Cristian Prieto-Garcia,Oliver Hartmann,Michaela Reissland,Fabian Braun,Thomas Fischer,Susanne Walz,Christina Schülein-Völk,Ursula Eilers,Carsten P Ade,Marco A Calzado,Amir Orian,Hans M Maric,Christian Münch,Mathias Rosenfeldt,Martin Eilers,Markus E Diefenbacher

    The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically

  • Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-03-02
    Lidia Moyano-Galceran,Elina A Pietilä,S Pauliina Turunen,Sara Corvigno,Elisabet Hjerpe,Daria Bulanova,Ulrika Joneborg,Twana Alkasalias,Yuichiro Miki,Masakazu Yashiro,Anastasiya Chernenko,Joonas Jukonen,Madhurendra Singh,Hanna Dahlstrand,Joseph W Carlson,Kaisa Lehti

    Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly

  • FGF21 gene therapy as treatment for obesity and insulin resistance
    EMBO Mol. Med. (IF 10.624) Pub Date : 2018-07-09
    Veronica Jimenez; Claudia Jambrina; Estefania Casana; Victor Sacristan; Sergio Muñoz; Sara Darriba; Jordi Rodó; Cristina Mallol; Miquel Garcia; Xavier León; Sara Marcó; Albert Ribera; Ivet Elias; Alba Casellas; Ignasi Grass; Gemma Elias; Tura Ferré; Sandra Motas; Sylvie Franckhauser; Francisca Mulero; Marc Navarro; Virginia Haurigot; Jesus Ruberte; Fatima Bosch
  • "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

  • "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

  • 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
  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.
    EMBO Mol. Med. (IF 10.624) Pub Date : 2020-01-09
    Sofie Mohlin,Karin Hansson,Katarzyna Radke,Sonia Martinez,Carmen Blanco-Aparicio,Cristian Garcia-Ruiz,Charlotte Welinder,Javanshir Esfandyari,Michael O'Neill,Joaquin Pastor,Kristoffer von Stedingk,Daniel Bexell

  • 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

  • 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.

  • 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

  • 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

  • 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
  • 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
  • 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
  • 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
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全球疫情及响应:BMC Medicine专题征稿