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  •   YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-19
    Ruize Gao, Ravi K R Kalathur, Mairene Coto-Llerena, Caner Ercan, David Buechel, Song Shuang, Salvatore Piscuoglio, Michael T Dill, Fernando D Camargo, Gerhard Christofori, Fengyuan Tang

    Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis

  •   Inhibiting parasite proliferation using a rationally designed anti-tubulin agent
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-18
    Natacha Gaillard, Ashwani Sharma, Izra Abbaali, Tianyang Liu, Fiona Shilliday, Alexander D Cook, Valentin Ehrhard, Mamata Bangera, Anthony J Roberts, Carolyn A Moores, Naomi Morrissette, Michel O Steinmetz

    Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical

  •   Flower lose, a cell fitness marker, predicts COVID-19 prognosis
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-18
    Michail Yekelchyk, Esha Madan, Jochen Wilhelm, Kirsty R Short, António M Palma, Linbu Liao, Denise Camacho, Everlyne Nkadori, Michael T Winters, Emily S Rice, Inês Rolim, Raquel Cruz-Duarte, Christopher J Pelham, Masaki Nagane, Kartik Gupta, Sahil Chaudhary, Thomas Braun, Raghavendra Pillappa, Mark S Parker, Thomas Menter, Matthias Matter, Jasmin Dionne Haslbauer, Markus Tolnay, Kornelia D Galior,

    Risk stratification of COVID-19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe-Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe-Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID-19 patients

  •   Brain Cross-Protection against SARS-CoV-2 Variants by a Lentiviral Vaccine in New Transgenic Mice.
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-14
    Min-Wen Ku,Pierre Authié,Maryline Bourgine,François Anna,Amandine Noirat,Fanny Moncoq,Benjamin Vesin,Fabien Nevo,Jodie Lopez,Philippe Souque,Catherine Blanc,Ingrid Fert,Sébastien Chardenoux,Llta Lafosse,Delphine Cussigh,David Hardy,Kirill Nemirov,Françoise Guinet,Francina Langa Vives,Laleh Majlessi,Pierre Charneau

    COVID-19 vaccines already in use or in clinical development may have reduced efficacy against emerging SARS-CoV-2 variants. In addition, although the neurotropism of SARS-CoV-2 is well established, the vaccine strategies currently developed have not taken into account protection of the central nervous system. Here, we generated a transgenic mouse strain expressing the human Angiotensin Converting Enzyme

  •   A microRNA signature that correlates with cognition and is a target against cognitive decline
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-11
    Md Rezaul Islam, Lalit Kaurani, Tea Berulava, Urs Heilbronner, Monika Budde, Tonatiuh Pena Centeno, Vakthang Elerdashvili, Maria-Patapia Zafieriou, Eva Benito, Sinem M Sertel, Maria Goldberg, Fanny Senner, Janos L Kalman, Susanne Burkhardt, Anne Sophie Oepen, Mohammad Sadman Sakib, Cemil Kerimolgu, Oliver Wirths, Heike Bickeböller, Claudia Bartels, Frederic Brosseron, Katharina Buerger, Nicoleta-Carmen

    While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches

  •   CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-11
    Barbara A Perez, Hannah K Shorrock, Monica Banez-Coronel, Tao Zu, Lisa EL Romano, Lauren A Laboissonniere, Tammy Reid, Yoshio Ikeda, Kaalak Reddy, Christopher M Gomez, Thomas Bird, Tetsuo Ashizawa, Lawrence J Schut, Alfredo Brusco, J Andrew Berglund, Lis F Hasholt, Jorgen E Nielsen, SH Subramony, Laura PW Ranum

    Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77)

  •   Deconstructing progressive inflammatory fibrosis in recessive dystrophic epidermolysis bullosa
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-13
    Christen L Ebens

    Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disease, resulting from biallelic mutations in COL7A1, the gene encoding type VII collagen (C7). At mucocutaneous barriers, tissue integrity relies upon linked extracellular matrix (ECM) proteins forming a physiologic suture, connecting basal epidermal keratinocytes to the underlying dermis. C7 secreted from epidermal

  •   Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-27
    Alvaro González-Dominguez, Raúl Montañez, Beatriz Castejón-Vega, Jéssica Nuñez-Vasco, Débora Lendines-Cordero, Chun Wang, Gabriel Mbalaviele, José M Navarro-Pando, Elísabet Alcocer-Gómez, Mario D Cordero

    Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson–Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal

  •   Pro-inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang-(1-7)
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-30
    Rocco Bernasconi, Kerstin Thriene, Elena Romero-Fernández, Christine Gretzmeier, Tobias Kühl, Mareike Maler, Pauline Nauroy, Svenja Kleiser, Anne-Catherine Rühl-Muth, Michael Stumpe, Dimitra Kiritsi, Stefan F Martin, Boris Hinz, Leena Bruckner-Tuderman, Jörn Dengjel, Alexander Nyström

    Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence

  •   Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-19
    Chiara Soldati, Irene Lopez-Fabuel, Luca G Wanderlingh, Marina Garcia-Macia, Jlenia Monfregola, Alessandra Esposito, Gennaro Napolitano, Marta Guevara-Ferrer, Anna Scotto Rosato, Einar K Krogsaeter, Dominik Paquet, Christian M Grimm, Sandro Montefusco, Thomas Braulke, Stephan Storch, Sara E Mole, Maria A De Matteis, Andrea Ballabio, Julio L Sampaio, Tristan McKay, Ludger Johannes, Juan P Bolaños, Diego

    Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing

  •   Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-06
    Or Kakhlon, Hilla Vaknin, Kumudesh Mishra, Jeevitha D’Souza, Monzer Marisat, Uri Sprecher, Shane Wald-Altman, Anna Dukhovny, Yuval Raviv, Benny Da’adoosh, Hamutal Engel, Sandrine Benhamron, Keren Nitzan, Sahar Sweetat, Anna Permyakova, Anat Mordechai, Hasan Orhan Akman, Hanna Rosenmann, Alexander Lossos, Joseph Tam, Berge A. Minassian, Miguel Weil

    This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys)

  •   Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-19
    Florian Uhlitz, Philip Bischoff, Stefan Peidli, Anja Sieber, Alexandra Trinks, Mareen Lüthen, Benedikt Obermayer, Eric Blanc, Yana Ruchiy, Thomas Sell, Soulafa Mamlouk, Roberto Arsie, Tzu-Ting Wei, Kathleen Klotz-Noack, Roland F Schwarz, Birgit Sawitzki, Carsten Kamphues, Dieter Beule, Markus Landthaler, Christine Sers, David Horst, Nils Blüthgen, Markus Morkel

    In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non-cancerous tissues of twelve colorectal cancer patients

  •   Myeloid cell-based delivery of IFN-γ reprograms the leukemia microenvironment and induces anti-tumoral immune responses
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-30
    Adele Mucci, Gabriele Antonarelli, Carolina Caserta, Francesco Maria Vittoria, Giacomo Desantis, Riccardo Pagani, Beatrice Greco, Monica Casucci, Giulia Escobar, Laura Passerini, Nico Lachmann, Francesca Sanvito, Matteo Barcella, Ivan Merelli, Luigi Naldini, Bernhard Gentner

    The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that interferon-γ

  •   Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-02
    Adrian T Press, Petra Babic, Bianca Hoffmann, Tina Müller, Wanling Foo, Walter Hauswald, Jovana Benecke, Martina Beretta, Zoltán Cseresnyés, Stephanie Hoeppener, Ivo Nischang, Sina M Coldewey, Markus H Gräler, Reinhard Bauer, Falk Gonnert, Nikolaus Gaßler, Reinhard Wetzker, Marc Thilo Figge, Ulrich S Schubert, Michael Bauer

    Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites

  •   Discovery of a transdermally deliverable pentapeptide for activating AdipoR1 to promote hair growth
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-06
    Jungyoon Ohn, Kyung Wook Been, Jin Yong Kim, Eun Ju Kim, Taeyong Park, Hye-Jin Yoon, Jeong Seok Ji, Miki Okada-Iwabu, Masato Iwabu, Toshimasa Yamauchi, Yeon Kyung Kim, Chaok Seok, Ohsang Kwon, Kyu Han Kim, Hyung Ho Lee, Jin Ho Chung

    Alopecia induced by aging or side effects of medications affects millions of people worldwide and impairs the quality of life; however, there is a limit to the current medications. Here, we identify a small transdermally deliverable 5-mer peptide (GLYYF; P5) that activates adiponectin receptor 1 (AdipoR1) and promotes hair growth. P5 sufficiently reproduces the biological effect of adiponectin protein

  •   Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-20
    Tien-Fen Kuo, Shuo-Wen Hsu, Shou-Hsien Huang, Cicero Lee-Tian Chang, Ching-Shan Feng, Ming-Guang Huang, Tzung-Yan Chen, Meng-Ting Yang, Si-Tse Jiang, Tuan-Nan Wen, Chun-Yen Yang, Chung-Yu Huang, Shu-Huei Kao, Keng-Chang Tsai, Greta Yang, Wen-Chin Yang

    Loss of β-cell number and function is a hallmark of diabetes. β-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in β-cells. This expression was up-regulated in β-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose

  •   rs41291957 controls miR-143 and miR-145 expression and impacts coronary artery disease risk
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-22
    Ignacio Fernando Hall, Montserrat Climent, Chiara Viviani Anselmi, Laura Papa, Vinicius Tragante, Luca Lambroia, Floriana Maria Farina, Marcus E Kleber, Winfried März, Carlo Biguori, Gianluigi Condorelli, Leonardo Elia

    The role of single nucleotide polymorphisms (SNPs) in the etiopathogenesis of cardiovascular diseases is well known. The effect of SNPs on disease predisposition has been established not only for protein coding genes but also for genes encoding microRNAs (miRNAs). The miR-143/145 cluster is smooth muscle cell-specific and implicated in the pathogenesis of atherosclerosis. Whether SNPs within the genomic

  •   Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-10-04
    Antonietta Tarallo, Carla Damiano, Sandra Strollo, Nadia Minopoli, Alessia Indrieri, Elena Polishchuk, Francesca Zappa, Edoardo Nusco, Simona Fecarotta, Caterina Porto, Marcella Coletta, Roberta Iacono, Marco Moracci, Roman Polishchuk, Diego Luis Medina, Paola Imbimbo, Daria Maria Monti, Maria Antonietta De Matteis, Giancarlo Parenti

    Pompe disease is a metabolic myopathy due to acid alpha-glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha-glucosidase (rhGAA), currently the standard of care

  •   A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-29
    Qiong Pan, Gang Luo, Jiaquan Qu, Sheng Chen, Xiaoxun Zhang, Nan Zhao, Jingjing Ding, Hong Yang, Mingqiao Li, Ling Li, Ying Cheng, Xuan Li, Qiaoling Xie, Qiao Li, Xueqian Zhou, Huiling Zou, Shijun Fan, Lingyun Zou, Wei Liu, Guohong Deng, Shi-Ying Cai, James L Boyer, Jin Chai

    Semaphorin 7A (SEMA7A) is a membrane-bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA)

  •   Dependence receptors: new targets for cancer therapy
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-20
    Morgan Brisset, Mélodie Grandin, Agnès Bernet, Patrick Mehlen, Frédéric Hollande

    Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects

  •   SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-20
    Indranil Malik, Yi-Ju Tseng, Shannon E Wright, Kristina Zheng, Prithika Ramaiyer, Katelyn M Green, Peter K Todd

    Transcribed CGG repeat expansions cause neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat-associated RBPs by mass spectrometry

  •   Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-23
    Paul Wuh-Liang Hwu, Karl Kiening, Irina Anselm, David R Compton, Takeshi Nakajima, Thomas Opladen, Phillip L Pearl, Agathe Roubertie, Thomas Roujeau, Shin-ichi Muramatsu

    This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l-amino acid decarboxylase (AADC) deficiency and Parkinson’s disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this

  •   Oxidized low-density lipoproteins as a novel risk factor and therapeutic target for ACM
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-19
    Hoyee Tsui, Su Ji Han, Eva van Rooij

    Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease involving arrhythmia in young adults accompanied by structural changes at later stages. In this issue of EMBO Molecular Medicine, Sommariva et al (2021) identified a positive correlation between circulating levels of oxidized low-density lipoproteins (oxLDL) and ACM disease penetrance, which contributes to fibro-fatty cardiac remodeling

  •   Functional genomics approaches to improve pre-clinical drug screening and biomarker discovery
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-13
    Long V Nguyen, Carlos Caldas

    Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre-clinical

  •   The state of the art of bispecific antibodies for treating human malignancies
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-24
    Shuhang Wang, Kun Chen, Qi Lei, Peiwen Ma, Andy Qingan Yuan, Yong Zhao, Youwei Jiang, Hong Fang, Shujun Xing, Yuan Fang, Ning Jiang, Huilei Miao, Minghui Zhang, Shujun Sun, Zicheng Yu, Wei Tao, Qi Zhu, Yingjie Nie, Ning Li

    Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles

  •   Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-09
    Ameneh Khatami, Ruby C Y Lin, Aleksandra Petrovic-Fabijan, Sivan Alkalay-Oren, Sulaiman Almuzam, Philip N Britton, Michael J Brownstein, Quang Dao, Joe Fackler, Ronen Hazan, Bri’Anna Horne, Ran Nir-Paz, Jonathan R Iredell

    Adjunctive phage therapy was used in an attempt to avoid catastrophic outcomes from extensive chronic Pseudomonas aeruginosa osteoarticular infection in a 7-year-old child. Monitoring of phage and bacterial kinetics allowed real-time phage dose adjustment, and along with markers of the human host response, indicated a significant therapeutic effect within two weeks of starting adjunctive phage therapy

  •   Loss of PIKfyve drives the spongiform degeneration in prion diseases
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-22
    Asvin K K Lakkaraju, Karl Frontzek, Emina Lemes, Uli Herrmann, Marco Losa, Rajlakshmi Marpakwar, Adriano Aguzzi

    Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases

  •   LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-26
    Marc Emmenegger, Elena De Cecco, Marian Hruska-Plochan, Timo Eninger, Matthias M Schneider, Melanie Barth, Elena Tantardini, Pierre de Rossi, Mehtap Bacioglu, Rebekah G Langston, Alice Kaganovich, Nora Bengoa-Vergniory, Andrès Gonzalez-Guerra, Merve Avar, Daniel Heinzer, Regina Reimann, Lisa M Häsler, Therese W Herling, Naunehal S Matharu, Natalie Landeck, Kelvin Luk, Ronald Melki, Philipp J Kahle

    While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3

  •   Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-08
    Zhang Yang, Shun-Qing Liang, Maria Saliakoura, Haitang Yang, Eric Vassella, Georgia Konstantinidou, Mario Tschan, Balazs Hegedüs, Liang Zhao, Yanyun Gao, Duo Xu, Haibin Deng, Thomas M Marti, Gregor J Kocher, Wenxiang Wang, Ralph A Schmid, Ren-Wang Peng

    KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1

  •   Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-11
    Carmen Herranz, Francesca Mateo, Alexandra Baiges, Gorka Ruiz de Garibay, Alexandra Junza, Simon R Johnson, Suzanne Miller, Nadia García, Jordi Capellades, Antonio Gómez, August Vidal, Luis Palomero, Roderic Espín, Ana I Extremera, Eline Blommaert, Eva Revilla-López, Berta Saez, Susana Gómez-Ollés, Julio Ancochea, Claudia Valenzuela, Tamara Alonso, Piedad Ussetti, Rosalía Laporta, Antoni Xaubet, José

    Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical

  •   Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-02
    Elena Sommariva, Ilaria Stadiotti, Michela Casella, Valentina Catto, Antonio Dello Russo, Corrado Carbucicchio, Lorenzo Arnaboldi, Simona De Metrio, Giuseppina Milano, Alessandro Scopece, Manuel Casaburo, Daniele Andreini, Saima Mushtaq, Edoardo Conte, Mattia Chiesa, Walter Birchmeier, Elisa Cogliati, Adolfo Paolin, Eva König, Viviana Meraviglia, Monica De Musso, Chiara Volani, Giada Cattelan, Werner

    Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low-density lipoprotein (oxLDL)-dependent

  •   Functional multispectral optoacoustic tomography imaging of hepatic steatosis development in mice
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-19
    Shan Huang, Andreas Blutke, Annette Feuchtinger, Uwe Klemm, Robby Zachariah Tom, Susanna M Hofmann, Andre C Stiel, Vasilis Ntziachristos

    The increasing worldwide prevalence of obesity, fatty liver diseases and the emerging understanding of the important roles lipids play in various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. We investigated the potential of multispectral optoacoustic tomography

  •   Rational design of West Nile virus vaccine through large replacement of 3′ UTR with internal poly(A)
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-05
    Ya-Nan Zhang, Na Li, Qiu-Yan Zhang, Jing Liu, Shun-Li Zhan, Lei Gao, Xiang-Yue Zeng, Fang Yu, Hong-Qing Zhang, Xiao-Dan Li, Cheng-Lin Deng, Pei-Yong Shi, Zhi-Ming Yuan, Shao-Peng Yuan, Han-Qing Ye, Bo Zhang

    The genus Flavivirus comprises numerous emerging and re-emerging arboviruses causing human illness. Vaccines are the best approach to prevent flavivirus diseases. But pathogen diversities are always one of the major hindrances for timely development of new vaccines when confronting unpredicted flavivirus outbreaks. We used West Nile virus (WNV) as a model to develop a new live-attenuated vaccine (LAV)

  •   A spoonful of L-fucose—an efficient therapy for GFUS-CDG, a new glycosylation disorder
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-09-01
    René G Feichtinger, Andreas Hüllen, Andreas Koller, Dieter Kotzot, Valerian Grote, Erdmann Rapp, Peter Hofbauer, Karin Brugger, Christian Thiel, Johannes A Mayr, Saskia B Wortmann

    Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co- and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth

  •   Aducanumab: a new phase in therapeutic development for Alzheimer’s disease?
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-08-02
    Giovanna Lalli, Jonathan M Schott, John Hardy, Bart De Strooper

    On 7 June, the FDA approved aducanumab, the first new drug for Alzheimer’s disease in almost 20 years—and notably, the first drug with a putative disease-modifying mechanism for the treatment of this devastating disorder, namely the removal of β-amyloid (or Aβ) plaques from the brain.

  •   Immunological barriers to immunotherapy in primary and metastatic breast cancer
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-15
    Mara De Martino, Claire Vanpouille-Box, Lorenzo Galluzzi

    Patients with breast cancer obtain limited clinical benefits from immune checkpoint inhibitors (ICIs), pointing to the existence of multiple immunological alterations that cannot be simultaneously normalized with immunotherapy. Accumulating preclinical evidence suggests that radiation therapy (RT) can be harnessed to sensitize primary and metastatic mouse mammary carcinomas to ICIs. However, various

  •   Fuse your mitochondria, lose appetite: an anorexic, anti-obesity sphingolipid
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-19
    Carolin Muley, Alexander Bartelt

    Aberrant production of ceramides, the precursors of complex sphingolipids, is a hallmark of obesity and strongly linked to metabolic dysfunction (Meikle and Summers 2017). Ceramides are formed by recycling or de novo synthesis from sphingosine and a fatty acid side chain moiety. The side chain length determines lipotoxicity of ceramides, as those composed of C16:0 or C18:0 side chains are toxic whereas

  •   Individual COVID-19 disease trajectories revealed by plasma proteomics
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-14
    Danish Memon, Inigo Barrio-Hernandez, Pedro Beltrao

    Since the start of 2020, the world has been upended by the pandemic caused by the severe acute respiratory coronavirus type 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). It has not only led to a tragic loss of life and terrible economic costs but has also been met with an unprecedented response of the scientific and medical communities. In an effort to better understand

  •   Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-21
    Christopher R S Banerji, Peter S Zammit

    Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal-most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription

  •   Intrathecal activation of CD8+ memory T cells in IgG4-related disease of the brain parenchyma
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-13
    Mirco Friedrich, Niklas Kehl, Niko Engelke, Josephine Kraus, Katharina Lindner, Philipp Münch, Iris Mildenberger, Christoph Groden, Achim Gass, Nima Etminan, Marc Fatar, Andreas von Deimling, David Reuss, Michael Platten, Lukas Bunse

    IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4-RD remain elusive. There are very few cases of IgG4-RD with isolated central nervous system manifestation. By leveraging single-cell sequencing of the cerebrospinal

  •   Gut microbiota-CRAMP axis shapes intestinal barrier function and immune responses in dietary gluten-induced enteropathy
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-14
    Zhengnan Ren, Li-Long Pan, Yiwen Huang, Hongbing Chen, Yu Liu, He Liu, Xing Tu, Yanyan Liu, Binbin Li, Xiaoliang Dong, Xiaohua Pan, Hanfei Li, Yu V Fu, Birgitta Agerberth, Julien Diana, Jia Sun

    In the gut, cathelicidin-related antimicrobial peptide (CRAMP) has been largely described for its anti-infective activities. With an increasing recognition of its immune regulatory effects in extra-intestinal diseases, the role of CRAMP in gluten-induced small intestinal enteropathy celiac disease remains unknown. This study aimed to investigate the unexplored role of CRAMP in celiac disease. By applying

  •   Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-16
    Sebastian J Theobald, Alexander Simonis, Theodoros Georgomanolis, Christoph Kreer, Matthias Zehner, Hannah S Eisfeld, Marie-Christine Albert, Jason Chhen, Susanne Motameny, Florian Erger, Julia Fischer, Jakob J Malin, Jessica Gräb, Sandra Winter, Andromachi Pouikli, Friederike David, Boris Böll, Philipp Koehler, Kanika Vanshylla, Henning Gruell, Isabelle Suárez, Michael Hallek, Gerd Fätkenheuer, Norma

    Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust

  •   High-resolution serum proteome trajectories in COVID-19 reveal patient-specific seroconversion
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-07
    Philipp E Geyer, Florian M Arend, Sophia Doll, Marie-Luise Louiset, Sebastian Virreira Winter, Johannes B Müller-Reif, Furkan M Torun, Michael Weigand, Peter Eichhorn, Mathias Bruegel, Maximilian T Strauss, Lesca M Holdt, Matthias Mann, Daniel Teupser

    A deeper understanding of COVID-19 on human molecular pathophysiology is urgently needed as a foundation for the discovery of new biomarkers and therapeutic targets. Here we applied mass spectrometry (MS)-based proteomics to measure serum proteomes of COVID-19 patients and symptomatic, but PCR-negative controls, in a time-resolved manner. In 262 controls and 458 longitudinal samples of 31 patients

  •   Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-12
    Guilherme Dias de Melo, Françoise Lazarini, Florence Larrous, Lena Feige, Etienne Kornobis, Sylvain Levallois, Agnès Marchio, Lauriane Kergoat, David Hardy, Thomas Cokelaer, Pascal Pineau, Marc Lecuit, Pierre-Marie Lledo, Jean-Pierre Changeux, Hervé Bourhy

    The devastating pandemic due to SARS-CoV-2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID-19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard

  •   Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-20
    Iart Luca Shytaj, Francesco Andrea Procopio, Mohammad Tarek, Irene Carlon-Andres, Hsin-Yao Tang, Aaron R Goldman, MohamedHusen Munshi, Virender Kumar Pal, Mattia Forcato, Sheetal Sreeram, Konstantin Leskov, Fengchun Ye, Bojana Lucic, Nicolly Cruz, Lishomwa C Ndhlovu, Silvio Bicciato, Sergi Padilla-Parra, Ricardo Sobhie Diaz, Amit Singh, Marina Lusic, Jonathan Karn, David Alvarez-Carbonell, Andrea Savarino

    HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show

  •   Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-21
    Simon Hirschberger, Gabriele Strauß, David Effinger, Xaver Marstaller, Alicia Ferstl, Martin B Müller, Tingting Wu, Max Hübner, Tim Rahmel, Hannah Mascolo, Nicole Exner, Julia Heß, Friedrich W Kreth, Kristian Unger, Simone Kreth

    Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly

  •   Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-07
    Vaishali Jayashankar, Elizabeth Selwan, Sarah E Hancock, Amandine Verlande, Maggie O Goodson, Kazumi H Eckenstein, Giedre Milinkeviciute, Brianna M Hoover, Bin Chen, Angela G Fleischman, Karina S Cramer, Stephen Hanessian, Selma Masri, Nigel Turner, Aimee L Edinger

    Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events

  •   Targeting prominin2 transcription to overcome ferroptosis resistance in cancer
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-05
    Caitlin W Brown, Peter Chhoy, Dimpi Mukhopadhyay, Emmet R Karner, Arthur M Mercurio

    Understanding how cancer cells resist ferroptosis is a significant problem that impacts ongoing efforts to stimulate ferroptosis as a therapeutic strategy. We reported that prominin2 is induced by ferroptotic stimuli and functions to resist ferroptotic death. Although this finding has significant implications for therapy, specific prominin2 inhibitors are not available. We rationalized that the mechanism

  •   Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-22
    Florent Mouliere, Christopher G Smith, Katrin Heider, Jing Su, Ymke van der Pol, Mareike Thompson, James Morris, Jonathan C M Wan, Dineika Chandrananda, James Hadfield, Marta Grzelak, Irena Hudecova, Dominique-Laurent Couturier, Wendy Cooper, Hui Zhao, Davina Gale, Matthew Eldridge, Colin Watts, Kevin Brindle, Nitzan Rosenfeld, Richard Mair

    Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. We determined the glioma-derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually

  •   Tau PET correlates with different Alzheimer’s disease-related features compared to CSF and plasma p-tau biomarkers
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-13
    Rik Ossenkoppele, Juhan Reimand, Ruben Smith, Antoine Leuzy, Olof Strandberg, Sebastian Palmqvist, Erik Stomrud, Henrik Zetterberg, , Philip Scheltens, Jeffrey L Dage, Femke Bouwman, Kaj Blennow, Niklas Mattsson-Carlgren, Shorena Janelidze, Oskar Hansson

    PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181

  •   Modeling genetic epileptic encephalopathies using brain organoids
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-07-15
    Daniel J Steinberg, Srinivasarao Repudi, Afifa Saleem, Irina Kustanovich, Sergey Viukov, Baraa Abudiab, Ehud Banne, Muhammad Mahajnah, Jacob H Hanna, Shani Stern, Peter L Carlen, Rami I Aqeilan

    Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain-containing oxidoreductase (WWOX) are associated with a relatively mild autosomal recessive spinocerebellar ataxia-12 (SCAR12)

  •   PI3Kα targeting, nipping pancreatic cancer evolution in the bud
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-05-31
    Glancis Luzeena Raja Arul, Martin E Fernandez-Zapico

    Thibault et al (2021) elucidate key signalling events mediating metastatic evolution in pancreatic ductal adenocarcinoma (PDAC) by demonstrating a role of PI3Kα in the regulation of macro-metastatic disease and a corresponding pro-tumoural immune response supporting disease progression.

  •   NAD+ homeostasis in human health and disease
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-05-27
    Rubén Zapata-Pérez, Ronald J A Wanders, Clara D M van Karnebeek, Riekelt H Houtkooper

    Depletion of nicotinamide adenine dinucleotide (NAD+), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD+ homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD+ homeostasis, such as increased NAD+ consumption

  •   Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-14
    Kabir A Khan, Florence TH Wu, William Cruz-Munoz, Robert S Kerbel

    Anti-angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early-stage (resectable) cancers. Newer investigational anti-angiogenic drugs have been designed to inhibit the Angiopoietin (Ang)-Tie pathway

  •   Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-14
    Alberto Catanese, Sandeep Rajkumar, Daniel Sommer, Dennis Freisem, Alexander Wirth, Amr Aly, David Massa-López, Andrea Olivieri, Federica Torelli, Valentin Ioannidis, Joanna Lipecka, Ida Chiara Guerrera, Daniel Zytnicki, Albert Ludolph, Edor Kabashi, Medhanie A Mulaw, Francesco Roselli, Tobias M Böckers

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics

  •   Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-07
    Jason Sadek, Derek T Hall, Bianca Colalillo, Amr Omer, Anne-Marie K Tremblay, Virginie Sanguin-Gendreau, William Muller, Sergio Di Marco, Marco Emilio Bianchi, Imed-Eddine Gallouzi

    Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against

  •   Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-05-25
    Benoit Thibault, Fernanda Ramos-Delgado, Elvire Pons-Tostivint, Nicole Therville, Celia Cintas, Silvia Arcucci, Stephanie Cassant-Sourdy, Gabriela Reyes-Castellanos, Marie Tosolini, Amelie V Villard, Coralie Cayron, Romain Baer, Justine Bertrand-Michel, Delphine Pagan, Dina Ferreira Da Mota, Hongkai Yan, Chiara Falcomatà, Fabrice Muscari, Barbara Bournet, Jean-Pierre Delord, Ezra Aksoy, Alice Carrier

    Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised

  •   Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-05-27
    Marie Shamseddin, Fabio De Martino, Céline Constantin, Valentina Scabia, Anne-Sophie Lancelot, Csaba Laszlo, Ayyakkannu Ayyannan, Laura Battista, Wassim Raffoul, Marie-Christine Gailloud-Matthieu, Philipp Bucher, Maryse Fiche, Giovanna Ambrosini, George Sflomos, Cathrin Brisken

    Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk

  •   HSD17B7 gene in self-renewal and oncogenicity of keratinocytes from Black versus White populations
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-29
    Xiaoying Xu, Beatrice Tassone, Paola Ostano, Atul Katarkar, Tatiana Proust, Jean-Marc Joseph, Chiara Riganti, Giovanna Chiorino, Zoltan Kutalik, Karine Lefort, Gian Paolo Dotto

    Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte-derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self-renewal potential, which are inversely related to mitochondrial electron transfer chain

  •   miR-9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC
    EMBO Mol. Med. (IF 12.137) Pub Date : 2021-06-01
    Francesca Citron, Ilenia Segatto, Lorena Musco, Ilenia Pellarin, Gian Luca Rampioni Vinciguerra, Giovanni Franchin, Giuseppe Fanetti, Francesco Miccichè, Vittorio Giacomarra, Valentina Lupato, Andrea Favero, Isabella Concina, Sanjana Srinivasan, Michele Avanzo, Isabella Castiglioni, Luigi Barzan, Sandro Sulfaro, Gianluigi Petrone, Andrea Viale, Giulio F Draetta, Andrea Vecchione, Barbara Belletti,

    Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains

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