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Patient- and xenograft-derived organoids recapitulate pediatric brain tumor features and patient treatments EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-30 Chiara Lago, Aniello Federico, Gloria Leva, Norman L Mack, Benjamin Schwalm, Claudio Ballabio, Matteo Gianesello, Luana Abballe, Isabella Giovannoni, Sofia Reddel, Sabrina Rossi, Nicolas Leone, Andrea Carai, Angela Mastronuzzi, Alessandra Bisio, Alessia Soldano, Concetta Quintarelli, Franco Locatelli, Marcel Kool, Evelina Miele, Luca Tiberi
Brain tumors are the leading cause of cancer-related death in children. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of pediatric brain cancers are limited and hard to establish. We present a protocol that enables efficient generation, expansion, and biobanking of pediatric brain cancer organoids. Utilizing our protocol, we have established patient-derived
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Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-27 Jelle Verhoeven, Kathryn A Jacobs, Francesca Rizzollo, Francesca Lodi, Yichao Hua, Joanna Poźniak, Adhithya Narayanan Srinivasan, Diede Houbaert, Gautam Shankar, Sanket More, Marco B Schaaf, Nikolina Dubroja Lakic, Maarten Ganne, Jochen Lamote, Johan Van Weyenbergh, Louis Boon, Oliver Bechter, Francesca Bosisio, Yasuo Uchiyama, Mathieu JM Bertrand, Jean Christophe Marine, Diether Lambrechts, Gabriele
Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing
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HMBA ameliorates obesity by MYH9- and ACTG1-dependent regulation of hypothalamic neuropeptides EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-20 Seokjae Park, Sungjoon Oh, Nayoun Kim, Eun-Kyoung Kim
The global epidemic of obesity remains a daunting problem. Here, we report hexamethylene bisacetamide (HMBA) as a potent anti-obesity compound. Peripheral and central administration of HMBA to diet-induced obese mice regulated the expression of hypothalamic neuropeptides critical for energy balance, leading to beneficial metabolic effects such as anorexia and weight loss. We found that HMBA bound to
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Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-22 Ming-Yue Wu, Yun-Jun Ge, Er-Jin Wang, Qi-Wen Liao, Zheng-Yu Ren, Yang Yu, Guoyuan Zhu, Chun-Ping Liu, Meng-Ni Zhang, Huanxing Su, Han-Ming Shen, Ye Chen, Lei Wang, Yi-Tao Wang, Min Li, Zhaoxiang Bian, Jin Chai, Richard D Ye, Jia-Hong Lu
Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL)
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A new chapter of healthy indoor air: antiviral air treatments EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-16 Irina Glas, Shannon C David
Aerosol transmission remains a major challenge for the control of respiratory viruses. To date, prevention strategies include masks, vaccinations, physical distancing, travel restrictions, and lockdowns. Such measures are effective but come with heavy societal burdens and rely on public compliance. Additionally, most are simply not suitable as long-term measures. Other strategies evolve around the
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Propylene glycol inactivates respiratory viruses and prevents airborne transmission EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-16 Christine T Styles, Jie Zhou, Katie E Flight, Jonathan C Brown, Charlotte Lewis, Xinyu Wang, Michael Vanden Oever, Thomas P Peacock, Ziyin Wang, Rosie Millns, John S O'Neill, Alexander Borodavka, Joe Grove, Wendy S Barclay, John S Tregoning, Rachel S Edgar
Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally
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Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-16 Pazhanichamy Kalailingam, Khalilatul-Hanisah Mohd-Kahliab, SoFong Cam Ngan, Ranjith Iyappan, Evelin Melekh, Tian Lu, Gan Wei Zien, Bhargy Sharma, Tiannan Guo, Adam J MacNeil, Rebecca EK MacPherson, Evangelia Litsa Tsiani, Deborah D O'Leary, Kah Leong Lim, I Hsin Su, Yong-Gui Gao, A Mark Richards, Raj N Kalaria, Christopher P Chen, Neil E McCarthy, Siu Kwan Sze
Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in “gain-of-function” conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked
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LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-15 Sarah Proteau, Imène Krossa, Chrystel Husser, Maxime Guéguinou, Federica Sella, Karine Bille, Marie Irondelle, Mélanie Dalmasso, Thibault Barouillet, Yann Cheli, Céline Pisibon, Nicole Arrighi, Sacha Nahon-Estève, Arnaud Martel, Lauris Gastaud, Sandra Lassalle, Olivier Mignen, Patrick Brest, Nathalie M Mazure, Frédéric Bost, Stéphanie Baillif, Solange Landreville, Simon Turcotte, Dan Hasson, Saul Carcamo
Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This
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Acquired immunity against SARS-CoV-2 infection and vaccination EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-15 Laurent Renia, Lisa FP Ng
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 700 million confirmed infections and ~7 million fatalities worldwide since its emergence in December 2019. SARS-CoV-2 is part of a family of positive-sense, enveloped RNA viruses known as coronaviruses. Today, at least seven human coronaviruses have been identified and are known to cause respiratory
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Real-time analysis of the cancer genome and fragmentome from plasma and urine cell-free DNA using nanopore sequencing EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-09 Ymke van der Pol, Normastuti Adhini Tantyo, Nils Evander, Anouk E Hentschel, Birgit MM Wever, Jip Ramaker, Sanne Bootsma, Marieke F Fransen, Kristiaan J Lenos, Louis Vermeulen, Famke L Schneiders, Idris Bahce, Jakko A Nieuwenhuijzen, Renske DM Steenbergen, D Michiel Pegtel, Norbert Moldovan, Florent Mouliere
Cell-free DNA (cfDNA) can be isolated and sequenced from blood and/or urine of cancer patients. Conventional short-read sequencing lacks deployability and speed and can be biased for short cfDNA fragments. Here, we demonstrate that with Oxford Nanopore Technologies (ONT) sequencing we can achieve delivery of genomic and fragmentomic data from liquid biopsies. Copy number aberrations and cfDNA fragmentation
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Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-08 Laura Pascual-Reguant, Queralt Serra-Camprubí, Debayan Datta, Damiano Cianferoni, Savvas Kourtis, Antoni Gañez-Zapater, Chiara Cannatá, Lorena Espinar, Jessica Querol, Laura García-López, Sara Musa-Afaneh, Maria Guirola, Anestis Gkanogiannis, Andrea Miró Canturri, Marta Guzman, Olga Rodríguez, Andrea Herencia-Ropero, Joaquin Arribas, Violeta Serra, Luis Serrano, Tian V Tian, Sandra Peiró, Sara Sdelci
Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle
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Paired box 6 gene delivery preserves beta cells and improves islet transplantation efficacy EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-07 Wing Yan So, Yilie Liao, Wai Nam Liu, Guy A Rutter, Weiping Han
Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-βH1, db/db mouse and human islets displayed
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Combinatorial activation of the WNT-dependent fibrogenic program by distinct complement subunits in dystrophic muscle EMBO Mol. Med. (IF 11.1) Pub Date : 2023-11-06 Francesca Florio, Sara Vencato, Filomena T Papa, Michela Libergoli, Eyemen Kheir, Imen Ghzaiel, Thomas A Rando, Yvan Torrente, Stefano Biressi
Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro-adipogenic progenitors and macrophages,
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Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-30 Stefan Prekovic, Theofilos Chalkiadakis, Merel Roest, Daniel Roden, Catrin Lutz, Karianne Schuurman, Mark Opdam, Liesbeth Hoekman, Nina Abbott, Tanja Tesselaar, Maliha Wajahat, Amy R Dwyer, Isabel Mayayo-Peralta, Gabriela Gomez, Maarten Altelaar, Roderick Beijersbergen, Balázs Győrffy, Leonie Young, Sabine Linn, Jos Jonkers, Wayne Tilley, Theresa Hickey, Damir Vareslija, Alexander Swarbrick, Wilbert
Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico-designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that
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Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-26 Guglielmo Schiano, Jennifer Lake, Marta Mariniello, Céline Schaeffer, Marianne Harvent, Luca Rampoldi, Eric Olinger, Olivier Devuyst
Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain-of-function mutations, end-organ damage and disease progression in ADTKD. Based on two prevalent missense
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Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-20 Andrés Fuentes-Flores, Cristian Geronimo-Olvera, Karina Girardi, David Necuñir-Ibarra, Sandip Kumar Patel, Joanna Bons, Megan C Wright, Daniel Geschwind, Ahmet Hoke, Jose A Gomez-Sanchez, Birgit Schilling, Daniela L Rebolledo, Judith Campisi, Felipe A Court
Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression
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Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-20 Jyothi Padiadpu, Manuel Garcia-Jaramillo, Nolan K Newman, Jacob W Pederson, Richard Rodrigues, Zhipeng Li, Sehajvir Singh, Philip Monnier, Giorgio Trinchieri, Kevin Brown, Amiran K Dzutsev, Natalia Shulzhenko, Donald B Jump, Andrey Morgun
Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi-omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced
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IL-27 produced during acute malaria infection regulates Plasmodium-specific memory CD4+ T cells EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-19 Maria Lourdes Macalinao, Shin-Ichi Inoue, Sanjaadorj Tsogtsaikhan, Hirotaka Matsumoto, Ganchimeg Bayarsaikhan, Jiun-Yu Jian, Kazumi Kimura, Yoshiaki Yasumizu, Tsuyoshi Inoue, Hiroki Yoshida, Julius Hafalla, Daisuke Kimura, Katsuyuki Yui
Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter
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Looking at a baby's heart through the lens of the mother's blood EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-16 Paolo Madeddu
Congenital heart disease (CHD) comprises several cardiovascular abnormalities existing from birth. Cardiac defects range from minor asymptomatic lesions to potentially life-threatening situations. Early fetal echocardiography, the gold standard for the in-utero diagnosis of CHD, is inaccurate at identifying defects in pulmonary veins and atrioventricular valves or lesions that occur later or progress
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Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-16 Ya-Nan Yin, Li Cao, Jie Wang, Yu-Ling Chen, Hai-Ou Yang, Su-Bei Tan, Ke Cai, Zhe-Qi Chen, Jie Xiang, Yuan-Xin Yang, Hao-Ran Geng, Ze-Yu Zhou, An-Na Shen, Xiang-Yu Zhou, Yan Shi, Rui Zhao, Kun Sun, Chen Ding, Jian-Yuan Zhao
Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age—the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case–control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104)
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Downregulation of stromal syntenin sustains AML development EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-11 Raphael Leblanc, Rania Ghossoub, Armelle Goubard, Rémy Castellano, Joanna Fares, Luc Camoin, Stephane Audebert, Marielle Balzano, Berna Bou-Tayeh, Cyril Fauriat, Norbert Vey, Sylvain Garciaz, Jean-Paul Borg, Yves Collette, Michel Aurrand-Lions, Guido David, Pascale Zimmermann
The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency
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The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-09 Daniela Magliulo, Matilde Simoni, Carolina Caserta, Cristina Fracassi, Serena Belluschi, Kety Giannetti, Raffaella Pini, Ettore Zapparoli, Stefano Beretta, Martina Uggè, Eleonora Draghi, Federico Rossari, Nadia Coltella, Cristina Tresoldi, Marco J Morelli, Raffaella Di Micco, Bernhard Gentner, Luca Vago, Rosa Bernardi
One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the
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NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5 EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-09 Selina Gurri, Beat Siegenthaler, Michael Cangkrama, Gaetana Restivo, Marcel Huber, James Saliba, Reinhard Dummer, Volker Blank, Daniel Hohl, Sabine Werner
Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted
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Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-06 Arjan F Theil, Alex Pines, Tuğba Kalayci, José M Heredia-Genestar, Anja Raams, Marion H Rietveld, Sriram Sridharan, Sabine EJ Tanis, Klaas W Mulder, Nesimi Büyükbabani, Birsen Karaman, Zehra O Uyguner, Hülya Kayserili, Jan HJ Hoeijmakers, Hannes Lans, Jeroen AA Demmers, Joris Pothof, Umut Altunoglu, Abdoelwaheb El Ghalbzouri, Wim Vermeulen
The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However,
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Malaria: moving beyond the search for magic bullets. EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-04 Elena Levashina,Dominique Soldati-Favre,Andrew P Waters,Friedrich Frischknecht,Julian C Rayner
Round table discussion on challenges and opportunities in malaria research with Elena Levashina, Dominique Soldati-Favre, Andrew Waters, Friedrich Frischknecht, and Julian Rayner.
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DGAT inhibition at the post-absorptive phase reduces plasma FA by increasing FA oxidation. EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-04 Anand Kumar Sharma,Christian Wolfrum
In this Correspondence, A. Sharma & C. Wolfrum report that DGAT1/2 pharmacological inhibition at post-absorptive phase in mice leads to increased fatty acid oxidation and reduced plasma fatty acid levels, which could open new therapeutic avenues to avoid GI complications observed in clinical trials.
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Single-cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-04 Lise Finotto, Basiel Cole, Wolfgang Giese, Elisabeth Baumann, Annelies Claeys, Maxime Vanmechelen, Brecht Decraene, Marleen Derweduwe, Nikolina Dubroja Lakic, Gautam Shankar, Madhu Nagathihalli Kantharaju, Jan Philipp Albrecht, Ilse Geudens, Fabio Stanchi, Keith L Ligon, Bram Boeckx, Diether Lambrechts, Kyle Harrington, Ludo Van Den Bosch, Steven De Vleeschouwer, Frederik De Smet, Holger Gerhardt
Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions
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Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2 EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-04 Marzia Indrigo, Ilaria Morella, Daniel Orellana, Raffaele d'Isa, Alessandro Papale, Riccardo Parra, Antonia Gurgone, Daniela Lecca, Anna Cavaccini, Cezar M Tigaret, Alfredo Cagnotto, Kimberley Jones, Simon Brooks, Gian Michele Ratto, Nicholas D Allen, Mariah J Lelos, Silvia Middei, Maurizio Giustetto, Anna R Carta, Raffaella Tonini, Mario Salmona, Jeremy Hall, Kerrie Thomas, Riccardo Brambilla, Stefania
Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced
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Intratumoral co-injection of NK cells and NKG2A-neutralizing monoclonal antibodies EMBO Mol. Med. (IF 11.1) Pub Date : 2023-10-02 Ignacio Melero, Maria C Ochoa, Carmen Molina, Sandra Sanchez-Gregorio, Saray Garasa, Carlos Luri-Rey, Sandra Hervas-Stubbs, Noelia Casares, Edurne Elizalde, Gabriel Gomis, Assunta Cirella, Pedro Berraondo, Alvaro Teijeira, Maite Alvarez
NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1b blocking monoclonal antibodies against solid mouse
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Single cell RNA sequencing sheds light on infiltrating T cells in idiopathic inflammatory myopathies EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-28 Momina Yazdani, Lukas Mach, Michela Noseda
Idiopathic inflammatory myopathies (IIM), also referred to as “myositis,” are a group of heterogeneous autoimmune disorders characterised by muscle weakness, atrophy and progressive reduced mobility (Lundberg et al, 2021). IIM represent a significant health burden in adult populations, affecting individuals at a mean age of 50 with an estimated prevalence of 2.9–34 per 100,000 (Dobloug et al, 2015;
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Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-28 Vignesh Ramesh, Paradesi Naidu Gollavilli, Luisa Pinna, Mohammad Aarif Siddiqui, Adriana Martinez Turtos, Francesca Napoli, Yasmin Antonelli, Aldo Leal-Egaña, Jesper Foged Havelund, Simon Toftholm Jakobsen, Elisa Le Boiteux, Marco Volante, Nils Joakim Færgeman, Ole N Jensen, Rasmus Siersbæk, Kumar Somyajit, Paolo Ceppi
The epithelial-to-mesenchymal transition (EMT) plays a central role in the development of cancer metastasis and resistance to chemotherapy. However, its pharmacological treatment remains challenging. Here, we used an EMT-focused integrative functional genomic approach and identified an inverse association between short-chain fatty acids (propionate and butanoate) and EMT in non-small cell lung cancer
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mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-28 Kate E Mastraccio, Celeste Huaman, Si'Ana A Coggins, Caitlyn Clouse, Madeline Rader, Lianying Yan, Pratyusha Mandal, Imran Hussain, Anwar E Ahmed, Trung Ho, Austin Feasley, Bang K Vu, Ina L Smith, Wanda Markotter, Dawn L Weir, Eric D Laing, Christopher C Broder, Brian C Schaefer
Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human
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Transfixed by transgenics: how pathology assumptions are slowing progress in Alzheimer's disease and related dementia research EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-26 Luciano D'Adamio
Model organisms of human diseases are invaluable tools for unraveling pathogenic mechanisms, identifying potential targets for drug development, and evaluating the therapeutic efficacy of candidates in preclinical trials. The utility of model organisms hinges upon their ability to faithfully replicate the underlying pathogenic mechanisms of the human disease. For rodent models of Alzheimer's disease
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PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-19 Anna J Kordala, Jessica Stoodley, Nina Ahlskog, Muhammad Hanifi, Antonio Garcia Guerra, Amarjit Bhomra, Wooi Fang Lim, Lyndsay M Murray, Kevin Talbot, Suzan M Hammond, Matthew JA Wood, Carlo Rinaldi
Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long-lasting benefits for patients. Protein arginine methyltransferases
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Rebalancing polyamine levels to treat Snyder–Robinson syndrome EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-15 Susan K Gilmour
Snyder–Robinson syndrome (SRS) is a rare genetic disorder characterized by intellectual disability and delayed development beginning early in childhood. It was first described in a single family in 1969 as a sex-linked disorder (Snyder & Robinson, 1969) and has since been only identified in less than 100 individuals worldwide. Inherited in an X-linked recessive pattern, SRS has only been identified
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Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-13 Tracy Murray Stewart, Jackson R Foley, Cassandra E Holbert, Maxim Khomutov, Noushin Rastkari, Xianzun Tao, Alex R Khomutov, R Grace Zhai, Robert A Casero
Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting
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Macrophage colony-stimulating factor as a weapon against cytomegalovirus EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-12 Eric Solary
Cytomegalovirus (CMV) infection is one of the severe opportunistic infections faced by severely immunocompromised patients. High viral loads cause tissue-invasive disease and expose to death or various indirect effects. Substantial progress was made in monitoring active infection, and antiviral drugs were developed. However, dose-limiting toxicities and genotypic resistance limit therapeutic efficacy
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Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-11 Guang-Jie Zhu, Yuhang Huang, Linqing Zhang, Keji Yan, Cui Qiu, Yihan He, Qing Liu, Chengwen Zhu, Matías Morín, Miguel Ángel Moreno-Pelayo, Min-Sheng Zhu, Xin Cao, Han Zhou, Xiaoyun Qian, Zhigang Xu, Jie Chen, Xia Gao, Guoqiang Wan
Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates
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Sterile triggers drive joint inflammation in TNF- and IL-1β-dependent mouse arthritis models EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-11 Alexandra Thiran, Ioanna Petta, Gillian Blancke, Marie Thorp, Guillaume Planckaert, Maude Jans, Vanessa Andries, Korneel Barbry, Elisabeth Gilis, Julie Coudenys, Tino Hochepied, Christian Vanhove, Eric Gracey, Emilie Dumas, Teddy Manuelo, Ivan Josipovic, Geert van Loo, Dirk Elewaut, Lars Vereecke
Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed “the gut-joint-axis.” The clinical association between gut and joint inflammation is further supported by the success of common
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Full eradication of pre-clinical human papilloma virus-induced tumors by a lentiviral vaccine EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-07 Laëtitia Douguet, Ingrid Fert, Jodie Lopez, Benjamin Vesin, Fabien Le Chevalier, Fanny Moncoq, Pierre Authié, Trang-My Nguyen, Amandine Noirat, Fabien Névo, Catherine Blanc, Maryline Bourgine, David Hardy, François Anna, Laleh Majlessi, Pierre Charneau
Human papillomavirus (HPV) infections are the cause of all cervical and numerous oropharyngeal and anogenital cancers. The currently available HPV vaccines, which induce neutralizing antibodies, have no therapeutic effect on established tumors. Here, we developed an immuno-oncotherapy against HPV-induced tumors based on a non-integrative lentiviral vector encoding detoxified forms of the Early E6 and
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ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome EMBO Mol. Med. (IF 11.1) Pub Date : 2023-09-07 Lola Rodríguez-Ruiz, Juan M Lozano-Gil, Elena Naranjo-Sánchez, Elena Martínez-Balsalobre, Alicia Martínez-López, Christophe Lachaud, Miguel Blanquer, Toan K Phung, Diana García-Moreno, María L Cayuela, Sylwia D Tyrkalska, Ana B Pérez-Oliva, Victoriano Mulero
Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased
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Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-29 Valda Pauzuolyte, Aara Patel, James R Wawrzynski, Neil J Ingham, Yeh Chwan Leong, Rajvinder Karda, Maria Bitner-Glindzicz, Wolfgang Berger, Simon N Waddington, Karen P Steel, Jane C Sowden
Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg)
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M-CSF directs myeloid and NK cell differentiation to protect from CMV after hematopoietic cell transplantation EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-28 Prashanth K Kandalla, Julien Subburayalu, Clément Cocita, Bérengère de Laval, Elena Tomasello, Johanna Iacono, Jessica Nitsche, Maria M Canali, Wilfried Cathou, Gilles Bessou, Noushin Mossadegh-Keller, Caroline Huber, Guy Mouchiroud, Roland P Bourette, Marie-France Grasset, Martin Bornhäuser, Sandrine Sarrazin, Marc Dalod, Michael H Sieweke
Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection
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Metformin rescues migratory deficits of cells derived from patients with periventricular heterotopia EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-23 Cedric Bressan, Marta Snapyan, Marina Snapyan, Johannes Klaus, Francesco di Matteo, Stephen P Robertson, Barbara Treutlein, Martin Parent, Silvia Cappello, Armen Saghatelyan
Periventricular neuronal heterotopia (PH) is one of the most common forms of cortical malformation in the human cortex. We show that human neuronal progenitor cells (hNPCs) derived from PH patients with a DCHS1 or FAT4 mutation as well as isogenic lines had altered migratory dynamics when grafted in the mouse brain. The affected migration was linked to altered autophagy as observed in vivo with an
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Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-17 Matthew Brown, Alicia Leon, Katarzyna Kedzierska, Charlotte Moore, Hayley L Belnoue-Davis, Susanne Flach, John P Lydon, Francesco J DeMayo, Annabelle Lewis, Tjalling Bosse, Ian Tomlinson, David N Church
High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers.
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Alteration of tumor suppressors changes the endometrial tumor spectrum EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-17 Lindsey D Mayo
The most common gynecological cancer in Europe and the United States is endometrial. Like most cancers, early-stage endometrial cancer has a more favorable prognosis, while high-grade, including endometrioid and nonendometrioid, has the worst prognosis. In endometrioid human tumors, the tumor suppressor genes PTEN and p53 (Trp53) are frequently altered or lost, as identified in datasets from The Cancer
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Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-17 Sudarshan R Iyer, Kevin Nusser, Kristen Jones, Pushkar Shinde, Clare Keddy, Catherine Z Beach, Erin Aguero, Jeremy Force, Ujwal Shinde, Monika A Davare
ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated
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Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-14 Satoru Torii, Satoko Arakawa, Shigeto Sato, Kei-ichi Ishikawa, Daisuke Taniguchi, Hajime Tajima Sakurai, Shinya Honda, Yuuichi Hiraoka, Masaya Ono, Wado Akamatsu, Nobutaka Hattori, Shigeomi Shimizu
Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α-Synuclein aggregation, and we here identified the pathogenesis of the T61I mutation, the most common disease-causing mutation of CHCHD2. In Neuro2a cells, CHCHD2 is in
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Spleen-targeted neoantigen DNA vaccine for personalized immunotherapy of hepatocellular carcinoma EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-08 Ming Wu, Zijin Luo, Zhixiong Cai, Qianqian Mao, Zhenli Li, Hao Li, Cao Zhang, Yuting Zhang, Aoxue Zhong, Liming Wu, Xiaolong Liu
Neoantigens are emerging as attractive targets to develop personalized cancer vaccines, but their immunization efficacy is severely hampered by their restricted accessibility to lymphoid tissues where immune responses are initiated. Leveraging the capability of red blood cells (RBCs) to capture and present pathogens in peripheral blood to the antigen-presenting cells (APCs) in spleen, we developed
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Deconvoluting gene and environment interactions to develop an “epigenetic score meter” of disease EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-04 Alessio Butera, Lena Smirnova, Elisa Ferrando-May, Thomas Hartung, Thomas Brunner, Marcel Leist, Ivano Amelio
Human health is determined both by genetics (G) and environment (E). This is clearly illustrated in groups of individuals who are exposed to the same environmental factor showing differential responses. A quantitative measure of the gene–environment interactions (GxE) effects has not been developed and in some instances, a clear consensus on the concept has not even been reached; for example, whether
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Graft conditioning with fluticasone propionate reduces graft-versus-host disease upon allogeneic hematopoietic cell transplantation in mice EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-04 Erika S Varady, L Angel Ayala, Pauline U Nguyen, Vanessa M Scarfone, Alborz Karimzadeh, Cuiwen Zhou, Xiyu Chen, Scott A Greilach, Craig M Walsh, Matthew A Inlay
Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft-versus-host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate
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Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-03 Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling
Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse
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Viral anti-inflammatory serpin reduces immuno-coagulopathic pathology in SARS-CoV-2 mouse models of infection EMBO Mol. Med. (IF 11.1) Pub Date : 2023-08-03 Liqiang Zhang, Yize (Henry) Li, Karen Kibler, Simona Kraberger, Arvind Varsani, Julie Turk, Nora Elmadbouly, Emily Aliskevich, Laurel Spaccarelli, Bereket Estifanos, Junior Enow, Isabela Rivabem Zanetti, Nicholas Saldevar, Efrem Lim, Jessika Schlievert, Kyle Browder, Anjali Wilson, Fernando Arcos Juan, Aubrey Pinteric, Aman Garg, Henna Monder, Rohan Saju, Savanah Gisriel, Bertram Jacobs, Timothy L
SARS-CoV-2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti-viral drugs and monoclonal antibodies reduce early COVID-19 severity, but treatments for late-stage immuno-thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus-derived Serp-1 protein is
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Single-cell profiling of muscle-infiltrating T cells in idiopathic inflammatory myopathies EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-31 Alexandra Argyriou, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Juan Sebastian Diaz-Boada, Merel Sijbranda, Antonella Notarnicola, Lara Dani, Annika van Vollenhoven, Daniel Ramsköld, Inger Nennesmo, Maryam Dastmalchi, Ingrid E Lundberg, Lina-Marcela Diaz-Gallo, Karine Chemin
Idiopathic inflammatory myopathies (IIM) are rare autoimmune systemic diseases characterized by muscle weakness and the presence of muscle-infiltrating T cells. IIM represent a clinical challenge due to heterogeneity of symptoms and variability of response to immunosuppressive treatment. Here, we performed in-depth single-cell sequencing on muscle-infiltrating T cells and peripheral blood memory T
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Quantitative multiorgan proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-31 Lisa Schweizer, Tina Schaller, Maximilian Zwiebel, Özge Karayel, Johannes Bruno Müller-Reif, Wen-Feng Zeng, Sebastian Dintner, Thierry M Nordmann, Klaus Hirschbühl, Bruno Märkl, Rainer Claus, Matthias Mann
SARS-CoV-2 may directly and indirectly damage lung tissue and other host organs, but there are few system-wide, untargeted studies of these effects on the human body. Here, we developed a parallelized mass spectrometry (MS) proteomics workflow enabling the rapid, quantitative analysis of hundreds of virus-infected FFPE tissues. The first layer of response to SARS-CoV-2 in all tissues was dominated
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Targeting CD301+ macrophages inhibits endometrial fibrosis and improves pregnancy outcome EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-31 Haining Lv, Haixiang Sun, Limin Wang, Simin Yao, Dan Liu, Xiwen Zhang, Zhongrui Pei, Jianjun Zhou, Huiyan Wang, Jianwu Dai, Guijun Yan, Lijun Ding, Zhiyin Wang, Chenrui Cao, Guangfeng Zhao, Yali Hu
Macrophages are a key and heterogeneous cell population involved in endometrial repair and regeneration during the menstrual cycle, but their role in the development of intrauterine adhesion (IUA) and sequential endometrial fibrosis remains unclear. Here, we reported that CD301+ macrophages were significantly increased and showed their most active interaction with profibrotic cells in the endometria
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Musculoskeletal defects associated with myosin heavy chain-embryonic loss of function are mediated by the YAP signaling pathway EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-26 Anushree Bharadwaj, Jaydeep Sharma, Jagriti Singh, Mahima Kumari, Tanushri Dargar, Bhargab Kalita, Sam J Mathew
Mutations in MYH3, the gene encoding the developmental myosin heavy chain-embryonic (MyHC-embryonic) skeletal muscle-specific contractile protein, cause several congenital contracture syndromes. Among these, recessive loss-of-function MYH3 mutations lead to spondylocarpotarsal synostosis (SCTS), characterized by vertebral fusions and scoliosis. We find that Myh3 germline knockout adult mice display
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Platelet-derived lipids promote insulin secretion of pancreatic β cells EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-25 Till Karwen, Katarzyna Kolczynska-Matysiak, Carina Gross, Mona C Löffler, Mike Friedrich, Angel Loza-Valdes, Werner Schmitz, Magdalena Wit, Filip Dziaczkowski, Andrei Belykh, Jonathan Trujillo-Viera, Rabih El-Merahbi, Carsten Deppermann, Sameena Nawaz, Benoit Hastoy, Agnieszka Demczuk, Manuela Erk, Mariusz R Wieckowski, Patrik Rorsman, Katrin G Heinze, David Stegner, Bernhard Nieswandt, Grzegorz Sumara
Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic β cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from β cells stimulate platelet activity and
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ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-25 Christopher W Schultz, Yang Zhang, Rajaa Elmeskini, Astrid Zimmermann, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Suresh Kumar, Nobuyuki Takahashi, Devon Atkinson, Liton Kumar Saha, Chien-Fei Lee, Brian Elenbaas, Parth Desai, Robin Sebastian, Ajit Kumar Sharma, Melissa Abel, Brett Schroeder, Manan Krishnamurthy, Rajesh Kumar, Nitin Roper, Mirit Aladjem, Frank T Zenke, Zoe Weaver Ohler, Yves Pommier
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia
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Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response EMBO Mol. Med. (IF 11.1) Pub Date : 2023-07-24 Le Zhang, Matthias Wirth, Upayan Patra, Jacob Stroh, Konstandina Isaakidis, Leonie Rieger, Susanne Kossatz, Maja Milanovic, Chuanbing Zang, Uta Demel, Jan Keiten-Schmitz, Kristina Wagner, Katja Steiger, Roland Rad, Florian Bassermann, Stefan Müller, Ulrich Keller, Markus Schick
The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5-SMC6 Complex Localization Factor 2 (SLF2) as