journal
MENU ▼
Read by QxMD icon Read
search

EMBO Molecular Medicine

journal
https://www.readbyqxmd.com/read/29463565/an-fgfr3-myc-positive-feedback-loop-provides-new-opportunities-for-targeted-therapies-in-bladder-cancers
#1
Mélanie Mahe, Florent Dufour, Hélène Neyret-Kahn, Aura Moreno-Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez-Quiles, Clementine Krucker, Marion Dorland-Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, Isabelle Bernard-Pierrot
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation...
February 20, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29449326/fatty-acid-synthase-mediates-egfr-palmitoylation-in-egfr-mutated-non-small-cell-lung-cancer
#2
Azhar Ali, Elena Levantini, Jun Ting Teo, Julian Goggi, John G Clohessy, Chan Shuo Wu, Leilei Chen, Henry Yang, Indira Krishnan, Olivier Kocher, Junyan Zhang, Ross A Soo, Kishore Bhakoo, Tan Min Chin, Daniel G Tenen
Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16-C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI-resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA-approved anti-obesity drug...
February 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29444897/role-of-nkp46-natural-killer-cells-in-house-dust-mite-driven-asthma
#3
Eline Haspeslagh, Mary J van Helden, Kim Deswarte, Sofie De Prijck, Justine van Moorleghem, Louis Boon, Hamida Hammad, Eric Vivier, Bart N Lambrecht
House dust mite (HDM)-allergic asthma is driven by T helper 2 (Th2) lymphocytes, but also innate immune cells control key aspects of the disease. The precise function of innate natural killer (NK) cells during the initiation and propagation of asthma has been very confusing, in part because different, not entirely specific, strategies were used to target these cells. We show that HDM inhalation rapidly led to the accumulation of NK cells in the lung-draining lymph nodes and of activated CD69 + NK cells in the bronchoalveolar lumen...
February 14, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29438985/inhibition-of-ddr1-bcr-signalling-by-nilotinib-as-a-new-therapeutic-strategy-for-metastatic-colorectal-cancer
#4
Maya Jeitany, Cédric Leroy, Priscillia Tosti, Marie Lafitte, Jordy Le Guet, Valérie Simon, Debora Bonenfant, Bruno Robert, Fanny Grillet, Caroline Mollevi, Safia El Messaoudi, Amaëlle Otandault, Lucile Canterel-Thouennon, Muriel Busson, Alain R Thierry, Pierre Martineau, Julie Pannequin, Serge Roche, Audrey Sirvent
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion...
February 9, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29437778/identification-of-potential-therapeutic-targets-in-prostate-cancer-through-a-cross-species-approach
#5
Sarah Jurmeister, Antonio Ramos-Montoya, Chiranjeevi Sandi, Nelma Pértega-Gomes, Karan Wadhwa, Alastair D Lamb, Mark J Dunning, Jan Attig, Jason S Carroll, Lee Gd Fryer, Sérgio L Felisbino, David E Neal
Genetically engineered mouse models of cancer can be used to filter genome-wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/Pten loxP/loxP and p53 loxP/lox P Rb loxP/loxP , and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species...
February 5, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29374012/mir-29-contributes-to-normal-endothelial-function-and-can-restore-it-in-cardiometabolic-disorders
#6
Michael E Widlansky, David M Jensen, Jingli Wang, Yong Liu, Aron M Geurts, Alison J Kriegel, Pengyuan Liu, Rong Ying, Guangyuan Zhang, Marc Casati, Chen Chu, Mobin Malik, Amberly Branum, Michael J Tanner, Sudhi Tyagi, Kristie Usa, Mingyu Liang
We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR-29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR-29a-3p or miR-29b-3p mimics restored normal endothelium-dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD Intraluminal delivery of anti-miR-29b-3p in arterioles from non-DM human subjects or rats or targeted mutation of Mir29b-1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats...
January 26, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29363490/dissecting-human-antibody-responses-useful-basic-and-surprising-findings
#7
Antonio Lanzavecchia
Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods have been developed to interrogate the human memory repertoire and isolate monoclonal antibodies. I will discuss how a target-agnostic approach based on high-throughput screening of antibodies produced by cultured B cells and plasma cells has not only provided potent and broadly neutralizing antibodies against a range of pathogens, but has also advanced our understanding of basic aspects of the immune response, from host-pathogen interaction to the role of somatic mutations in affinity maturation and in the diversification of the antibody response...
January 23, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29363489/cell-cell-signaling-in-blood-vessel-development-and-function
#8
Christer Betsholtz
The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell-cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non-vascularized regions and simultaneously acquire organ-specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell-cell signaling mechanisms governing angiogenic sprouting, mural cell recruitment, and vascular remodeling, and we have obtained the first insights into signals that induce and maintain vascular organotypicity...
January 23, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29348142/sema3c-drives-cancer-growth-by-transactivating-multiple-receptor-tyrosine-kinases-via-plexin-b1
#9
James W Peacock, Ario Takeuchi, Norihiro Hayashi, Liangliang Liu, Kevin J Tam, Nader Al Nakouzi, Nastaran Khazamipour, Tabitha Tombe, Takashi Dejima, Kevin Ck Lee, Masaki Shiota, Daksh Thaper, Wilson Cw Lee, Daniel Hf Hui, Hidetoshi Kuruma, Larissa Ivanova, Parvin Yenki, Ivy Zf Jiao, Shahram Khosravi, Alice L-F Mui, Ladan Fazli, Amina Zoubeidi, Mads Daugaard, Martin E Gleave, Christopher J Ong
Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition...
January 18, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29343498/the-gpr120-agonist-tug-891-promotes-metabolic-health-by-stimulating-mitochondrial-respiration-in-brown-fat
#10
Maaike Schilperoort, Andrea D van Dam, Geerte Hoeke, Irina G Shabalina, Anthony Okolo, Aylin C Hanyaloglu, Lea H Dib, Isabel M Mol, Natarin Caengprasath, Yi-Wah Chan, Sami Damak, Anne Reifel Miller, Tamer Coskun, Bharat Shimpukade, Trond Ulven, Sander Kooijman, Patrick Cn Rensen, Mark Christian
Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice...
January 17, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29335339/inhibition-of-drp1-fis1-interaction-slows-progression-of-amyotrophic-lateral-sclerosis
#11
Amit U Joshi, Nay L Saw, Hannes Vogel, Anna D Cunnigham, Mehrdad Shamloo, Daria Mochly-Rosen
Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression...
January 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29335338/crth2-promotes-endoplasmic-reticulum-stress-induced-cardiomyocyte-apoptosis-through-m-calpain
#12
Shengkai Zuo, Deping Kong, Chenyao Wang, Jiao Liu, Yuanyang Wang, Qiangyou Wan, Shuai Yan, Jian Zhang, Juan Tang, Qianqian Zhang, Luheng Lyu, Xin Li, Zhixin Shan, Li Qian, Yujun Shen, Ying Yu
Apoptotic death of cardiac myocytes is associated with ischemic heart disease and chemotherapy-induced cardiomyopathy. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH2 activation specifically facilitated endoplasmic reticulum (ER) stress-induced cardiomyocyte apoptosis via caspase-12-dependent pathway...
January 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29335337/salivary-glands-regenerate-after-radiation-injury-through-sox2-mediated-secretory-cell-replacement
#13
Elaine Emmerson, Alison J May, Lionel Berthoin, Noel Cruz-Pacheco, Sara Nathan, Aaron J Mattingly, Jolie L Chang, William R Ryan, Aaron D Tward, Sarah M Knox
Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co-morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation...
January 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29311134/loss-of-kallikrein-related-peptidase-7-exacerbates-amyloid-pathology-in-alzheimer-s-disease-model-mice
#14
Kiwami Kidana, Takuya Tatebe, Kaori Ito, Norikazu Hara, Akiyoshi Kakita, Takashi Saito, Sho Takatori, Yasuyoshi Ouchi, Takeshi Ikeuchi, Mitsuhiro Makino, Takaomi C Saido, Masahiro Akishita, Takeshi Iwatsubo, Yukiko Hori, Taisuke Tomita
Deposition of amyloid-β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive Aβ pathology in AD model mice...
January 8, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29311133/dual-ire1-rnase-functions-dictate-glioblastoma-development
#15
Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares-Lupon, Kathleen Schmit, Pierre-Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, Eric Chevet
Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes...
January 8, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29295868/the-immunoproteasome-specific-inhibitor-onx-0914-reverses-susceptibility-to-acute-viral-myocarditis
#16
Nadine Althof, Carl Christoph Goetzke, Meike Kespohl, Karolin Voss, Arnd Heuser, Sandra Pinkert, Ziya Kaya, Karin Klingel, Antje Beling
Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3-induced myocarditis, this study describes ONX 0914-an immunoproteasome-specific inhibitor-as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant pathology...
January 2, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29288165/regenerating-human-epithelia-with-cultured-stem-cells-feeder-cells-organoids-and-beyond
#17
REVIEW
Robert E Hynds, Paola Bonfanti, Sam M Janes
More than 40 years ago, Howard Green's laboratory developed a method for long-term expansion of primary human epidermal keratinocytes by co-culture with 3T3 mouse embryonic fibroblasts. This was a breakthrough for in vitro cultivation of cells from human skin and later for other epithelia: it led to the first stem cell therapy using cultured cells and has vastly increased our understanding of epithelial stem cell biology. In recent years, new methods to expand epithelial cells as three-dimensional organoids have provided novel means to investigate the functions of these cells in health and disease...
December 29, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29282224/loss-of-rasgrp1-in-humans-impairs-t-cell-expansion-leading-to-epstein-barr-virus-susceptibility
#18
Sarah Winter, Emmanuel Martin, David Boutboul, Christelle Lenoir, Sabah Boudjemaa, Arnaud Petit, Capucine Picard, Alain Fischer, Guy Leverger, Sylvain Latour
Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1...
December 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29246970/compounds-producing-an-effective-combinatorial-regimen-for-disruption-of-hiv-1-latency
#19
Pargol Hashemi, Kris Barreto, Wendy Bernhard, Adam Lomness, Nicolette Honson, Tom A Pfeifer, P Richard Harrigan, Ivan Sadowski
Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compounds that are capable of reversing HIV latency without affecting the general T-cell activation state. The new compounds exhibit synergy for reactivation of latent provirus with other latency-reversing agents (LRAs), in particular ingenol-3-angelate/PEP005...
December 15, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29246969/allele-specific-silencing-therapy-for-dynamin-2-related-dominant-centronuclear-myopathy
#20
Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, Laura Julien, Sofia Benkhelifa-Ziyyat, Aymen Rabai, Kamel Mamchaoui, Arnaud Ferry, Jocelyn Laporte, Pascale Guicheney, Stéphane Vassilopoulos, Marc Bitoun
Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal-dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM2 gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine DNM2-mRNA harbouring the p.R465W mutation without affecting the wild-type allele...
December 15, 2017: EMBO Molecular Medicine
journal
journal
42177
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"