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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/29674392/cholesterol-metabolism-promotes-b-cell-positioning-during-immune-pathogenesis-of-chronic-obstructive-pulmonary-disease
#1
Jie Jia, Thomas M Conlon, Rim Sj Sarker, Demet Taşdemir, Natalia F Smirnova, Barkha Srivastava, Stijn E Verleden, Gizem Güneş, Xiao Wu, Cornelia Prehn, Jiaqi Gao, Katharina Heinzelmann, Jutta Lintelmann, Martin Irmler, Stefan Pfeiffer, Michael Schloter, Ralf Zimmermann, Martin Hrabé de Angelis, Johannes Beckers, Jerzy Adamski, Hasan Bayram, Oliver Eickelberg, Ali Önder Yildirim
The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus-associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD In both COPD patients and cigarette smoke (CS)-exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS-induced B-cell migration and iBALT formation...
April 19, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29666146/identification-of-circadian-clock-modulators-from-existing-drugs
#2
T Katherine Tamai, Yusuke Nakane, Wataru Ota, Akane Kobayashi, Masateru Ishiguro, Naoya Kadofusa, Keisuke Ikegami, Kazuhiro Yagita, Yasufumi Shigeyoshi, Masaki Sudo, Taeko Nishiwaki-Ohkawa, Ayato Sato, Takashi Yoshimura
Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone)...
April 17, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661911/patl2-is-a-key-actor-of-oocyte-maturation-whose-invalidation-causes-infertility-in-women-and-mice
#3
Marie Christou-Kent, Zine-Eddine Kherraf, Amir Amiri-Yekta, Emilie Le Blévec, Thomas Karaouzène, Béatrice Conne, Jessica Escoffier, Said Assou, Audrey Guttin, Emeline Lambert, Guillaume Martinez, Magalie Boguenet, Selima Fourati Ben Mustapha, Isabelle Cedrin Durnerin, Lazhar Halouani, Ouafi Marrakchi, Mounir Makni, Habib Latrous, Mahmoud Kharouf, Charles Coutton, Nicolas Thierry-Mieg, Serge Nef, Serge P Bottari, Raoudha Zouari, Jean Paul Issartel, Pierre F Ray, Christophe Arnoult
The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2 , a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively...
April 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661910/myeloid-cell-deficiency-of-p38%C3%AE-p38%C3%AE-protects-against-candidiasis-and-regulates-antifungal-immunity
#4
Dayanira Alsina-Beauchamp, Alejandra Escós, Pilar Fajardo, Diego González-Romero, Ester Díaz-Mora, Ana Risco, Miguel A Martín-Serrano, Carlos Del Fresno, Jorge Dominguez-Andrés, Noelia Aparicio, Rafal Zur, Natalia Shpiro, Gordon D Brown, Carlos Ardavín, Mihai G Netea, Susana Alemany, Juan J Sanz-Ezquerro, Ana Cuenda
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C...
April 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661909/a-novel-combination-treatment-against-melanoma-with-nras-mutation-and-therapy-resistance
#5
Yanlin Yu
No abstract text is available yet for this article.
April 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29650805/co-targeting-bet-and-mek-as-salvage-therapy-for-mapk-and-checkpoint-inhibitor-resistant-melanoma
#6
Ileabett M Echevarría-Vargas, Patricia I Reyes-Uribe, Adam N Guterres, Xiangfan Yin, Andrew V Kossenkov, Qin Liu, Gao Zhang, Clemens Krepler, Chaoran Cheng, Zhi Wei, Rajasekharan Somasundaram, Giorgos Karakousis, Wei Xu, Jennifer Jd Morrissette, Yiling Lu, Gordon B Mills, Ryan J Sullivan, Miao Benchun, Dennie T Frederick, Genevieve Boland, Keith T Flaherty, Ashani T Weeraratna, Meenhard Herlyn, Ravi Amaravadi, Lynn M Schuchter, Christin E Burd, Andrew E Aplin, Xiaowei Xu, Jessie Villanueva
Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS -mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy...
April 12, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29626112/amyloid-blood-biomarker-detects-alzheimer-s-disease
#7
Andreas Nabers, Laura Perna, Julia Lange, Ute Mons, Jonas Schartner, Jörn Güldenhaupt, Kai-Uwe Saum, Shorena Janelidze, Bernd Holleczek, Dan Rujescu, Oskar Hansson, Klaus Gerwert, Hermann Brenner
Alzheimer's disease (AD) is currently incurable, but there is general agreement that a minimally invasive blood biomarker for screening in preclinical stages would be crucial for future therapy. Diagnostic tools for detection of AD are either invasive like cerebrospinal fluid (CSF) biomarkers or expensive such as positron emission tomography (PET) scanning. Here, we determine the secondary structure change of amyloid-β (Aβ) in human blood. This change used as blood amyloid biomarker indicates prodromal AD and correlates with CSF AD biomarkers and amyloid PET imaging in the cross-sectional BioFINDER cohort...
April 6, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29567797/human-alpi-deficiency-causes-inflammatory-bowel-disease-and-highlights-a-key-mechanism-of-gut-homeostasis
#8
Marianna Parlato, Fabienne Charbit-Henrion, Jie Pan, Claudio Romano, Rémi Duclaux-Loras, Marie-Helene Le Du, Neil Warner, Paola Francalanci, Julie Bruneau, Marc Bras, Mohammed Zarhrate, Bernadette Bègue, Nicolas Guegan, Sabine Rakotobe, Nathalie Kapel, Paola De Angelis, Anne M Griffiths, Karoline Fiedler, Eileen Crowley, Frank Ruemmele, Aleixo M Muise, Nadine Cerf-Bensussan
Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function...
March 22, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29540470/sprouty2-loss-induced-il6-drives-castration-resistant-prostate-cancer-through-scavenger-receptor-b1
#9
Rachana Patel, Janis Fleming, Ernest Mui, Carolyn Loveridge, Peter Repiscak, Arnaud Blomme, Victoria Harle, Mark Salji, Imran Ahmad, Katy Teo, Freddie C Hamdy, Ann Hedley, Niels van den Broek, Gillian Mackay, Joanne Edwards, Owen J Sansom, Hing Y Leung
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours...
March 14, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29531022/retraction-haemophilus-influenzae-responds-to-glucocorticoids-used-in-asthma-therapy-by-modulation-of-biofilm-formation-and-antibiotic-resistance
#10
(no author information available yet)
Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P RyanThe above article, published May 20 2015 in EMBO Molecular Medicine , has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork...
March 12, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29531021/tranilast-directly-targets-nlrp3-to-treat-inflammasome-driven-diseases
#11
Yi Huang, Hua Jiang, Yun Chen, Xiaqiong Wang, Yanqing Yang, Jinhui Tao, Xianming Deng, Gaolin Liang, Huafeng Zhang, Wei Jiang, Rongbin Zhou
The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti-allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization...
March 12, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29523594/dual-inhibition-of-akt-mtor-and-ar-signaling-by-targeting-hdac3-in-pten-or-spop-mutated-prostate-cancer
#12
Yuqian Yan, Jian An, Yinhui Yang, Di Wu, Yang Bai, William Cao, Linlin Ma, Junhui Chen, Zhendong Yu, Yundong He, Xin Jin, Yunqian Pan, Tao Ma, Shangqian Wang, Xiaonan Hou, Saravut John Weroha, R Jeffrey Karnes, Jun Zhang, Jennifer J Westendorf, Liguo Wang, Yu Chen, Wanhai Xu, Runzhi Zhu, Dejie Wang, Haojie Huang
AKT-mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine-63-chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1...
March 9, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29507082/trio-sequencing-in-pediatric-cancer-and-clinical-implications
#13
Michaela Kuhlen, Arndt Borkhardt
No abstract text is available yet for this article.
March 5, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29483133/an-allosteric-inhibitor-of-mycobacterium-tuberculosis-argj-implications-to-a-novel-combinatorial-therapy
#14
Archita Mishra, Ashalatha S Mamidi, Raju S Rajmani, Ananya Ray, Rajanya Roy, Avadhesha Surolia
The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb 's arginine biosynthetic enzyme, Ornithine acetyltransferase ( Mt ArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb , and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen...
February 26, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29472246/counteracting-the-effects-of-tnf-receptor-1-has-therapeutic-potential-in-alzheimer-s-disease
#15
Sophie Steeland, Nina Gorlé, Charysse Vandendriessche, Sriram Balusu, Marjana Brkic, Caroline Van Cauwenberghe, Griet Van Imschoot, Elien Van Wonterghem, Riet De Rycke, Anneke Kremer, Saskia Lippens, Edward Stopa, Conrad E Johanson, Claude Libert, Roosmarijn E Vandenbroucke
Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti-TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood-cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology...
February 22, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29463565/an-fgfr3-myc-positive-feedback-loop-provides-new-opportunities-for-targeted-therapies-in-bladder-cancers
#16
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
#17
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
#18
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
#19
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
#20
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
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