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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/28100566/loss-of-axin1-drives-acquired-resistance-to-wnt-pathway-blockade-in-colorectal-cancer-cells-carrying-rspo3-fusions
#1
Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Giovanni Crisafulli, Luca Novara, Andrea Acquaviva, Alberto Bardelli, Enzo Medico
In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in-depth characterization. Using a pipeline designed to suppress stroma-derived signal, we find that RSPO3 "outlier" expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411 cells as carriers of, respectively, a canonical PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) fusion...
January 18, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28069640/sequence-variation-in-ppp1r13l-results-in-a-novel-form-of-cardio-cutaneous-syndrome
#2
Tzipora C Falik-Zaccai, Yiftah Barsheshet, Hanna Mandel, Meital Segev, Avraham Lorber, Shachaf Gelberg, Limor Kalfon, Shani Ben Haroush, Adel Shalata, Liat Gelernter-Yaniv, Sarah Chaim, Dorith Raviv Shay, Morad Khayat, Michal Werbner, Inbar Levi, Yishay Shoval, Galit Tal, Stavit Shalev, Eli Reuveni, Emily Avitan-Hersh, Eugene Vlodavsky, Liat Appl-Sarid, Dorit Goldsher, Reuven Bergman, Zvi Segal, Ora Bitterman-Deutsch, Orly Avni
Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice...
January 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28053183/the-transcription-factor-gata4-promotes-myocardial-regeneration-in-neonatal-mice
#3
Mona Malek Mohammadi, Badder Kattih, Andrea Grund, Natali Froese, Mortimer Korf-Klingebiel, Anna Gigina, Ulrike Schrameck, Carsten Rudat, Qiangrong Liang, Andreas Kispert, Kai C Wollert, Johann Bauersachs, Joerg Heineke
Heart failure is often the consequence of insufficient cardiac regeneration. Neonatal mice retain a certain capability of myocardial regeneration until postnatal day (P)7, although the underlying transcriptional mechanisms remain largely unknown. We demonstrate here that cardiac abundance of the transcription factor GATA4 was high at P1, but became strongly reduced at P7 in parallel with loss of regenerative capacity. Reconstitution of cardiac GATA4 levels by adenoviral gene transfer markedly improved cardiac regeneration after cryoinjury at P7...
January 4, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28031255/rock-signaling-promotes-collagen-remodeling-to-facilitate-invasive-pancreatic-ductal-adenocarcinoma-tumor-cell-growth
#4
Nicola Rath, Jennifer P Morton, Linda Julian, Lena Helbig, Shereen Kadir, Ewan J McGhee, Kurt I Anderson, Gabriela Kalna, Margaret Mullin, Andreia V Pinho, Ilse Rooman, Michael S Samuel, Michael F Olson
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras(G12D)/p53(R172H) mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities...
December 28, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28028013/how-to-tackle-antimalarial-resistance
#5
Didier Leroy
No abstract text is available yet for this article.
December 27, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28028012/genetically-engineered-mouse-models-in-oncology-research-and-cancer-medicine
#6
REVIEW
Kelly Kersten, Karin E de Visser, Martine H van Miltenburg, Jos Jonkers
Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start...
December 27, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28011860/reprogramming-derived-gene-cocktail-increases-cardiomyocyte-proliferation-for-heart-regeneration
#7
Yuan-Yuan Cheng, Yu-Ting Yan, David J Lundy, Annie Ha Lo, Yu-Ping Wang, Shu-Chian Ruan, Po-Ju Lin, Patrick Ch Hsieh
Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction...
December 23, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003336/polysialic-acid-blocks-mononuclear-phagocyte-reactivity-inhibits-complement-activation-and-protects-from-vascular-damage-in-the-retina
#8
Marcus Karlstetter, Jens Kopatz, Alexander Aslanidis, Anahita Shahraz, Albert Caramoy, Bettina Linnartz-Gerlach, Yuchen Lin, Anika Lückoff, Sascha Fauser, Katharina Düker, Janine Claude, Yiner Wang, Johannes Ackermann, Tobias Schmidt, Veit Hornung, Christine Skerka, Thomas Langmann, Harald Neumann
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly population. Its pathophysiology is linked to reactive oxygen species (ROS) and activation of the complement system. Sialic acid polymers prevent ROS production of human mononuclear phagocytes via the inhibitory sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor. Here, we show that low-dose intravitreal injection of low molecular weight polysialic acid with average degree of polymerization 20 (polySia avDP20) in humanized transgenic mice expressing SIGLEC11 on mononuclear phagocytes reduced their reactivity and vascular leakage induced by laser coagulation...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003335/the-ras-related-gtpase-rhob-confers-resistance-to-egfr-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-via-an-akt-dependent-mechanism
#9
Olivier Calvayrac, Julien Mazières, Sarah Figarol, Claire Marty-Detraves, Isabelle Raymond-Letron, Emilie Bousquet, Magali Farella, Estelle Clermont-Taranchon, Julie Milia, Isabelle Rouquette, Nicolas Guibert, Amélie Lusque, Jacques Cadranel, Nathalie Mathiot, Ariel Savina, Anne Pradines, Gilles Favre
Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003334/huwe1-is-a-critical-colonic-tumour-suppressor-gene-that-prevents-myc-signalling-dna-damage-accumulation-and-tumour-initiation
#10
Kevin B Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balázs Győrffy, Mamun Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan, Basanta Gurung, Evan Barry, Angeliki Malliri, Fernando Camargo, David J Adams, Antonio Iavarone, Anna Lasorella, Owen J Sansom
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27974353/vegf-blockade-enhances-the-antitumor-effect-of-brafv600e-inhibition
#11
Valentina Comunanza, Davide Corà, Francesca Orso, Francesca Maria Consonni, Emanuele Middonti, Federica Di Nicolantonio, Anton Buzdin, Antonio Sica, Enzo Medico, Dario Sangiolo, Daniela Taverna, Federico Bussolino
The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer-associated fibroblasts...
December 14, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27965270/immune-checkpoint-blockade-can-synergize-with-radiation-therapy-even-in-tumors-resistant-to-checkpoint-monotherapy
#12
Jan Dörrie
No abstract text is available yet for this article.
December 12, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27932443/pd-l1-blockade-enhances-response-of-pancreatic-ductal-adenocarcinoma-to-radiotherapy
#13
Abul Azad, Su Yin Lim, Zenobia D'Costa, Keaton Jones, Angela Diana, Owen J Sansom, Philipp Kruger, Stanley Liu, W Gillies McKenna, Omer Dushek, Ruth J Muschel, Emmanouil Fokas
Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts...
December 8, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27940445/impaired-liver-regeneration-in-aged-mice-can-be-rescued-by-silencing-hippo-core-kinases-mst1-and-mst2
#14
Giulio Loforese, Thomas Malinka, Adrian Keogh, Felix Baier, Cedric Simillion, Matteo Montani, Thanos D Halazonetis, Daniel Candinas, Deborah Stroka
The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two-thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration...
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27932444/activin-promotes-skin-carcinogenesis-by-attraction-and-reprogramming-of-macrophages
#15
Maria Antsiferova, Aleksandra Piwko-Czuchra, Michael Cangkrama, Mateusz Wietecha, Dilara Sahin, Katharina Birkner, Valerie C Amann, Mitchell Levesque, Daniel Hohl, Reinhard Dummer, Sabine Werner
Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes...
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27881461/lysosomal-dysfunction-disrupts-presynaptic-maintenance-and-restoration-of-presynaptic-function-prevents-neurodegeneration-in-lysosomal-storage-diseases
#16
Irene Sambri, Rosa D'Alessio, Yulia Ezhova, Teresa Giuliano, Nicolina Cristina Sorrentino, Vincenzo Cacace, Maria De Risi, Mauro Cataldi, Lucio Annunziato, Elvira De Leonibus, Alessandro Fraldi
Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα)...
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861129/an-evaluation-of-the-therapeutic-potential-of-fecal-microbiota-transplantation-to-treat-infectious-and-metabolic-diseases
#17
Albert K Groen, Max Nieuwdorp
No abstract text is available yet for this article.
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861127/nec-1-alleviates-cognitive-impairment-with-reduction-of-a%C3%AE-and-tau-abnormalities-in-app-ps1-mice
#18
Seung-Hoon Yang, Dongkeun Kenneth Lee, Jisu Shin, Sejin Lee, Seungyeop Baek, Jiyoon Kim, Hoyong Jung, Jung-Mi Hah, YoungSoo Kim
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive symptoms of learning and memory deficits. Such cognitive impairments are attributed to brain atrophy resulting from progressive neuronal and synaptic loss; therefore, alleviation of neural cell death is as an important target of treatment as other classical hallmarks of AD, such as aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau. Here, we found that an anti-necroptotic molecule necrostatin-1 (Nec-1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models...
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27856619/coq-deficiency-causes-disruption-of-mitochondrial-sulfide-oxidation-a-new-pathomechanism-associated-with-this-syndrome
#19
Marta Luna-Sánchez, Agustín Hidalgo-Gutiérrez, Tatjana M Hildebrandt, Julio Chaves-Serrano, Eliana Barriocanal-Casado, Ángela Santos-Fandila, Miguel Romero, Ramy Ka Sayed, Juan Duarte, Holger Prokisch, Markus Schuelke, Felix Distelmaier, Germaine Escames, Darío Acuña-Castroviejo, Luis C López
Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism...
January 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27856618/coenzyme-q-deficiency-causes-impairment-of-the-sulfide-oxidation-pathway
#20
Marcello Ziosi, Ivano Di Meo, Giulio Kleiner, Xing-Huang Gao, Emanuele Barca, Maria J Sanchez-Quintero, Saba Tadesse, Hongfeng Jiang, Changhong Qiao, Richard J Rodenburg, Emmanuel Scalais, Markus Schuelke, Belinda Willard, Maria Hatzoglou, Valeria Tiranti, Catarina M Quinzii
Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2(kd/kd) mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion...
January 2017: EMBO Molecular Medicine
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