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Yuan Huang, Yaoshi Wu, Jiahong Dong, Dongdong Han, Shiwei Yang, Lin Jiang
Gallbladder carcinoma (GBC) is the most common biliary tract malignancy with high mortality. The median survival time is 6 months, and the 5-year survival rate less than 5% for GBC patients. Thus, it is imperative to investigate the molecular mechanisms underlying the pathogenesis of GBC. miR-133a may exert anti-tumor effects on a variety of cancers. However, the role of miR-133a in the pathogenesis of GBC remains unclear. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) showed the miR-133a-3p expression markedly decreased in GBC as compared to adjacent normal tissues...
2016: American Journal of Cancer Research
Rachel V Guest, Luke Boulter, Benjamin J Dwyer, Timothy J Kendall, Tak-Yung Man, Sarah E Minnis-Lyons, Wei-Yu Lu, Andrew J Robson, Sofia Ferreira Gonzalez, Alexander Raven, Davina Wojtacha, Jennifer P Morton, Mina Komuta, Tania Roskams, Stephen J Wigmore, Owen J Sansom, Stuart J Forbes
The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
Humberto Contreras-Cornejo, Germán Saucedo-Correa, Javier Oviedo-Boyso, Juan José Valdez-Alarcón, Víctor Manuel Baizabal-Aguirre, Marcos Cajero-Juárez, Alejandro Bravo-Patiño
The Notch signaling pathway is a reiteratively used cell to cell communication pathway that triggers pleiotropic effects. The correct regulation of the pathway permits the efficient regulation of genes involved in cell fate decision throughout development. This activity relies notably on the CSL proteins, (an acronym for CBF-1/RBPJ-κ in Homo sapiens/Mus musculus respectively, Suppressor of Hairless in Drosophila melanogaster, Lag-1 in Caenorhabditis elegans) which is the unique transcription factor and DNA binding protein involved in this pathway...
2016: Cell Division
Tiago C Luis, Sidinh Luc, Takuo Mizukami, Hanane Boukarabila, Supat Thongjuea, Petter S Woll, Emanuele Azzoni, Alice Giustacchini, Michael Lutteropp, Tiphaine Bouriez-Jones, Harsh Vaidya, Adam J Mead, Deborah Atkinson, Charlotta Böiers, Joana Carrelha, Iain C Macaulay, Roger Patient, Frederic Geissmann, Claus Nerlov, Rickard Sandberg, Marella F T R de Bruijn, C Clare Blackburn, Isabelle Godin, Sten Eirik W Jacobsen
The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors...
December 2016: Nature Immunology
Shin Yup Lee, Hyo-Gyoung Kang, Jin Eun Choi, Deuk Kju Jung, Won Kee Lee, Hyun Chul Lee, So Yeon Lee, Seung Soo Yoo, Jaehee Lee, Yangki Seok, Eung Bae Lee, Seung Ick Cha, Sukki Cho, Chang Ho Kim, Myung Hoon Lee, Jae Yong Park
We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication...
October 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Meritxell Nus, Beatriz Martínez-Poveda, Donal MacGrogan, Rafael Chevre, Gaetano D'Amato, Mauro Sbroggio, Cristina Rodríguez, José Martínez-González, Vicente Andrés, Andrés Hidalgo, José Luis de la Pompa
AIMS: To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis. METHODS AND RESULTS: We have generated a mouse model of endothelial-specific (Cdh5-driven) depletion of the Notch effector RBPJ (ApoE(-/-);RBPJ(flox/flox);Cdh5-Cre(ERT)). Endothelial-specific deletion of RBPJ or systemic deletion of Notch1 in athero-susceptible ApoE(-/-) mice fed a high cholesterol diet for 6 weeks resulted in reduced atherosclerosis in the aortic arch and sinus...
August 5, 2016: Cardiovascular Research
Akio Yamasaki, Hideya Onishi, Akira Imaizumi, Makoto Kawamoto, Akiko Fujimura, Yasuhiro Oyama, Mitsuo Katano
Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia...
August 2016: Anticancer Research
(no author information available yet)
[This corrects the article DOI: 10.1371/journal.pgen.1004204.].
July 2016: PLoS Genetics
Beate Roese-Koerner, Laura Stappert, Thomas Berger, Nils Christian Braun, Monika Veltel, Johannes Jungverdorben, Bernd O Evert, Michael Peitz, Lodovica Borghese, Oliver Brüstle
Tight regulation of the balance between self-renewal and differentiation of neural stem cells is crucial to assure proper neural development. In this context, Notch signaling is a well-known promoter of stemness. In contrast, the bifunctional brain-enriched microRNA miR-9/9(∗) has been implicated in promoting neuronal differentiation. Therefore, we set out to explore the role of both regulators in human neural stem cells. We found that miR-9/9(∗) decreases Notch activity by targeting NOTCH2 and HES1, resulting in an enhanced differentiation...
August 9, 2016: Stem Cell Reports
(no author information available yet)
RBPJ is required for GBM tumor-initiating cell self-renewal and tumor growth.
August 2016: Cancer Discovery
Henar Cuervo, Corinne M Nielsen, Douglas A Simonetto, Linda Ferrell, Vijay H Shah, Rong A Wang
UNLABELLED: Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results in liver vascular pathologies. However, whether Notch in endothelium is essential for hepatic vascular structure and function remains unknown. To uncover the function of endothelial Notch in the liver, we deleted Rbpj, a transcription factor mediating all canonical Notch signaling, or Notch1 from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Ramón Díaz-Trelles, Maria Cecilia Scimia, Paul Bushway, Danh Tran, Anna Monosov, Edward Monosov, Kirk Peterson, Stacey Rentschler, Pedro Cabrales, Pilar Ruiz-Lozano, Mark Mercola
Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes...
June 30, 2016: Nature Communications
Gerd Meyer Zu Horste, Chuan Wu, Chao Wang, Le Cong, Mathias Pawlak, Youjin Lee, Wassim Elyaman, Sheng Xiao, Aviv Regev, Vijay K Kuchroo
Interleukin-17 (IL-17)-producing helper T cells (Th17 cells) play an important role in autoimmune diseases. However, not all Th17 cells induce tissue inflammation or autoimmunity. Th17 cells require IL-23 receptor (IL-23R) signaling to become pathogenic. The transcriptional mechanisms controlling the pathogenicity of Th17 cells and IL-23R expression are unknown. Here, we demonstrate that the canonical Notch signaling mediator RBPJ is a key driver of IL-23R expression. In the absence of RBPJ, Th17 cells fail to upregulate IL-23R, lack stability, and do not induce autoimmune tissue inflammation in vivo, whereas overexpression of IL-23R rescues this defect and promotes pathogenicity of RBPJ-deficient Th17 cells...
July 12, 2016: Cell Reports
Yadong Zhang, Shiyi Dong, Weicai Wang, Jianning Wang, Miao Wang, Mu Chen, Jinsong Hou, Hongzhang Huang
Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation...
August 26, 2016: Biochemical and Biophysical Research Communications
Xing Fan
Targeting glioblastoma stem cells with γ-secretase inhibitors (GSIs) disrupts the Notch pathway and has shown some benefit in both pre-clinical models and in patients during phase I/II clinical trials. However, it is largely unknown why some glioblastoma (GBM) does not respond to GSI treatment. In this issue of the JCI, Xie et al. determined that GSI-resistant brain tumor-initiating cells (BTICs) from GBM express a higher level of the gene RBPJ, which encodes a mediator of canonical Notch signaling, compared to non-BTICs...
July 1, 2016: Journal of Clinical Investigation
Qi Xie, Qiulian Wu, Leo Kim, Tyler E Miller, Brian B Liau, Stephen C Mack, Kailin Yang, Daniel C Factor, Xiaoguang Fang, Zhi Huang, Wenchao Zhou, Kareem Alazem, Xiuxing Wang, Bradley E Bernstein, Shideng Bao, Jeremy N Rich
Glioblastomas co-opt stem cell regulatory pathways to maintain brain tumor-initiating cells (BTICs), also known as cancer stem cells. NOTCH signaling has been a molecular target in BTICs, but NOTCH antagonists have demonstrated limited efficacy in clinical trials. Recombining binding protein suppressor of hairless (RBPJ) is considered a central transcriptional mediator of NOTCH activity. Here, we report that pharmacologic NOTCH inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While NOTCH inhibitors decreased canonical NOTCH gene expression, RBPJ regulated a distinct profile of genes critical to BTIC stemness and cell cycle progression...
July 1, 2016: Journal of Clinical Investigation
Hélène Ragot, Astrid Monfort, Mathilde Baudet, Fériel Azibani, Loubina Fazal, Régine Merval, Evelyne Polidano, Alain Cohen-Solal, Claude Delcayre, Nicolas Vodovar, Christos Chatziantoniou, Jane-Lise Samuel
Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout...
August 2016: Hypertension
Oh-Joon Kwon, Li Zhang, Jianghua Wang, Qingtai Su, Qin Feng, Xiang H F Zhang, Sendurai A Mani, Robia Paulter, Chad J Creighton, Michael M Ittmann, Li Xin
Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression...
July 1, 2016: Journal of Clinical Investigation
Cecilia I Lopez, Katherine E Saud, Rodrigo Aguilar, F Andrés Berndt, José Cánovas, Martín Montecino, Manuel Kukuljan
The development of the cerebral cortex is a dynamic and coordinated process in which cell division, cell death, migration and differentiation must be highly regulated to acquire the final architecture and functional competence of the mature organ. Notch pathway is an important regulator of differentiation and it is essential to maintain neural stem cell (NSC) pool. Here we studied the role of epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and its interactor CoREST in the regulation of the Notch pathway activity during the development of the cerebral cortex...
April 25, 2016: Developmental Neurobiology
Philipp W Becker, Natalia Sacilotto, Svanhild Nornes, Alice Neal, Max O Thomas, Ke Liu, Chris Preece, Indrika Ratnayaka, Benjamin Davies, George Bou-Gharios, Sarah De Val
OBJECTIVE: The vascular endothelial growth factor (VEGF) receptor Flk1 is essential for vascular development, but the signaling and transcriptional pathways by which its expression is regulated in endothelial cells remain unclear. Although previous studies have identified 2 Flk1 regulatory enhancers, these are dispensable for Flk1 expression, indicating that additional enhancers contribute to Flk1 regulation in endothelial cells. In the present study, we sought to identify Flk1 enhancers contributing to expression in endothelial cells...
June 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
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