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https://www.readbyqxmd.com/read/28294973/fusion-guided-hypothesis-development-leads-to-the-identification-of-n%C3%A2-n%C3%A2-dimethyladenosine-a-marine-derived-akt-pathway-inhibitor
#1
Rachel M Vaden, Nathaniel W Oswald, Malia B Potts, John B MacMillan, Michael A White
Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N⁶,N⁶-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines...
March 15, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28255027/akt-activation-mediates-acquired-resistance-to-fibroblast-growth-factor-receptor-inhibitor-bgj398
#2
Jharna Datta, Senthilkumar Damodaran, Hannah Parks, Cristina Ocrainiciuc, Jharna Miya, Lianbo Yu, Elijah P Gardner, Eric Samorodnitsky, Michele R Wing, Darshna Bhatt, John Hays, Julie W Reeser, Sameek Roychowdhury
Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines...
March 2, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28254151/role-of-cyclooxygenase-2-pathway-in-creating-an-immunosuppressive-microenvironment-and-in-initiation-and-progression-of-wilms-tumor
#3
Paramahamsa Maturu, Devin Jones, E Cristy Ruteshouser, Qianghua Hu, Joseph M Reynolds, John Hicks, Nagireddy Putluri, Suhendan Ekmekcioglu, Elizabeth A Grimm, Chen Dong, Willem W Overwijk
Wilms' tumors (WT), which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT...
March 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28216608/expression-of-iron-related-proteins-differentiate-non-cancerous-and-cancerous-breast-tumors
#4
Sara Pizzamiglio, Maida De Bortoli, Elena Taverna, Michele Signore, Silvia Veneroni, William Chi-Shing Cho, Rosaria Orlandi, Paolo Verderio, Italia Bongarzone
We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA) or reverse-phase protein array (RPPA), were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors...
February 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28185526/low-expression-of-ash2l-protein-correlates-with-a-favorable-outcome-in-acute-myeloid-leukemia
#5
Jill S Butler, Yi Hua Qiu, Nianxiang Zhang, Suk-Young Yoo, Kevin R Coombes, Sharon Y R Dent, Steven M Kornblau
ASH2L encodes a trithorax group protein that is a core component of all characterized mammalian histone H3K4 methyltransferase complexes, including mixed lineage leukemia (MLL) complexes. ASH2L protein levels in primary leukemia patient samples have not yet been defined. We analyzed ASH2L protein expression in 511 primary AML patient samples using reverse phase protein array (RPPA) technology. We discovered that ASH2L expression is significantly increased in a subset of patients carrying fms-related tyrosine kinase 3 (FLT3) mutations...
May 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28183315/pyruvate-kinase-m2-and-the-mitochondrial-atpase-inhibitory-factor-1-provide-novel-biomarkers-of-dermatomyositis-a-metabolic-link-to-oncogenesis
#6
Fulvio Santacatterina, María Sánchez-Aragó, Marc Catalán-García, Glòria Garrabou, Cristina Nuñez de Arenas, Josep M Grau, Francesc Cardellach, José M Cuezva
BACKGROUND: Metabolic alterations play a role in the development of inflammatory myopathies (IMs). Herein, we have investigated through a multiplex assay whether proteins of energy metabolism could provide biomarkers of IMs. METHODS: A cohort of thirty-two muscle biopsies and forty plasma samples comprising polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (sIBM) and control donors was interrogated with monoclonal antibodies against proteins of energy metabolism using reverse phase protein microarrays (RPPA)...
February 10, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28157711/the-repurposed-anthelmintic-mebendazole-in-combination-with-trametinib-suppresses-refractory-nrasq61k-melanoma
#7
Cynthia M Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F Petricoin, Michael B Atkins, Stephen W Byers, Dean S Rosenthal
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28003305/co-occurring-mutations-of-tumor-suppressor-genes-lats2-and-nf2-in-malignant-pleural-mesothelioma
#8
Robin Tranchant, Lisa Quetel, Anne Tallet, Clément Meiller, Annie Renier, Leanne de Koning, Aurélien de Reyniès, Francoise Le Pimpec Barthes, Jessica Zucman-Rossi, Marie-Claude Jaurand, Didier Jean
PURPOSE: To better define MPM heterogeneity and identify molecular subtypes of malignant pleural mesothelioma (MPM), we focus on the tumor suppressor gene LATS2, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis. EXPERIMENTAL DESIGN: Sixty-one MPM primary cultures established in our laboratory were screened for mutations in LATS2. Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, western blot and RPPA...
December 21, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27933927/three-dimensionally-functionalized-reverse-phase-glycoprotein-array-for-cancer-biomarker-discovery-and-validation
#9
Li Pan, Hillary Andaluz Aguilar, Linna Wang, Anton Iliuk, W Andy Tao
Glycoproteins have vast structural diversity that plays an important role in many biological processes and have great potential as disease biomarkers. Here, we report a novel functionalized reverse phase protein array (RPPA), termed polymer-based reverse phase glycoprotein array (polyGPA), to capture and profile glycoproteomes specifically, and validate glycoproteins. Nitrocellulose membrane functionalized with globular hydroxyaminodendrimers was used to covalently capture preoxidized glycans on glycoproteins from complex protein samples such as biofluids...
November 30, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27883284/novel-biomarkers-of-nasopharyngeal-carcinoma-metastasis-risk-identified-by-reverse-phase-protein-array-based-tumor-profiling-with-consideration-of-plasma-epstein-barr-virus-dna-load
#10
Tao Xu, Bojin Su, Peiyu Huang, Weihong Wei, Yanming Deng, Vasudha Sehgal, Donghui Wang, Jun Jiang, Guoyi Zhang, Anfei Li, Huiling Yang, Francois X Claret
PURPOSE: In patients with Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC), intertumor heterogeneity causes interpatient heterogeneity in the risk of distant metastasis. We aimed to identify novel biomarkers of metastasis risk using reverse phase protein array (RPPA) profiling of NPC patients at risk for metastasis and considering plasma EBV DNA load. EXPERIMENTAL DESIGN: A total of 98 patients with NPC with and without metastasis after treatment, matched with respect to clinical parameters, are enrolled...
November 24, 2016: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/27861902/the-molecular-basis-of-breast-cancer-pathological-phenotypes
#11
Yujing J Heng, Susan C Lester, Gary Mk Tse, Rachel E Factor, Kimberly H Allison, Laura C Collins, Yunn-Yi Chen, Kristin C Jensen, Nicole B Johnson, Jong Cheol Jeong, Rahi Punjabi, Sandra J Shin, Kamaljeet Singh, Gregor Krings, David A Eberhard, Puay Hoon Tan, Konstanty Korski, Frederic M Waldman, David A Gutman, Melinda Sanders, Jorge S Reis-Filho, Sydney R Flanagan, Deena Ma Gendoo, Gregory M Chen, Benjamin Haibe-Kains, Giovanni Ciriello, Katherine A Hoadley, Charles M Perou, Andrew H Beck
The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA)...
February 2017: Journal of Pathology
https://www.readbyqxmd.com/read/27858266/reverse-phase-protein-arrays-enable-glioblastoma-molecular-subtyping
#12
Gregor Hutter, Martin Sailer, Tej Deepak Azad, André O von Bueren, Peter Nollau, Stephan Frank, Cristobal Tostado, Durga Sarvepalli, Arkasubhra Ghosh, Marie-Françoise Ritz, Jean-Louis Boulay, Luigi Mariani
In the present study we investigated the phosphorylation status of the 12 most important signaling cascades in glioblastomas. More than 60 tumor and control biopsies from tumor center and periphery (based on neuronavigation) were subjected to selective protein expression analysis using reverse-phase protein arrays (RPPA) incubated with antibodies against posttranslationally modified cancer pathway proteins. The ratio between phosphorylated (or modified) and non-phosphorylated protein was assessed. All samples were histopathologically validated and proteomic profiles correlated with clinical and survival data...
November 17, 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27825696/a-pilot-study-exploring-the-molecular-architecture-of-the-tumor-microenvironment-in-human-prostate-cancer-using-laser-capture-microdissection-and-reverse-phase-protein-microarray
#13
Elisa Pin, Steven Stratton, Claudio Belluco, Lance Liotta, Ray Nagle, K Alex Hodge, Jianghong Deng, Ting Dong, Elisa Baldelli, Emanuel Petricoin, Mariaelena Pierobon
The cross-talk between tumor epithelium and surrounding stromal/immune microenvironment is essential to sustain tumor growth and progression and provides new opportunities for the development of targeted treatments focused on disrupting the tumor ecology. Identification of novel approaches to study these interactions is of primary importance. Using laser capture microdissection (LCM) coupled with reverse phase protein microarray (RPPA) based protein signaling activation mapping we explored the molecular interconnection between tumor epithelium and surrounding stromal microenvironment in 18 prostate cancer (PCa) specimens...
December 2016: Molecular Oncology
https://www.readbyqxmd.com/read/27813428/how-may-targeted-proteomics-complement-genomic-data-in-breast-cancer
#14
Mathilde Guerin, Anthony Gonçalves, Yves Toiron, Emilie Baudelet, Stéphane Audebert, Jean-Baptiste Boyer, Jean-Paul Borg, Luc Camoin
Breast cancer (BC) is the most common female cancer in the world and was recently deconstructed in different molecular entities. Although most of the recent assays to characterize tumors at the molecular level are genomic-based, proteins are the actual executors of cellular functions and represent the vast majority of targets for anticancer drugs. Accumulated data has demonstrated an important level of quantitative and qualitative discrepancies between genomic/transcriptomic alterations and their protein counterparts, mostly related to the large number of post-translational modifications...
January 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/27751915/defining-the-na-h-exchanger-nhe1-interactome-in-triple-negative-breast-cancer-cells
#15
Schammim Ray Amith, Krista Marie Vincent, Jodi Marie Wilkinson, Lynne Marie Postovit, Larry Fliegel
Mounting evidence supports a major role for the Na(+)/H(+) exchanger NHE1 in cancer progression and metastasis. NHE1 is hyperactive at the onset of oncogenic transformation, resulting in intracellular alkalinization and extracellular microenvironmental acidification. These conditions promote invasion and facilitate metastasis. However, the signal pathways governing the regulation of exchanger activity are still unclear. This is especially important in the aggressively metastatic, triple-negative basal breast cancer subtype...
January 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27663479/using-reverse-phase-protein-arrays-as-pharmacodynamic-assays-for-functional-proteomics-biomarker-discovery-and-drug-development-in-cancer
#16
REVIEW
Yiling Lu, Shiyun Ling, Apurva M Hegde, Lauren A Byers, Kevin Coombes, Gordon B Mills, Rehan Akbani
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents...
August 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/27658583/hypoxia-promotes-chemoresistance-in-acute-lymphoblastic-leukemia-cell-lines-by-modulating-death-signaling-pathways
#17
C Petit, F Gouel, I Dubus, C Heuclin, K Roget, J P Vannier
BACKGROUND: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood. METHODS: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL)...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27622568/reverse-phase-protein-arrays-for-compound-profiling
#18
Nathan Moerke, Mohammad Fallahi-Sichani
Reverse phase protein arrays (RPPAs), also called reverse phase lysate arrays (RPLAs), involve immobilizing cell or tissue lysates, in small spots, onto solid supports which are then probed with primary antibodies specific for proteins or post-translational modifications of interest. RPPA assays are well suited for large-scale, high-throughput measurement of protein and PTM levels in cells and tissues. RPPAs are affordable and highly multiplexable, as a large number of arrays can readily be produced in parallel and then probed separately with distinct primary antibodies...
2016: Current Protocols in Chemical Biology
https://www.readbyqxmd.com/read/27600857/mir-564-acts-as-a-dual-inhibitor-of-pi3k-and-mapk-signaling-networks-and-inhibits-proliferation-and-invasion-in-breast-cancer
#19
Merve Mutlu, Özge Saatci, Suhail A Ansari, Emre Yurdusev, Huma Shehwana, Özlen Konu, Umar Raza, Özgür Şahin
Dysregulation of PI3K and MAPK pathways promotes uncontrolled cell proliferation, apoptotic inhibition and metastasis. Individual targeting of these pathways using kinase inhibitors has largely been insufficient due to the existence of cross-talks between these parallel cascades. MicroRNAs are small non-coding RNAs targeting several genes simultaneously and controlling cancer-related processes. To identify miRNAs repressing both PI3K and MAPK pathways in breast cancer, we re-analyzed our previous miRNA mimic screen data with reverse phase protein array (RPPA) output, and identified miR-564 inhibiting both PI3K and MAPK pathways causing markedly decreased cell proliferation through G1 arrest...
September 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27579675/identification-of-igfbp2-and-igfbp3-as-compensatory-biomarkers-for-ca19-9-in-early-stage-pancreatic-cancer-using-a-combination-of-antibody-based-and-lc-ms-ms-based-proteomics
#20
Toshihiro Yoneyama, Sumio Ohtsuki, Kazufumi Honda, Makoto Kobayashi, Motoki Iwasaki, Yasuo Uchida, Takuji Okusaka, Shoji Nakamori, Masashi Shimahara, Takaaki Ueno, Akihiko Tsuchida, Naohiro Sata, Tatsuya Ioka, Yohichi Yasunami, Tomoo Kosuge, Takashi Kaneda, Takao Kato, Kazuhiro Yagihara, Shigeyuki Fujita, Wilber Huang, Tesshi Yamada, Masanori Tachikawa, Tetsuya Terasaki
Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics...
2016: PloS One
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