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Veronika Reiterer, Cristina Figueras-Puig, Francois Le Guerroue, Stefano Confalonieri, Manuela Vecchi, Dasaradha Jalapothu, Sandip M Kanse, Raymond J Deshaies, Pier Paolo Di Fiore, Christian Behrends, Hesso Farhan
No abstract text is available yet for this article.
March 15, 2018: EMBO Journal
X Chen, X Y Li, M Long, X Wang, Z W Gao, Y Cui, J Ren, Z Zhang, C Liu, K Dong, H Zhang
Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation...
2018: Neoplasma
Haitham Mirghani, Ludovic Lacroix, Caroline Rossoni, Roger Sun, Anne Aupérin, Odile Casiraghi, Aude Villepelet, Roger Lacave, Gladwys Faucher, Virginie Marty, Charles Ferté, Jean Charles Soria, Caroline Even
BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) patients are characterised by a better prognosis than their HPV-negative counterparts. However, this significant survival advantage is not homogeneous and among HPV-positive patients those with a smoking history have a significantly increased risk of oncologic failure. The reason why tobacco consumption impacts negatively the prognosis is still elusive. Tobacco might induce additional genetic alterations leading to a more aggressive phenotype...
March 10, 2018: European Journal of Cancer
Andreas W Berger, Katja Raedler, Cord Langner, Leopold Ludwig, Nektarios Dikopoulos, Karl F Becker, Julia Slotta-Huspenina, Michael Quante, Daniel Schwerdel, Lukas Perkhofer, Alexander Kleger, Eugen Zizer, Franz Oswald, Thomas Seufferlein, Alexander Meining
Background and objective: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk. Methods: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina))...
March 2018: United European Gastroenterology Journal
Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Milena Urbini, Janice Patterson, Margherita Nannini, Maristella Saponara, Lidia Gatto, Donatella Santini, Italo F do Valle, Gastone Castellani, Daniel Remondini, Michelangelo Fiorentino, Margaret von Mehren, Giovanni Brandi, Guido Biasco, Michael C Heinrich, Maria Aabbondanza Pantaleo
Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha ( PDGFRA ) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course...
March 4, 2018: International Journal of Molecular Sciences
Edyta Kisielnicka, Ryuji Minasaki, Christian R Eckmann
RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit...
March 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mitra Mehrad, Somak Roy, William A LaFramboise, Patti Petrosko, Caitlyn Miller, Pimpin Incharoen, Sanja Dacic
Pulmonary Sarcomatoid Carcinoma (PSC) is a poorly-differentiated non-small cell lung carcinoma (NSCLC) with aggressive behavior. This study aimed to evaluate the prognostic clinicopathologic and genetic characteristics of PSCs. Fifty-three cases of surgically treated PSCs were selected, of which 23 were subjected to mutation and copy number variation analysis using 50-gene Ion AmpliSeq Cancer Panel. Majority of the patients were male (32/53, 60.3%) and smoker (51/53, 96.2%). Overall, 25 (47.1%) patients died within 2 to 105 months (mean 22...
February 28, 2018: Histopathology
Jiejie Zhao, Xuelian Xiong, Yao Li, Xing Liu, Tao Wang, Hong Zhang, Yang Jiao, Jingjing Jiang, Huijie Zhang, Qiqun Tang, Xin Gao, Xuejun Li, Yan Lu, Bin Liu, Cheng Hu, Xiaoying Li
Type 2 diabetes has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin-protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p. Ala204Thr) in Chinese population, which is associated with elevated blood glucose and type 2 diabetes risk...
February 23, 2018: Diabetes
Shogo Nakayama, Kanae Yumimoto, Atsuki Kawamura, Keiichi I Nakayama
The ubiquitin-proteasome system regulates the abundance of many cellular proteins by mediating their targeted degradation. We previously developed a method-differential proteomics-based identification of ubiquitylation substrates (DiPIUS)-for the comprehensive identification of substrates for a given F-box protein subunit of SCF-type ubiquitin ligases. We have now applied DiPIUS to the F-box protein Fbxw7 in three cell lines (mHepa, Neuro2A, and C2C12) and thereby identified myelin regulatory factor (MyRF)-an endoplasmic reticulum-anchored transcription factor that is essential for myelination of nerves in the central nervous system-as a candidate substrate of Fbxw7 specifically in mHepa cells...
February 22, 2018: Journal of Biological Chemistry
Hongchao He, Jun Dai, Zhaoping Xu, Wei He, Xiaojing Wang, Yu Zhu, Haofei Wang
F-box and WD repeat domain containing 7 (Fbxw7) is an F-box protein that belongs to the SKP1-CUL1-F-box protein E3 ligase complex and is responsible for transferring the ubiquitin molecule to the substrate, which results in its recognition and subsequent degradation by proteasomes. Furthermore, it can identify a network of signaling proteins that function in cell growth, diversion and apoptosis. In the present study, Fbxw7 was downregulated in renal cell carcinoma (RCC) tissues compared with the adjacent non-tumor tissues and its expression was significantly associated with the tumor-node-metastasis stage, lymph node metastasis and distant metastasis in patients with RCC...
March 2018: Oncology Letters
Brooke R Druliner, Panwen Wang, Taejeong Bae, Saurabh Baheti, Seth Slettedahl, Douglas Mahoney, Nikolaos Vasmatzis, Hang Xu, Minsoo Kim, Matthew Bockol, Daniel O'Brien, Diane Grill, Nathaniel Warner, Miguel Munoz-Gomez, Kimberlee Kossick, Ruth Johnson, Mohamad Mouchli, Donna Felmlee-Devine, Jill Washechek-Aletto, Thomas Smyrk, Ann Oberg, Junwen Wang, Nicholas Chia, Alexej Abyzov, David Ahlquist, Lisa A Boardman
The majority of colorectal cancer (CRC) arises from precursor lesions known as polyps. The molecular determinants that distinguish benign from malignant polyps remain unclear. To molecularly characterize polyps, we utilized Cancer Adjacent Polyp (CAP) and Cancer Free Polyp (CFP) patients. CAPs had tissues from the residual polyp of origin and contiguous cancer; CFPs had polyp tissues matched to CAPs based on polyp size, histology and dysplasia. To determine whether molecular features distinguish CAPs and CFPs, we conducted Whole Genome Sequencing, RNA-seq, and RRBS on over 90 tissues from 31 patients...
February 16, 2018: Scientific Reports
Colin J R Stewart, Susan Bigby, Tino Giardina, Fabienne Grieu-Iacopetta, Benhur Amanuel
Papillary proliferations of the endometrium (PPEs) are uncommon lesions that are often associated with endometrial polyps. PPEs occasionally precede or co-exist with atypical endometrial hyperplasia or adenocarcinoma, but their pathogenesis and relationship to endometrial neoplasia is uncertain. In the present study 11 PPEs, including eight benign papillary proliferations (BPPs) and three complex papillary hyperplasias (CPHs) were examined immunohistochemically for expression of PAX2, BAF250a, p16, β-catenin and DNA mismatch repair (MMR) proteins...
February 12, 2018: Pathology
Noriyuki Murai, Yasuko Murakami, Ayasa Tajima, Senya Matsufuji
The proto-oncogene c-Myc encodes a short-lived protein c-Myc that regulates various cellular processes including cell growth, differentiation and apoptosis. Degradation of c-Myc is catalyzed by the proteasome and requires phosphorylation of Thr-58 for ubiquitination by E3 ubiquitin ligase, Fbxw7/ FBW7. Here we show that a polyamine regulatory protein, antizyme 2 (AZ2), interacts with c-Myc in the nucleus and nucleolus, to accelerate proteasome-mediated c-Myc degradation without ubiquitination or Thr-58 phosphorylation...
February 14, 2018: Scientific Reports
Mi-Ryung Han, Sun Shin, Hyeon-Chun Park, Min Sung Kim, Sung Hak Lee, Seung Hyun Jung, Sang Yong Song, Sug Hyung Lee, Yeun-Jun Chung
Vulvar squamous cell carcinoma (SCC) consists of two different etiologic categories: human papilloma virus (HPV)-associated (HPV (+)) and HPV-non-associated (HPV (-)). There have been no genome-wide studies on the genetic alterations of vulvar SCCs or on the differences between HPV (+) and HPV (-) vulvar SCCs. In this study, we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (-) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (-) SCCs...
February 9, 2018: Experimental & Molecular Medicine
Andreas W Berger, Daniel Schwerdel, Thomas J Ettrich, Alexander Hann, Stefan A Schmidt, Alexander Kleger, Ralf Marienfeld, Thomas Seufferlein
Purpose: Precision medicine in pancreatic ductal adenocarcinoma (PDAC) could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor. In particular, noninvasive approaches are desirable, but not validated. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Experimental Design: Blood samples from patients with metastatic PDAC prior to and during palliative treatment were collected. ctDNA and corresponding tumor tissue were analyzed by targeted next generation sequencing and droplet digital PCR for the 7 most frequently mutated genes in PDAC (TP53, SMAD4, CDKN2A, KRAS, APC, ATM, and FBXW7)...
January 5, 2018: Oncotarget
Wulfran Cacheux, Virginie Dangles-Marie, Etienne Rouleau, Julien Lazartigues, Elodie Girard, Adrien Briaux, Pascale Mariani, Sophie Richon, Sophie Vacher, Bruno Buecher, Marion Richard-Molard, Emmanuelle Jeannot, Nicolas Servant, Fereshteh Farkhondeh, Odette Mariani, Thomas Rio-Frio, Sergio Roman-Roman, Emmanuel Mitry, Ivan Bieche, Astrid Lièvre
Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours...
January 2, 2018: Oncotarget
Elisa Melucci, Beatrice Casini, Livia Ronchetti, Laura Pizzuti, Francesca Sperati, Matteo Pallocca, Francesca De Nicola, Frauke Goeman, Enzo Gallo, Carla Azzurra Amoreo, Domenico Sergi, Irene Terrenato, Patrizia Vici, Luigi Di Lauro, Maria Grazia Diodoro, Edoardo Pescarmona, Maddalena Barba, Marco Mazzotta, Marcella Mottolese, Maurizio Fanciulli, Gennaro Ciliberto, Ruggero De Maria, Simonetta Buglioni, Marcello Maugeri-Saccà
BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. METHODS: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice...
February 5, 2018: Journal of Translational Medicine
Dejan Juric, Jordi Rodon, Josep Tabernero, Filip Janku, Howard A Burris, Jan H M Schellens, Mark R Middleton, Jordan Berlin, Martin Schuler, Marta Gil-Martin, Hope S Rugo, Ruth Seggewiss-Bernhardt, Alan Huang, Douglas Bootle, David Demanse, Lars Blumenstein, Christina Coughlin, Cornelia Quadt, José Baselga
Purpose We report the first-in-human phase Ia study to our knowledge ( identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily...
February 5, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Tsuneo Ikenoue, Yumi Terakado, Chi Zhu, Xun Liu, Tomoyuki Ohsugi, Daisuke Matsubara, Tomoki Fujii, Shigeru Kakuta, Sachiko Kubo, Takuma Shibata, Kiyoshi Yamaguchi, Yoichiro Iwakura, Yoichi Furukawa
F-box and WD40 domain protein 7 (FBXW7) is a component of the SKP1-CUL1-F-box protein (SCF) complex that mediates the ubiquitination of diverse oncogenic target proteins. The exploration of FBXW7 mutations in human primary cancer has revealed three mutation hotspots at conserved arginine residues (Arg465 , Arg479 , and Arg505 ) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7R465C , the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7R468C corresponding to human FBXW7R465C ...
January 31, 2018: Scientific Reports
Norihiro Ishii, Kenichiro Araki, Takehiko Yokobori, Dorgormaa Gantumur, Takahiro Yamanaka, Bolag Altan, Mariko Tsukagoshi, Takamichi Igarashi, Akira Watanabe, Norio Kubo, Yasuo Hosouchi, Hiroyuki Kuwano, Ken Shirabe
Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer...
December 22, 2017: Oncotarget
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