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Cdkn2a

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https://www.readbyqxmd.com/read/29229598/cdkn2a-p16-deletion-in-head-and-neck-cancer-cells-is-associated-with-cdk2-activation-replication-stress-and-vulnerability-to-chk1-inhibition
#1
Mayur A Gadhikar, Jiexin Zhang, Li Shen, Xiayu Rao, Jing Wang, Mei Zhao, Nene N Kalu, Faye M Johnson, Lauren A Byers, John Heymach, Walter N Hittelman, Durga Udayakumar, Raj K Pandita, Tej K Pandita, Curtis R Pickering, Abena Redwood, Helen Piwnica-Worms, Katharina Schlacher, Mitchell J Frederick, Jeffrey N Myers
Checkpoint kinase inhibitors (CHKi) exhibit striking single agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of Chk1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29227283/sharpin-mediated-regulation-of-protein-arginine-methyltransferase-5-controls-melanoma-growth
#2
Hironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Ji Yun Han, Ayako Murao, Scott J Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, Ze'ev A Ronai
SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29216274/functional-analysis-of-a-cdkn2a-5-utr-germline-variant-associated-with-pancreatic-cancer-development
#3
William Bruno, Virginia Andreotti, Alessandra Bisio, Lorenza Pastorino, Giuseppe Fornarini, Stefania Sciallero, Giovanna Bianchi-Scarrà, Alberto Inga, Paola Ghiorzo
CDKN2A coding region germline variants are associated with pancreatic adenocarcinoma (PC) susceptibility. Recently, we described functional germline 5'UTR CDKN2A variants from melanoma patients affecting the post-transcriptional regulation of p16INK4a mRNA that is dependent, at least in part, on an Internal Ribosome Entry Site (IRES) in the 5'UTR region. Here we describe a 5'UTR c.-201_-198delinsCTTT CDKN2A variant (frequency 0.0028 based on 350 PC patients), which seems to be private to PC, since it has never been found in public databases nor in thousands of melanoma patients tested...
2017: PloS One
https://www.readbyqxmd.com/read/29215650/phenocopies-in-melanoma-prone-families-with-germ-line-cdkn2a-mutations
#4
Hildur Helgadottir, Håkan Olsson, Margaret A Tucker, Xiaohong R Yang, Veronica Höiom, Alisa M Goldstein
PurposeCarriers of CDKN2A mutations have high risks of melanoma and certain other cancers. In this study we examined the occurrence of tumors among CDKN2A wild type (wt) members of melanoma-prone families with CDKN2A mutations.MethodsSwedish and US melanoma-prone families with CDKN2A mutations were included. Data was collected on tumors diagnosed among family members. Among the CDKN2A mutated families, members with CDKN2A wt status who were diagnosed with melanoma were designated phenocopies.ResultsOf patients with melanoma in the CDKN2A mutated families (n = 266), 7...
December 7, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29212231/zbp-89-function-in-colonic-stem-cells-and-during-butyrate-induced-senescence
#5
Ramon Ocadiz-Ruiz, Amanda L Photenhauer, Michael M Hayes, Lin Ding, Eric R Fearon, Juanita L Merchant
ZBP-89 (Zfp148, ZNF148) is a Kruppel-type zinc-finger family transcription factor that binds to GC-rich DNA elements. Earlier studies in cell lines demonstrated that ZBP-89 cooperates with Wnt β-catenin signaling by inducing β-catenin gene expression. Since β-catenin levels are normally highest at the crypt base, we examined whether ZBP-89 is required for stem cell maintenance. Lineage-tracing using a Zfp148CreERT2 transgenic line demonstrated expression in both intestine and colonic stem cells. Deleting the Zfp148 locus in the colon using the Cdx2NLSCreERT2 transgene, reduced the size and number of polyps formed in the Apc-deleted mice...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29211306/telomerase-reverse-transcriptase-promoter-alterations-across-cancer-types-as-detected-by-next-generation-sequencing-a-clinical-and-molecular-analysis-of-423-patients
#6
Maria Schwaederle, Nithya Krishnamurthy, Gregory A Daniels, David E Piccioni, Santosh Kesari, Paul T Fanta, Richard B Schwab, Sandip P Patel, Barbara A Parker, Razelle Kurzrock
BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015...
December 6, 2017: Cancer
https://www.readbyqxmd.com/read/29199525/molecular-genetic-profile-in-bcr-abl1-negative-pediatric-b-cell-acute-lymphoblastic-leukemia-can-further-refine-outcome-prediction-in-addition-to-that-by-end-induction-minimal-residual-disease-detection
#7
Sanjeev Kumar Gupta, Sameer Bakhshi, Anita Chopra, Vineet Kumar Kamal
The recently proposed molecular genetic criteria promise improved risk-prediction in B-cell acute lymphoblastic leukemia (B-ALL). This study assesses their utility in BCR-ABL1 negative pediatric B-ALL, particularly with respect to end-induction minimal residual disease (MRD). The DNA was analyzed for copy number alterations in CDKN2A/B, PAX5, IKZF1, and other genes. Seventy-six cases with median age 7 years (2 months-18 years) included MRD-positive (24; 32%), and MRD negative-standard (20; 26%), intermediate (20; 26%), & high risk (12;16%) cases...
December 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29197760/lifetime-exposure-to-ambient-air-pollution-and-methylation-of-tumor-suppressor-genes-in-breast-tumors
#8
Catherine L Callahan, Matthew R Bonner, Jing Nie, Daikwon Han, Youjin Wang, Meng-Hua Tao, Peter G Shields, Catalin Marian, Kevin H Eng, Maurizio Trevisan, Jan Beyea, Jo L Freudenheim
BACKGROUND: We previously reported increased risk of breast cancer associated with early life exposure to two measures of air pollution exposure, total suspended particulates (TSP) and traffic emissions (TE), possible proxies for exposure to polycyclic aromatic hydrocarbons (PAHs). Exposure to PAHs has been shown to be associated with aberrant patterns of DNA methylation in peripheral blood of healthy individuals. Exposure to PAHs and methylation in breast tumor tissue has received little attention...
November 30, 2017: Environmental Research
https://www.readbyqxmd.com/read/29194093/cdkn2a-b-deletion-and-double-hit-mutations-of-the-mapk-pathway-underlie-the-aggressive-behavior-of-langerhans-cell-tumors
#9
Luc Xerri, José Adélaïde, Cornel Popovici, Séverine Garnier, Arnaud Guille, Lenaïg Mescam-Mancini, Camille Laurent, Pierre Brousset, Carole Coze, Gérard Michel, Max Chaffanet, Reda Bouabdallah, Diane Coso, François Bertucci, Daniel Birnbaum
Langerhans cell histiocytosis (LCH) has a mostly favorable outcome, whereas Langerhans cell sarcoma (LCS) is an aggressive tumor. It is still unclear whether any specific molecular alterations could underlie the aggressive behavior of Langerhans cell proliferations. We used targeted next-generation sequencing and array-comparative genomic hybridization to profile 22 LCH samples from different patients together with 3 LCS samples corresponding to different relapses from the same patient. The third LCS relapse was a composite tumor including both B-cell chronic lymphocytic leukemia and LCS components...
November 29, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29168898/association-of-p16-cdkn2a-polymorphisms-with-the-development-of-hpv16-related-precancerous-lesions-and-cervical-cancer-in-the-greek-population
#10
D Tsakogiannis, G D Moschonas, E Bella, Z Kyriakopoulou, G D Amoutzias, T G Dimitriou, C Kottaridi, P Markoulatos
The tumor suppressor protein p16 plays a fundamental role in cell cycle regulation and exerts a protective effect against tumor growth. Two different polymorphisms at positions 540 and 580 at the 3'UTR of exon 3 of p16 gene are implicated in several types of cancer, while their role in cervical cancer development remains rather vague. In the present study, we investigated for the impact of p16 genotypes/haplotypes on patients' vulnerability to cervical disease and examined whether these factors can be used as progression markers in the Greek population...
November 23, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/29162510/unravelling-the-link-between-embryogenesis-and-cancer-metastasis
#11
Kanisha Shah, Shanaya Patel, Sheefa Mirza, Rakesh M Rawal
PURPOSE: Cancer as opposed to embryonic development is characterized by dysregulated, uncontrolled and clonal growth of cells. Inspite of that they share certain commonality in gene expression patterns and a number of cellular & molecular features. Consequently, in the present study we aimed to evaluate the role of a definite set of genes in fetal liver, primary liver cancers and metastatic liver tissue. METHODS: The relative expression of fourteen candidate genes obtained by data mining and manual curation of published data (CXCL12, CXCR4, CK7, CDH1, CTNNB1, CLDN4, VEGFA, HIF1A, MMP9, p53, OPN, CDKN2A, TGFBR2, MUC16, β-actin) were performed on 62 tissues (32 liver metastasis tissues and 30 primary Liver cancer tissues), Fetal liver tissues (below and above 20weeks of gestation) and 2 sets of control samples by real-time quantitative reverse transcription PCR (qRT-PCR)...
November 18, 2017: Gene
https://www.readbyqxmd.com/read/29161966/altered-downstream-target-gene-expression-of-the-placental-vitamin-d-receptor-in-human-idiopathic-fetal-growth-restriction
#12
Thy Ph Nguyen, Hannah Ej Yong, Tejasvy Chollangi, Shaun P Brennecke, Susan J Fisher, Euan M Wallace, Peter R Ebeling, Padma Murthi
Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes...
November 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29161788/aggressive-supratentorial-ependymoma-rela-fusion-positive-with-extracranial-metastasis-a-case-report
#13
Seong-Ik Kim, Yoojin Lee, Seung Ki Kim, Hyoung Jin Kang, Sung-Hye Park
Ependymoma is the third most common pediatric primary brain tumor. Ependymomas are categorized according to their locations and genetic abnormalities, and these two parameters are important prognostic factors for patient outcome. For supratentorial (ST) ependymomas, RELA fusion-positive ependymomas show a more aggressive behavior than YAP1 fusion-positive ependymomas. Extracranial metastases of intra-axial neuroepithelial tumors are extremely rare. In this paper, we report a case of aggressive anaplastic ependymoma arising in the right frontoparietal lobe, which had genetically 1q25 gain, CDKN2A homozygous deletion, and L1CAM overexpression...
November 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/29156680/vemurafenib-resistance-via-de-novo-rbm-genes-mutations-and-chromosome-5-aberrations-is-overcome-by-combined-therapy-with-palbociclib-in-thyroid-carcinoma-with-braf-v600e
#14
Zeus A Antonello, Nancy Hsu, Manoj Bhasin, Giovanni Roti, Mukta Joshi, Paul Van Hummelen, Emily Ye, Agnes S Lo, S Ananth Karumanchi, Christine R Bryke, Carmelo Nucera
Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAF(V600E) represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAF(WT/V600E)-positive PTC patient-derived cells with P16(-/-) (CDKN2A(-/-))...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156578/pancreatic-cancer-molecular-characterization-clonal-evolution-and-cancer-stem-cells
#15
REVIEW
Elvira Pelosi, Germana Castelli, Ugo Testa
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development...
November 18, 2017: Biomedicines
https://www.readbyqxmd.com/read/29152094/xenotransplantation-of-pediatric-low-grade-gliomas-confirms-the-enrichment-of-braf-v600e-mutation-and-preservation-of-cdkn2a-deletion-in-a-novel-orthotopic-xenograft-mouse-model-of-progressive-pleomorphic-xanthoastrocytoma
#16
Mari Kogiso, Lin Qi, Holly Lindsay, Yulun Huang, Xiumei Zhao, Zhigang Liu, Frank K Braun, Yuchen Du, Huiyuan Zhang, Goeun Bae, Sibo Zhao, Sarah G Injac, Mary Sobieski, David Brunell, Vidya Mehta, Diep Tran, Jeffrey Murray, Patricia A Baxter, Xiao-Jun Yuan, Jack M Su, Adekunle Adesina, Laszlo Perlaky, Murali Chintagumpala, D Williams Parsons, Ching C Lau, Clifford C Stephan, Xinyan Lu, Xiao-Nan Li
To identify cellular and molecular changes that driver pediatric low grade glioma (PLGG) progression, we analyzed putative cancer stem cells (CSCs) and evaluated key biological changes in a novel and progressive patient-derived orthotopic xenograft (PDOX) mouse model. Flow cytometric analysis of 22 PLGGs detected CD133(+) (<1.5%) and CD15(+) (20.7 ± 28.9%) cells, and direct intra-cranial implantation of 25 PLGGs led to the development of 1 PDOX model from a grade II pleomorphic xanthoastrocytoma (PXA). While CSC levels did not correlate with patient tumor progression, neurosphere formation and in vivo tumorigenicity, the PDOX model, IC-3635PXA, reproduced key histological features of the original tumor...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29148152/u-ch17p-m-and-s-a-new-cell-culture-system-for-tumour-diversity-and-progression-in-chordoma
#17
D Jäger, A Lechel, U Tharehalli, C Seeling, P Möller, T F E Barth, K Mellert
Chordoma is a rare bone tumour with a known intrinsic heterogeneity. Here, we address this tumour heterogeneity in a new cell culture model for tumour diversity and progression in chordoma. The three cell lines U-CH17P, U-CH17M, and U-CH17S were established from a primary sacral chordoma and its derived metastases, a soft tissue and a skin metastasis, respectively. The lesions had divergent differentiation patterns which are conserved in the derived cell lines making them a suitable in vitro model for the analysis of tumorigenesis in chordoma...
November 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29144154/sleep-quality-and-methylation-status-of-selected-tumor-suppressor-genes-among-nurses-and-midwives
#18
Agnieszka Bukowska-Damska, Edyta Reszka, Pawel Kaluzny, Edyta Wieczorek, Monika Przybek, Shanbeh Zienolddiny, Beata Peplonska
Chronic sleep restriction may affect metabolism, hormone secretion patterns and inflammatory responses. Limited reports suggest also epigenetic effects, such as changes in DNA methylation profiles. The study aims to assess the potential association between poor sleep quality or sleep duration and the levels of 5-methylcytosine in the promoter regions of selected tumor suppressor genes. A cross-sectional study was conducted on 710 nurses and midwives aged 40-60 years. Data from interviews regarding sleep habits and potential confounders were used...
November 16, 2017: Chronobiology International
https://www.readbyqxmd.com/read/29143441/cellular-aging-dynamics-after-acute-malaria-infection-a-12-month-longitudinal-study
#19
Muhammad Asghar, Victor Yman, Manijeh Vafa Homann, Klara Sondén, Ulf Hammar, Dennis Hasselquist, Anna Färnert
Accelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real-time quantitative PCR, while telomerase activity and CDKN2A expression were measured by reverse transcriptase (RT)-qPCR...
November 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/29141020/genomic-analysis-of-atypical-fibroxanthoma
#20
Kevin Lai, Catherine A Harwood, Karin J Purdie, Charlotte M Proby, Irene M Leigh, Namita Ravi, Thaddeus W Mully, Lionel Brooks, Priscilla M Sandoval, Michael D Rosenblum, Sarah T Arron
Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found...
2017: PloS One
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