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https://www.readbyqxmd.com/read/28445466/human-pluripotent-stem-cells-recurrently-acquire-and-expand-dominant-negative-p53-mutations
#1
Florian T Merkle, Sulagna Ghosh, Nolan Kamitaki, Jana Mitchell, Yishai Avior, Curtis Mello, Seva Kashin, Shila Mekhoubad, Dusko Ilic, Maura Charlton, Genevieve Saphier, Robert E Handsaker, Giulio Genovese, Shiran Bar, Nissim Benvenisty, Steven A McCarroll, Kevin Eggan
Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28445112/tracking-the-evolution-of-non-small-cell-lung-cancer
#2
Mariam Jamal-Hanjani, Gareth A Wilson, Nicholas McGranahan, Nicolai J Birkbak, Thomas B K Watkins, Selvaraju Veeriah, Seema Shafi, Diana H Johnson, Richard Mitter, Rachel Rosenthal, Max Salm, Stuart Horswell, Mickael Escudero, Nik Matthews, Andrew Rowan, Tim Chambers, David A Moore, Samra Turajlic, Hang Xu, Siow-Ming Lee, Martin D Forster, Tanya Ahmad, Crispin T Hiley, Christopher Abbosh, Mary Falzon, Elaine Borg, Teresa Marafioti, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Rajesh Shah, Leena Joseph, Anne M Quinn, Phil A Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Jason F Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Stefan Dentro, Philippe Taniere, Brendan O'Sullivan, Helen L Lowe, John A Hartley, Natasha Iles, Harriet Bell, Yenting Ngai, Jacqui A Shaw, Javier Herrero, Zoltan Szallasi, Roland F Schwarz, Aengus Stewart, Sergio A Quezada, John Le Quesne, Peter Van Loo, Caroline Dive, Allan Hackshaw, Charles Swanton
Background Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. Methods In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy...
April 26, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28440963/clinical-sequencing-using-a-next-generation-sequencing-based-multiplex-gene-assay-in-patients-with-advanced-solid-tumors
#3
Tadayuki Kou, Masashi Kanai, Yoshihiro Yamamoto, Mayumi Kamada, Masahiko Nakatsui, Tomohiro Sakuma, Hiroaki Mochizuki, Akinori Hiroshima, Aiko Sugiyama, Eijiro Nakamura, Hidehiko Miyake, Sachiko Minamiguchi, Kyoichi Takaori, Shigemi Matsumoto, Hironori Haga, Hiroshi Seno, Shinji Kosugi, Yasushi Okuno, Manabu Muto
Advances in next-generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer-related genes at once in daily clinical practice. In April 2015, we introduced clinical sequencing using an NGS-based multiplex gene assay (OncoPrime(™) ) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy...
April 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28440428/inhibition-of-atr-potentiates-the-cytotoxic-effect-of-gemcitabine-on-pancreatic-cancer-cells-through-enhancement-of-dna-damage-and-abrogation-of-ribonucleotide-reductase-induction-by-gemcitabine
#4
Shuang Liu, Yubin Ge, Tingting Wang, Holly Edwards, Qihang Ren, Yiqun Jiang, Chengshi Quan, Guan Wang
Pancreatic cancer is a highly malignant disease with a dismal prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line treatment for patients with advanced disease, although its efficacy is very limited, mainly due to drug resistance. Ataxia telangiectasia and Rad3-related (ATR) plays a critical role in the DNA damage response (DDR) which has been implicated in GEM resistance. Thus, targeting ATR represents a promising approach to enhance GEM antitumor activity. In the present study, we tested the antitumor activity of AZ20, a novel ATR-selective inhibitor, alone or combined with GEM in 5 pancreatic cancer cell lines...
April 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28439615/wip1-phosphatase-as-pharmacological-target-in-cancer-therapy
#5
REVIEW
Soňa Pecháčková, Kamila Burdová, Libor Macurek
DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target...
April 24, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28435450/exome-sequencing-of-oral-squamous-cell-carcinoma-reveals-molecular-subgroups-and-novel-therapeutic-opportunities
#6
Shih-Chi Su, Chiao-Wen Lin, Yu-Fan Liu, Wen-Lang Fan, Mu-Kuan Chen, Chun-Ping Yu, Wei-En Yang, Chun-Wen Su, Chun-Yi Chuang, Wen-Hsiung Li, Wen-Hung Chung, Shun-Fa Yang
Oral squamous cell carcinoma (OSCC), an epithelial malignancy affecting a variety of subsites in the oral cavity, is prevalent in Asia. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. Improvement in therapeutic strategies and tailored treatment options is an unmet need. To unveil the mutational spectrum, whole-exome sequencing of 120 OSCC from male individuals in Taiwan was conducted. Analyzing the contributions of the five mutational signatures extracted from the dataset of somatic variations identified four groups of tumors that were significantly associated with demographic and clinical features...
2017: Theranostics
https://www.readbyqxmd.com/read/28435405/establishment-and-characterization-of-6-novel-patient-derived-primary-pancreatic-ductal-adenocarcinoma-cell-lines-from-korean-pancreatic-cancer-patients
#7
Mi-Ju Kim, Min-Sun Kim, Sung Joo Kim, Soyeon An, Jin Park, Hosub Park, Jae Hoon Lee, Ki-Byung Song, Dae Wook Hwang, Suhwan Chang, Kyu-Pyo Kim, Seong-Yun Jeong, Song Cheol Kim, Seung-Mo Hong
BACKGROUND: Pancreatic ductal adenocarcinomas are among the most malignant neoplasms and have very poor prognosis. Our understanding of various cancers has recently improved the survival of patients with cancer, except for pancreatic cancers. Establishment of primary cancer cell lines of pancreatic ductal adenocarcinomas will be useful for understanding the molecular mechanisms of this disease. METHODS: Eighty-one surgically resected pancreatic ductal adenocarcinomas were collected...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28435028/antagonistic-effects-of-p53-and-hif1a-on-microrna-34a-regulation-of-ppp1r11-and-stat3-and-hypoxia-induced-epithelial-to-mesenchymal-transition-in-colorectal-cancer-cells
#8
Huihui Li, Matjaz Rokavec, Longchang Jiang, David Horst, Heiko Hermeking
BACKGROUND & AIMS: In colorectal tumors, hypoxia causes resistance to therapy and promotes metastasis. Loss of the tumor suppressor p53 (encoded by TP53) provides cancer cells with a selective advantage under conditions of hypoxia, but little is known about the mediators of this effect. METHODS: Isogenic CRC cell lines with different TP53 genotypes were placed under conditions of hypoxia. We examined the effects on levels and activity of microRNA-34 a (MIR34A) in CRC cells...
April 20, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28432813/targeting-on-poly-adp-ribose-polymerase-activity-with-dna-damaging-hybrid-lactam-steroid-alkylators-in-wild-type-and-brca1-mutated-ovarian-cancer-cells
#9
Dimitrios T Trafalis, Aikaterini Polonifi, Panayiotis Dalezis, Nikolaos Nikoleousakos, Sotirios Katsamakas, Vassiliki Sarli
Conjugated lactam-steroid alkylators (LSA), have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemotherapy. Hybrid LSAs combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSAs that generate excellent anticancer activity against UWB1.289 and UWB1.289+BRCA1 human ovarian cancer cell lines...
April 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28432562/increased-expression-of-the-microrna-106b-25-cluster-and-its-host-gene-mcm7-in-corticotroph-pituitary-adenomas-is-associated-with-tumor-invasion-and-crooke-s-cell-morphology
#10
Filip Garbicz, Dawid Mehlich, Beata Rak, Emir Sajjad, Maria Maksymowicz, Wiktor Paskal, Grzegorz Zieliński, Paweł K Włodarski
PURPOSE: MCM7 (minichromosome maintenance complex component 7), a DNA replication licensing factor, is a host gene for the oncogenic miR-106b~25 cluster. It has been recently revealed as a relevant prognostic biomarker in a variety of cancers, including pituitary adenomas. The purpose of this study was to assess whether miR-106b~25 and MCM7 levels correlate with tumor invasiveness in a cohort of ACTH-immunopositive adenomas. METHODS: Tissue samples were obtained intraoperatively from 25 patients with pituitary adenoma...
April 21, 2017: Pituitary
https://www.readbyqxmd.com/read/28430874/developmental-sall2-transcription-factor-a-new-player-in-cancer
#11
Viviana E Hermosilla, Matias I Hepp, David Escobar, Carlos Farlas, Elizabeth N Riffo, Ariel F Castro, Roxana Pincheira
SALL2, also known as Spalt-like transcription factor 2, is a member of the SALL family of transcription factors involved in development and conserved through evolution. Since its identification in 1996, findings indicate that SALL2 plays a role in neurogenesis, neuronal differentiation and eye development. Consistently, SALL2 deficiency associates with neural tube defects and coloboma, a congenital eye disease. Relevant to cancer, clinical studies indicate that SALL2 is deregulated in various cancers, and is a specific biomarker for Synovial Sarcoma...
April 18, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28430579/antiangiogenesis-and-gene-aberration-related-therapy-may-improve-overall-survival-in-patients-with-concurrent-kras-and-tp53-hotspot-mutant-cancer
#12
Zhijie Wang, Sarina Piha-Paul, Filip Janku, Vivek Subbiah, Naiyi Shi, Jing Gong, Chetna Wathoo, Kenna Shaw, Kenneth Hess, Russell Broaddus, Aung Naing, David Hong, Apostolia M Tsimberidou, Daniel Karp, James Yao, Funda Meric-Bernstam, Siqing Fu
PURPOSE: Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations. RESULTS: Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429724/clonal-evolution-in-myelodysplastic-syndromes
#13
Pedro da Silva-Coelho, Leonie I Kroeze, Kenichi Yoshida, Theresia N Koorenhof-Scheele, Ruth Knops, Louis T van de Locht, Aniek O de Graaf, Marion Massop, Sarah Sandmann, Martin Dugas, Marian J Stevens-Kroef, Jaroslav Cermak, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Theo de Witte, Nicole M A Blijlevens, Petra Muus, Gerwin Huls, Bert A van der Reijden, Seishi Ogawa, Joop H Jansen
Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5-11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment...
April 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28429638/an-unusual-presentation-of-a-cervical-paraspinal-leiomyoma-in-an-adolescent-female
#14
Jeffrey A Swarz, Arayamparambil C Anilkumar, Douglas C Miller, N Scott Litofsky, Tomoko Tanaka
Objective We describe an apparently unique case of an extra-uterine leiomyoma in the cervical paraspinus including its evaluation and management. Methods A 14-year-old girl was referred to the neurology clinic for an abnormal head CT following a concussion. MRI revealed a homogenously enhancing left cervical paraspinal mass. The patient underwent complete resection and subsequent genetic testing and counseling were obtained to determine the presence of Li-Fraumeni Syndrome (LFS) or Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) mutations...
January 1, 2017: Pediatric and Developmental Pathology
https://www.readbyqxmd.com/read/28428144/association-of-aflatoxin-and-gallbladder-cancer
#15
Jill Koshiol, Yu-Tang Gao, Michael Dean, Patricia Egner, Chirag Nepal, Kristine Jones, Bingsheng Wang, Asif Rashid, Wen Luo, Alison Van Dyke, Catterina Ferreccio, Michael Malasky, Ming-Chang Shen, Bin Zhu, Jesper B Andersen, Allan Hildesheim, Ann W Hsing, John Groopman
BACKGROUND & AIMS: Aflatoxin, which causes hepatocellular carcinoma, may also cause gallbladder cancer. We investigated whether patients with gallbladder cancer have higher exposure to aflatoxin than patients with gallstones. METHODS: We measured aflatoxin B1 (AFB1)-lysine adducts in plasma samples from the Shanghai Biliary Tract Cancer case-control study, conducted from 1997 through 2001. We calculated age- and sex-adjusted odds ratios (ORs) and 95% CIs and the population-attributable fraction for 209 patients with gallbladder cancer and gallstones vs 250 patients with gallstones without cancer (controls)...
April 17, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28427204/an-extensive-molecular-cytogenetic-characterization-in-high-risk-chronic-lymphocytic-leukemia-identifies-karyotype-aberrations-and-tp53-disruption-as-predictors-of-outcome-and-chemorefractoriness
#16
Gian Matteo Rigolin, Luca Formigaro, Maurizio Cavallari, Francesca Maria Quaglia, Enrico Lista, Antonio Urso, Emanuele Guardalben, Sara Martinelli, Elena Saccenti, Cristian Bassi, Laura Lupini, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Massimo Negrini, Francesco Cavazzini, Antonio Cuneo
We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427202/clinical-implications-of-genomic-profiles-in-metastatic-breast-cancer-with-a-focus-on-tp53-and-pik3ca-the-most-frequently-mutated-genes
#17
Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park
Breast cancer (BC) has been genetically profiled through large-scale genome analyses. However, the role and clinical implications of genetic alterations in metastatic BC (MBC) have not been evaluated. Therefore, we conducted whole-exome sequencing (WES) and RNA-Seq of 37 MBC samples and targeted deep sequencing of another 29 MBCs. We evaluated somatic mutations from WES and targeted sequencing and assessed gene expression and performed pathway analysis from RNA-Seq. In this analysis, PIK3CA was the most commonly mutated gene in estrogen receptor (ER)-positive BC, while in ER-negative BC, TP53 was the most commonly mutated gene (p = 0...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427187/rita-displays-anti-tumor-activity-in-medulloblastomas-independent-of-tp53-status
#18
Aline Gottlieb, Kristina Althoff, Laura Grunewald, Theresa Thor, Andrea Odersky, Marc Schulte, Hedwig E Deubzer, Lukas Heukamp, Angelika Eggert, Alexander Schramm, Johannes H Schulte, Annette Künkele
Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40-70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427158/the-varied-distribution-and-impact-of-ras-codon-and-other-key-dna-alterations-across-the-translocation-cyclin-d-subgroups-in-multiple-myeloma
#19
Caleb K Stein, Charlotte Pawlyn, Shweta Chavan, Leo Rasche, Niels Weinhold, Adam Corken, Amy Buros, Pieter Sonneveld, Graham H Jackson, Ola Landgren, Tariq Mughal, Jie He, Bart Barlogie, P Leif Bergsagel, Faith E Davies, Brian A Walker, Gareth J Morgan
We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF...
February 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425916/combined-alk-and-mdm2-inhibition-increases-antitumor-activity-and-overcomes-resistance-in-human-alk-mutant-neuroblastoma-cell-lines-and-xenograft-models
#20
Hui Qin Wang, Ensar Halilovic, Xiaoyan Li, Jinsheng Liang, Yichen Cao, Daniel P Rakiec, David A Ruddy, Sebastien Jeay, Jens U Wuerthner, Noelito Timple, Shailaja Kasibhatla, Nanxin Li, Juliet A Williams, William R Sellers, Alan Huang, Fang Li
The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells...
April 20, 2017: ELife
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