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https://www.readbyqxmd.com/read/29666004/biallelic-tp53-gain-of-function-mutations-in-rapidly-progressing-solid-tumors
#1
Christopher M Sande, Brian Chang, Varun Monga, Aaron D Bossler, Deqin Ma
Recent studies are discovering TP53 mutations with gain of function (GOF) properties that promote tumorigenesis via a variety of mechanisms. To our knowledge, all reported compound mutations are allelic. We identified two patients with biallelic GOF TP53 mutations in their tumors and a third with allelic compound variants. The correlation with p53 expression was also examined. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and mutational analysis was performed using Ion AmpliSeq™Cancer HotSpot Panel V2...
April 2018: Cancer Genetics
https://www.readbyqxmd.com/read/29665004/thiostrepton-degrades-mutant-p53-by-eliciting-an-autophagic-response-in-sw480-cells
#2
Dhanya Kalathil, Manu Prasad, Maharrish Chelladurai, Samu John, Asha S Nair
Mutations in p53 gene are one of the hallmarks of tumor development. Specific targeting of mutant p53 protein has a promising role in cancer therapeutics. Our preliminary observation showed destabilization of mutant p53 protein in SW480, MiaPaCa and MDAMB231 cell lines upon thiostrepton treatment. In order to elucidate the mechanism of thiostrepton triggered mutant p53 degradation, we explored the impact of proteasome inhibition on activation of autophagy. Combined treatment of thiostrepton and cycloheximide/chloroquine prevented the degradation of mutant p53 protein, reinforcing autophagy as the means of mutant p53 destabilization...
April 17, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29664741/primary-vaginal-gastric-type-adenocarcinoma-and-vaginal-adenosis-exhibiting-gastric-differentiation-report-of-a-series-with-detailed-immunohistochemical-analysis
#3
Richard Wing-Cheuk Wong, Michelle Moore, Karen L Talia, Raji Ganesan, W Glenn McCluggage
So-called gastric-type adenocarcinoma and related premalignant lesions have been characterized in the cervix, but similar lesions are not widely recognized in the vagina. We report a series of 11 vaginal glandular lesions exhibiting gastric differentiation, comprising 5 cases of adenocarcinoma and 6 of adenosis. All cases occurred in adults (aged 33 to 69) with no known history of diethylstilboestrol exposure. The vaginal adenocarcinomas exhibited morphologic features identical to gastric-type adenocarcinoma of the cervix, but 1 case additionally demonstrated basaloid and sarcomatoid components, which have not been previously reported in cervical gastric-type adenocarcinoma...
April 16, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29662649/-18-fdg-pet-ct-and-molecular-markers-to-predict-response-to-neoadjuvant-chemotherapy-and-outcome-in-her2-negative-advanced-luminal-breast-cancers-patients
#4
Patricia de Cremoux, Lucie Biard, Brigitte Poirot, Philippe Bertheau, Luis Teixeira, Jacqueline Lehmann-Che, Fatiha A Bouhidel, Pascal Merlet, Marc Espié, Matthieu Resche-Rigon, Christos Sotiriou, David Groheux
Background: The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662640/potential-therapeutic-targets-of-tp53-gene-in-the-context-of-its-classically-canonical-functions-and-its-latest-non-canonical-functions-in-human-cancer
#5
REVIEW
Toshimichi Tanaka, Masahiko Watanabe, Keishi Yamashita
In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function. TP53 gene mutation is a major genomic aberration in various human cancers and is a critical event in the multi-step carcinogenesis process. TP53 mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network. TP53 gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29661172/mth1-deficiency-selectively-increases-non-cytotoxic-oxidative-dna-damage-in-lung-cancer-cells-more-bad-news-than-good
#6
Hussein H K Abbas, Kheloud M H Alhamoudi, Mark D Evans, George D D Jones, Steven S Foster
BACKGROUND: Targeted therapies are based on exploiting cancer-cell-specific genetic features or phenotypic traits to selectively kill cancer cells while leaving normal cells unaffected. Oxidative stress is a cancer hallmark phenotype. Given that free nucleotide pools are particularly vulnerable to oxidation, the nucleotide pool sanitising enzyme, MTH1, is potentially conditionally essential in cancer cells. However, findings from previous MTH1 studies have been contradictory, meaning the relevance of MTH1 in cancer is still to be determined...
April 16, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29660836/final-results-of-a-phase-2-open-label-study-of-indisulam-idarubicin-and-cytarabine-in-patients-with-relapsed-or-refractory-acute-myeloid-leukemia-and-high-risk-myelodysplastic-syndrome
#7
Rita Assi, Hagop M Kantarjian, Tapan M Kadia, Naveen Pemmaraju, Elias Jabbour, Nitin Jain, Naval Daver, Zeev Estrov, Taisuke Uehara, Takashi Owa, Jorge E Cortes, Gautam Borthakur
BACKGROUND: Indisulam possesses anticancer properties through down-regulation of various cell-cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors. METHODS: The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome...
April 16, 2018: Cancer
https://www.readbyqxmd.com/read/29660231/plakoglobin-restores-tumor-suppressor-activity-of-p53-r175h-mutant-by-sequestering-the-oncogenic-potential-of-%C3%AE-catenin
#8
Mahsa Alaee, Kristina Nool, Manijeh Pasdar
The tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins not only have lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H ) with well-documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signalling protein and a paralog of β-catenin. Unlike β-catenin that has oncogenic function via its role in Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor...
April 16, 2018: Cancer Science
https://www.readbyqxmd.com/read/29660164/high-grade-panin-presenting-with-localized-stricture-of-the-main-pancreatic-duct-a-clinicopathological-and-molecular-study-of-10-cases-suggests-a-clue-for-the-early-detection-of-pancreatic-cancer
#9
Masataka Yokode, Masayuki Akita, Kohei Fujikura, Mi-Ju Kim, Yukiko Morinaga, Seiichi Yoshikawa, Takuro Terada, Hiroshi Matsukiyo, Takuma Tajiri, Shiho Abe-Suzuki, Tomoo Itoh, Seung-Mo Hong, Yoh Zen
AIMS: This study aimed to identify the pathological features of high-grade PanIN that presents with imaging-detectable abnormalities. METHODS AND RESULTS: Ten cases of isolated, main-duct, high-grade PanIN as the primary clinical presentation were identified. All patients presented with stenosis of the main pancreatic duct, with 2 being associated with extensive upstream duct dilatation (>5 mm in diameter). Pancreatic juice cytology suggested adenocarcinoma in all 7 cases examined...
April 16, 2018: Histopathology
https://www.readbyqxmd.com/read/29652801/the-crystal-structure-of-the-r280k-mutant-of-human-p53-explains-the-loss-of-dna-binding
#10
Ana Sara Gomes, Filipa Trovão, Benedita Andrade Pinheiro, Filipe Freire, Sara Gomes, Carla Oliveira, Lucília Domingues, Maria João Romão, Lucília Saraiva, Ana Luísa Carvalho
The p53 tumor suppressor is widely found to be mutated in human cancer. This protein is regarded as a molecular hub regulating different cell responses, namely cell death. Compelling data have demonstrated that the impairment of p53 activity correlates with tumor development and maintenance. For these reasons, the reactivation of p53 function is regarded as a promising strategy to halt cancer. In the present work, the recombinant mutant p53R280K DNA binding domain (DBD) was produced for the first time, and its crystal structure was determined in the absence of DNA to a resolution of 2...
April 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29651325/the-relationship-between-tp53-gene-status-and-carboxylesterase-2-expression-in-human-colorectal-cancer
#11
Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Konomi Mizuguchi, Mikumi Endo, Ituro Inoue, Koichi Sato, Takehiko Yokomizo
Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1...
2018: Disease Markers
https://www.readbyqxmd.com/read/29644616/genetic-aberrations-of-the-k-ras-proto-oncogene-and-in-bladder-cancer-in-relation-to-pesticide-exposure
#12
Diaa A Hameed, Heba A Yassa, Michael N Agban, Randa T Hanna, Ahmed M Elderwy, Mohamed A Zwaita
In Egypt, bladder cancer is one of the most popular cancer, accounting for 31% of all cancer cases. It ranks first in males about 16.2% of male cancer. The incidence in rural areas among males is near 32 per 100,000. The exact etiology of bladder cancer is still unknown; K-ras gene is known as a critical DNA target for chemical carcinogens as a pesticide. Some occupational hazard exposure is thought to be directly genotoxic, while others might enhance the mutagenicity and carcinogenicity of directly acting genotoxic agents...
April 12, 2018: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29643855/targeting-sphingosine-kinase-isoforms-effectively-reduces-growth-and-survival-of-neoplastic-mast-cells-with-d816v-kit
#13
Geethani Bandara, Rosa Muñoz-Cano, Araceli Tobío, Yuzhi Yin, Hirsh D Komarow, Avanti Desai, Dean D Metcalfe, Ana Olivera
Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29629647/immunohistochemical-detection-of-p53-pten-rb-and-p16-in-canine-osteosarcoma-using-tissue-microarray
#14
Duncan S Russell, Lauren Jaworski, William C Kisseberth
Although inactivating mutations of tumor suppressor genes are well described in cell lines of canine osteosarcoma (OS), expression of tumor suppressor proteins in spontaneous disease is poorly characterized. We determined the immunohistochemical expression of p53, PTEN, Rb, and p16 in a large cohort of dogs with OS. Formalin-fixed, paraffin-embedded samples of canine OS were analyzed retrospectively. Primary tumor samples from 145 dogs, collected between 2003 and 2008, were evaluated by tissue microarray. Streptavidin-biotin complex immunohistochemistry was performed using monoclonal antibodies for Rb and PTEN and polyclonal antibodies for p16 and p53...
April 1, 2018: Journal of Veterinary Diagnostic Investigation
https://www.readbyqxmd.com/read/29627078/the-roles-of-jak2-in-dna-damage-and-repair-in-the-myeloproliferative-neoplasms-opportunities-for-targeted-therapy
#15
REVIEW
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29625247/added-value-of-50-gene-panel-sequencing-to-distinguish-multiple-primary-lung-cancers-from-pulmonary-metastases-a-systematic-investigation
#16
Paul Roepman, Alexandra Ten Heuvel, Karen C Scheidel, Tobias Sprong, Danielle A M Heideman, Cees A Seldenrijk, Gerarda J M Herder, J Alain Kummer
Differentiation between multiple primary lung cancers or pulmonary metastases has important implications for staging, prognosis, and treatment strategies. Clinical and immuno-histopathological criteria have been standardized; however, a substantial number of cases remain difficult to classify. Using next-generation sequencing it is now possible to improve classification of multiple lung cancer lesions. This study systematically investigated the value of routine morphological and immunohistochemical characteristics, p53 protein expression, TP53 mutation analysis, and 50-gene panel sequencing on 111 lesions from 50 patients with multiple lung lesions...
April 3, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29625050/oncogenic-signaling-pathways-in-the-cancer-genome-atlas
#17
Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K Chatila, Augustin Luna, Konnor C La, Sofia Dimitriadoy, David L Liu, Havish S Kantheti, Sadegh Saghafinia, Debyani Chakravarty, Foysal Daian, Qingsong Gao, Matthew H Bailey, Wen-Wei Liang, Steven M Foltz, Ilya Shmulevich, Li Ding, Zachary Heins, Angelica Ochoa, Benjamin Gross, Jianjiong Gao, Hongxin Zhang, Ritika Kundra, Cyriac Kandoth, Istemi Bahceci, Leonard Dervishi, Ugur Dogrusoz, Wanding Zhou, Hui Shen, Peter W Laird, Gregory P Way, Casey S Greene, Han Liang, Yonghong Xiao, Chen Wang, Antonio Iavarone, Alice H Berger, Trever G Bivona, Alexander J Lazar, Gary D Hammer, Thomas Giordano, Lawrence N Kwong, Grant McArthur, Chenfei Huang, Aaron D Tward, Mitchell J Frederick, Frank McCormick, Matthew Meyerson, Eliezer M Van Allen, Andrew D Cherniack, Giovanni Ciriello, Chris Sander, Nikolaus Schultz
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt...
April 5, 2018: Cell
https://www.readbyqxmd.com/read/29624814/eif2%C3%AE-a-subunit-of-translation-initiation-factor-eif2-is-a-potential-therapeutic-target-for-non-small-cell-lung-cancer
#18
Ichidai Tanaka, Mitsuo Sato, Toshio Kato, Daiki Goto, Tomohiko Kakumu, Ayako Miyazawa, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Yoshitaka Sekido, Luc Girard, John D Minna, Lauren A Byers, John V Heymach, Kevin R Coombes, Masashi Kondo, Yoshinori Hasegawa
To identify novel therapeutic targets for non-small cell lung cancer (NSCLC), we conducted an integrative study in the following three stages: (1) identification of potential target gene(s) through shRNA functional screens in two independent NSCLC cell lines, (2) validation of the clinical relevance of identified gene(s) using public databases, and (3) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi-genome wide shRNA screen was performed in NCI-H358 cells, and was integrated with data from our previous screen in NCI-H460 cells...
April 6, 2018: Cancer Science
https://www.readbyqxmd.com/read/29624782/a-molecular-pathological-study-of-four-cases-of-ciliated-muconodular-papillary-tumors-of-the-lung
#19
Toshiaki Kataoka, Koji Okudela, Mai Matsumura, Hideaki Mitsui, Takehisa Suzuki, Chihiro Koike, Tomoe Sawazumi, Shigeaki Umeda, Yoko Tateishi, Shoji Yamanaka, Yoshihiro Ishikawa, Hiromasa Arai, Michihiko Tajiri, Kenichi Ohashi
Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung...
April 6, 2018: Pathology International
https://www.readbyqxmd.com/read/29620284/enrichment-and-mutation-detection-of-circulating-tumor-cells-from-blood-samples
#20
Ruqin Kou, Jian Zhao, Priya Gogoi, Shannon Carskadon, Will Chow, Clara Hwang, Nallasivam Palanisamy, Conrad Leung, Yixin Wang
The potential of circulating tumor cells (CTCs) in the diagnosis and prognosis of cancer patients has become increasingly attractive. However, molecular analysis of CTCs is hindered by low sensitivity and a high level of background leukocytes in CTC enrichment technologies. We have developed a novel protocol using a microfluidic device, which enriches and retrieves CTCs from blood samples. The principle of CTC capturing is that tumor cells are larger and less deformable than normal blood cells. To evaluate the potential of utilizing Celsee PREP100 in CTC molecular analysis, we prepared prostate cancer cell lines PC3 and LNCaP, retrieved the captured cells and analyzed them using PCR amplicon sequencing...
March 30, 2018: Oncology Reports
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