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PIK3CA

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https://www.readbyqxmd.com/read/29352118/pi3k-mtor-inhibition-promotes-the-regression-of-experimental-vascular-malformations-driven-by-pik3ca-activating-mutations
#1
Laura di Blasio, Alberto Puliafito, Paolo Armando Gagliardi, Valentina Comunanza, Desiana Somale, Giulia Chiaverina, Federico Bussolino, Luca Primo
Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel-Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348864/the-macro-evolutionary-events-in-esophageal-squamous-cell-carcinoma
#2
Bin Yang, Ting Yan, Heyang Cui, Enwei Xu, Yanchun Ma, Caixia Cheng, Ling Zhang, Pengzhou Kong, Fang Wang, Yu Qian, Jian Yang, Yaoping Li, Hongyi Li, Yanghui Bi, Xiaoling Hu, Juan Wang, Bin Song, Jie Yang, Wei Gao, Jing Liu, Binbin Zou, Ruyi Shi, Yanyan Zhang, Haiyan Liu, Yiqian Liu, Yuanfang Zhai, Lu Chang, Yi Wang, Yingchun Zhang, Zhiwu Jia, Xing Chen, Yanfeng Xi, Guodong Li, Jianfang Liang, Jiansheng Guo, Shiping Guo, Rongsheng Zhang, Xiaolong Cheng, Yongping Cui
Understanding the evolutionary processes operative in cancer genome may provide insights into clinical outcome and drug-resistance. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. Here, we integrated published genomic sequencing data to investigate underlying evolutionary characteristics in ESCC. We found most of ESCC genomes were polyploidy with high genomic instability. Whole genome doubling that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348486/phase-i-dose-escalation-study-of-copanlisib-in-combination-with-gemcitabine-or-cisplatin-plus-gemcitabine-in-patients-with-advanced-cancer
#3
R D Kim, S R Alberts, C Peña, I Genvresse, A Ajavon-Hartmann, C Xia, A Kelly, J E Grilley-Olson
BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo...
January 18, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29346447/pik3ca-is-required-for-mouse-uterine-gland-development-and-pregnancy
#4
Hye Jin Chang, Hee Sung Shin, Tae Hoon Kim, Jung-Yoon Yoo, Hanna E Teasley, Jean J Zhao, Un-Hwan Ha, Jae-Wook Jeong
The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. The Pik3ca gene is mutated in a range of human cancers. It has been found to be oncogenic, and mutations lead to constitutive activation of the PI3K/AKT pathway. The expression patterns of PIK3CA proteins in the uterus of mice during early pregnancy indicate that it may play a role in the regulation of glandular epithelial cells, which is required to support uterine receptivity. To further investigate the role of Pik3ca in uterine function, Pik3ca was conditionally ablated only in the PGR-positive cells (Pgrcre/+Pik3caf/f; Pik3cad/d)...
2018: PloS One
https://www.readbyqxmd.com/read/29346025/linkage-of-metabolic-defects-to-activated-pik3ca-alleles-in-endothelial-cells-derived-from-lymphatic-malformation
#5
Kathryn Glaser, Peter Dickie, Derek Neilson, Alexander Osborn, Belinda Hsi Dickie
BACKGROUND: Lymphatic endothelial cells (LECs) derived from lymphatic malformations (LMs) bear activated PIK3CA alleles yet display an inflammatory gene expression profile. A basis for the inflammatory phenotype was sought by screening for coexisting somatic mutations. METHODS AND RESULTS: Fourteen independent LEC populations bearing activated PIK3CA alleles were isolated from LM. These were characterized by the expression of growth and inflammatory genes (VEGFC, IL-6, COX-2, IL-8, HO-1, E-SEL) by qRT-PCR...
January 18, 2018: Lymphatic Research and Biology
https://www.readbyqxmd.com/read/29345357/the-prognostic-value-of-pi3k-mutational-status-in-breast-cancer-a-meta-analysis
#6
N Sobhani, G Roviello, S P Corona, M Scaltriti, A Ianza, M Bortul, F Zanconati, D Generali
Breast cancer (BC) is the second most common cause of cancer-related deaths in women worldwide. The availability of reliable biomarkers of response/resistance to cancer treatments would benefit patients and clinicians allowing for a better selection of BC patients most likely to respond to a specific treatment. Phosphatidylinositol 3-kinase (PI3K) enzymes are involved in numerous cellular- functions and processes. The gene encoding for PI3K catalytic subunit p110α is mutated in 20-40% of BC. We performed a meta-analysis of the current literature on randomized clinical trials, investigating the role of PIK3CA mutational status as prognostic factor and predictor of response to anti-cancer treatments...
January 18, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29340043/clinical-significance-of-yap1-activation-in-head-and-neck-squamous-cell-carcinoma
#7
Young-Gyu Eun, Dongjin Lee, Young Chan Lee, Bo Hwa Sohn, Eui Hyun Kim, Sun Young Yim, Kee Hwan Kwon, Ju-Seog Lee
By analyzing the genomic data of head and neck squamous cell cancer (HNSCC), we investigated clinical significance of YAP1 activation. Copy number and mRNA expression of YAP1 were analyzed together to assess clinical relevance of YAP1 activation in HNSCC. The clinical significance of YAP1 activation was further validated in four independent test cohorts. We also assessed the correlation of YAP1 activation with genomic alterations such as copy number alteration, somatic mutation, and miRNA expression. The YAP1-activated (YA) subgroup showed worse prognosis for HNSCC as tested and validated in five cohorts...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29332342/study-on-the-association-between-pi3k-akt-mtor-signaling-pathway-gene-polymorphism-and-susceptibility-to-gastric-cancer
#8
Lei Qi, Kewen Sun, Yun Zhuang, Jing Yang, Jianping Chen
PURPOSE: Excessive activation of PI3K/AKT/mTOR signaling pathway is one of the most common changes in human cancers, and single nucleotide polymorphisms (SNPs) existing in its functional region can affect the occurrence process of a variety of cancers. This study aimed to screen out the SNPs associated with susceptibility to gastric cancer in the PI3K/AKT/mT0R signaling pathway. METHODS: In this case-control study, the tagging SNPs in the promoter region5'-UTR, exon region or 3'-UTR of PIK3CA, PIK3CB, PIK3R1, PIK3R2, PIK3R3, AKT1, AKT2, AKT3 and mTOR genes were screened out...
November 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/29331751/comprehensive-genomic-profiling-of-head-and-neck-squamous-cell-carcinoma-reveals-fgfr1-amplifications-and-tumour-genomic-alterations-burden-as-prognostic-biomarkers-of-survival
#9
C Dubot, V Bernard, M P Sablin, S Vacher, W Chemlali, A Schnitzler, G Pierron, K Ait Rais, N Bessoltane, E Jeannot, J Klijanienko, O Mariani, T Jouffroy, V Calugaru, C Hoffmann, M Lesnik, N Badois, F Berger, C Le Tourneau, M Kamal, I Bieche
BACKGROUND: We aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value. PATIENTS AND METHODS: We retrieved 122 HNSCC patients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis...
January 10, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29330617/characterizing-genomic-differences-of-human-cancer-stratified-by-the-tp53-mutation-status
#10
Mengyao Wang, Chao Yang, Xiuqing Zhang, Xiangchun Li
The key roles of the TP53 mutation in cancer have been well established. TP53 is the most frequently mutated gene, and its inactivation is widespread among human cancer types. However, the landscape of genomic alterations in human cancers stratified by the TP53 mutation has not yet been described. We obtained somatic mutation and copy number change data of 6551 regular-mutated samples from the Cancer Genome Atlas (TCGA) and compared significantly mutated genes (SMGs), copy number alterations, mutational signatures and mutational strand asymmetries between cancer samples with and without the TP53 mutation...
January 12, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29322935/classifying-cancer-genome-aberrations-by-their-mutually-exclusive-effects-on-transcription
#11
Jonathan B Dayton, Stephen R Piccolo
BACKGROUND: Malignant tumors are typically caused by a conglomeration of genomic aberrations-including point mutations, small insertions, small deletions, and large copy-number variations. In some cases, specific chemotherapies and targeted drug treatments are effective against tumors that harbor certain genomic aberrations. However, predictive aberrations (biomarkers) have not been identified for many tumor types and treatments. One way to address this problem is to examine the downstream, transcriptional effects of genomic aberrations and to identify characteristic patterns...
December 21, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/29322354/mutations-of-key-driver-genes-in-colorectal-cancer-progression-and-metastasis
#12
REVIEW
Dongdong Huang, Wenjie Sun, Yuwei Zhou, Peiwei Li, Fang Chen, Hanwen Chen, Dajing Xia, Enping Xu, Maode Lai, Yihua Wu, Honghe Zhang
The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis...
January 10, 2018: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29320776/v600e-braf-versus-non-v600e-braf-mutated-lung-adenocarcinomas-cytomorphology-histology-coexistence-of-other-driver-mutations-and-patient-characteristics
#13
Kevan J Salimian, Roghayeh Fazeli, Gang Zheng, David Ettinger, Zahra Maleki
OBJECTIVES: We analyzed the morphologic features and clinical characteristics of lung adenocarcinomas (ACAs) harboring mutated BRAF. STUDY DESIGN: A review of the histology/cytology of BRAF-mutated lung ACAs was performed at the Johns Hopkins Hospital from January 1, 2013, to January 1, 2015. Patient demographics, clinical history, and ACA morphology were assessed. RESULTS: Thirty-six cases were identified with a median age of 66 years (range 44-87), 58% (21/36) were female, and 94% (34/36) were current or former smokers...
January 11, 2018: Acta Cytologica
https://www.readbyqxmd.com/read/29320480/pharmacological-activation-of-rev-erbs-is-lethal-in-cancer-and-oncogene-induced-senescence
#14
Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J Kolar, Francesca Puca, Alan Saghatelian, Maksim V Plikus, Inder M Verma, Satchidananda Panda
The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock...
January 10, 2018: Nature
https://www.readbyqxmd.com/read/29317515/intratumoural-heterogeneity-may-hinder-precision-medicine-strategies-in-patients-with-clear-cell-renal-cell-carcinoma
#15
Maria Rosaria Raspollini, Ilaria Montagnani, Rodolfo Montironi, Francesca Castiglione, Guido Martignoni, Liang Cheng, Antonio Lopez-Beltran
Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status...
January 9, 2018: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29316426/clinical-sequencing-defines-the-genomic-landscape-of-metastatic-colorectal-cancer
#16
Rona Yaeger, Walid K Chatila, Marla D Lipsyc, Jaclyn F Hechtman, Andrea Cercek, Francisco Sanchez-Vega, Gowtham Jayakumaran, Sumit Middha, Ahmet Zehir, Mark T A Donoghue, Daoqi You, Agnes Viale, Nancy Kemeny, Neil H Segal, Zsofia K Stadler, Anna M Varghese, Ritika Kundra, Jianjiong Gao, Aijazuddin Syed, David M Hyman, Efsevia Vakiani, Neal Rosen, Barry S Taylor, Marc Ladanyi, Michael F Berger, David B Solit, Jinru Shia, Leonard Saltz, Nikolaus Schultz
Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29316280/giant-congenital-melanocytic-nevus-with-vascular-malformation-and-epidermal-cysts-associated-with-a-somatic-activating-mutation-in-braf
#17
Heather C Etchevers, Christian Rose, Birgit Kahle, Helmuth Vorbringer, Frédéric Fina, Pauline Heux, Irina Berger, Benjamin Schwarz, Stéphane Zaffran, Nicolas Macagno, Sven Krengel
Giant congenital melanocytic nevi may be symptomatically isolated, or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71-year old patient with a giant congenital melanocytic nevus of the lower back, buttocks and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts then developed within it...
January 5, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29312620/copy-number-variations-in-atypical-fibroxanthomas-and-pleomorphic-dermal-sarcomas
#18
Doris Helbig, Alexander Quaas, Cornelia Mauch, Sabine Merkelbach-Bruse, Reinhard Büttner, Michael Emberger, Marion Wobser, Vanessa Rüsseler, Katharina Pütz, Elke Binot, Jan Rehker, Jan Budczies, Michaela Angelika Ihle
Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are frequent cutaneous sarcomas typically arising on sun-exposed skin in elderly patients. In contrast to AFX, which generally do not recur after complete excision, PDS locally recur in up to 50% and metastasize in up to 20%. We recently detected characteristic UV-induced TP53 mutations as potential driver mutation in almost all PDS investigated as well as activating PIK3CA and RAS gene mutations in around one third of our tumors representing targets for personalized treatments in patients with unresectable or metastasized PDS...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29312580/therapeutic-strategies-and-genetic-profile-comparisons-in-small-cell-carcinoma-and-large-cell-neuroendocrine-carcinoma-of-the-lung-using-next-generation-sequencing
#19
Masaoki Ito, Yoshihiro Miyata, Shoko Hirano, Shingo Kimura, Fumiko Irisuna, Kyoko Ikeda, Kei Kushitani, Yasuhiro Tsutani, Daisuke Ueda, Norifumi Tsubokawa, Yukio Takeshima, Morihito Okada
Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29304903/locked-nucleic-acid-technology-for-highly-sensitive-detection-of-somatic-mutations-in-cancer
#20
Takayuki Ishige, Sakae Itoga, Kazuyuki Matsushita
The molecular diagnosis of the cancer mutational status is essential for modern clinical laboratory medicine. Mutations in EGFR, KRAS, BRAF, and PIK3CA genes are widely analyzed in solid tumors such as lung cancer, colorectal cancer, breast cancer, and melanoma. The allele-specific polymerase chain reaction, high-resolution melting, and Sanger sequencing are used for detecting and identifying gene mutations in many clinical laboratories. The locked nucleic acid (LNA) is a class of nucleic acid analogs that contain a methylene bridge connecting the 2' oxygen and 4' carbon in the ribose moiety...
2018: Advances in Clinical Chemistry
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