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https://www.readbyqxmd.com/read/28748401/system-biology-approach-to-identify-potential-receptor-for-targeting-cancer-and-biomolecular-interaction-studies-of-indole-2-1-a-isoquinoline-derivative-as-anticancerous-drug-candidate-against-it
#1
Devender Arora, Ritu Chaudhary, Ajeet Singh
Cancer is a public health concern which is spreading throughout the world. Different approaches have been employed to combat this disease. System biology approach has been used to understand the molecular mechanisms of drugs targeting cancer cell's receptor which have opened-up a window to develop effective drugs for it. We have demonstrated biomolecular interaction studies using the rational drug design of indole[2,1-a]isoquinoline derivative as a potent inhibitor against identified cancerous protein PIK3CA -a catalytic sub-unit of PI3K family protein-and compared its affinity with FDA approved drugs for receptors such as dactolisib, idelalisib, and several others such afatinib, avastin, ceritinib and crizotinib, etc...
July 26, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28746882/a-landscape-of-therapeutic-cooperativity-in-kras-mutant-cancers-reveals-principles-for-controlling-tumor-evolution
#2
Grace R Anderson, Peter S Winter, Kevin H Lin, Daniel P Nussbaum, Merve Cakir, Elizabeth M Stein, Ryan S Soderquist, Lorin Crawford, Jim C Leeds, Rachel Newcomb, Priya Stepp, Catherine Yip, Suzanne E Wardell, Jennifer P Tingley, Moiez Ali, Mengmeng Xu, Meagan Ryan, Shannon J McCall, Autumn J McRee, Christopher M Counter, Channing J Der, Kris C Wood
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28737257/unilateral-vestibular-schwannoma-and-meningiomas-in-a-patient-with-pik3ca-related-segmental-overgrowth-co-occurrence-of-mosaicism-for-two-rare-disorders
#3
John R Mills, Ann M Moyer, Benjamin R Kipp, Andrzej B Poplawski, Ludwine M Messiaen, Dusica Babovic-Vuksanovic
A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as three small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome...
July 24, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28734796/clonal-composition-of-human-ovarian-cancer-based-on-copy-number-analysis-reveals-a-reciprocal-relation-with-oncogenic-mutation-status
#4
Kazuko Sakai, Masayo Ukita, Jeanette Schmidt, Longyang Wu, Marco De Velasco, Alan Roter, Luis Jevons, Kazuto Nishio, Masaki Mandai
Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor...
July 19, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28734031/downregulation-of-dec1-contributes-to-the-neurotoxicity-induced-by-mpp-by-suppressing-pi3k-akt-gsk3%C3%AE-pathway
#5
Zhu Zhu, Yu-Wen Wang, Ding-Hao Ge, Ming Lu, Wei Liu, Jing Xiong, Gang Hu, Xiao-Ping Li, Jian Yang
AIM: Differentiated embryonic chondrocyte gene 1 (DEC1) is involved in the neuronal differentiation and development. The aim of this study is to investigate the role of DEC1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP(+) )-induced PD model. METHODS: The location of DEC1 and tyrosine hydroxylase (TH)-positive neurons were detected by immunofluorescence. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse subacute model of PD was established to evaluate the change of DEC1 expression in midbrain...
July 21, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28732357/profiling-cancer-related-gene-mutations-in-oral-squamous-cell-carcinoma-from-japanese-patients-by-targeted-amplicon-sequencing
#6
Takafumi Nakagaki, Miyuki Tamura, Kenta Kobashi, Ryota Koyama, Hisayo Fukushima, Tomoko Ohashi, Masashi Idogawa, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino, Yasushi Sasaki
Somatic mutation analysis is a standard practice in the study of human cancers to identify mutations that cause therapeutic sensitization and resistance. We performed comprehensive genomic analyses that used PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Forty-seven oral squamous cell carcinoma (OSCC) samples and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverage of the entire coding regions of 409 cancer-related genes (covered regions: 95...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28731050/genomic-abnormalities-in-invasive-endocervical-adenocarcinoma-correlate-with-pattern-of-invasion-biologic-and-clinical-implications
#7
Anjelica Hodgson, Yutaka Amemiya, Arun Seth, Matthew Cesari, Bojana Djordjevic, Carlos Parra-Herran
The pattern-based classification system for HPV-related endocervical adenocarcinoma, which classifies tumors based on the destructiveness of stromal invasion, is predictive of the risk of nodal metastases and adverse outcome. Previous studies have demonstrated clinically important molecular alterations in endocervical adenocarcinoma, including KRAS and PIK3CA mutations; however, correlation between the molecular landscape and pathological variables including pattern of invasion has not been thoroughly explored...
July 21, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28731047/targeted-next-generation-sequencing-supports-epidermoid-metaplasia-of-the-esophagus-as-a-precursor-to-esophageal-squamous-neoplasia
#8
Aatur D Singhi, Christina A Arnold, Dora M Lam-Himlin, Marina N Nikiforova, Lysandra Voltaggio, Marcia I Canto, Kevin M McGrath, Elizabeth A Montgomery
Esophageal epidermoid metaplasia is a rare condition that involves the proximal-to-middle third of the esophagus. It is sharply demarcated and defined histologically by epithelial hyperplasia, a prominent granular cell layer, and superficial hyperorthokeratosis. In addition, preliminary studies have suggested an association between esophageal epidermoid metaplasia and esophageal squamous neoplasia (squamous dysplasia and esophageal squamous cell carcinoma). To further characterize esophageal epidermoid metaplasia and better define its relationship to squamous neoplasia of the esophagus, we performed targeted next-generation sequencing on uninvolved esophageal squamous mucosa and matching esophageal epidermoid metaplasia specimens from 18 patients...
July 21, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28731042/molecular-alterations-of-coexisting-thyroid-papillary-carcinoma-and-anaplastic-carcinoma-identification-of-tert-mutation-as-an-independent-risk-factor-for-transformation
#9
Naoki Oishi, Tetsuo Kondo, Aya Ebina, Yukiko Sato, Junko Akaishi, Rumi Hino, Noriko Yamamoto, Kunio Mochizuki, Tadao Nakazawa, Hiroshi Yokomichi, Koichi Ito, Yuichi Ishikawa, Ryohei Katoh
Thyroid papillary carcinoma is the most common endocrine neoplasm and generally carries a favorable prognosis. However, a small subset of papillary carcinomas transforms into anaplastic carcinoma, an undifferentiated cancer with a dismal prognosis. Recent studies using next-generation sequencing revealed the genomic landscape of papillary carcinoma and anaplastic carcinoma. However, risk factors for anaplastic transformation in papillary carcinoma remain obscure. In the present study, we investigated molecular alterations of papillary carcinoma and anaplastic carcinoma components in 27 tumors in which anaplastic carcinoma coexisted with antecedent papillary carcinoma...
July 21, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28726194/association-between-the-prevalence-of-somatic-mutations-in-pik3ca-gene-in-tumors-and-clinical-and-morphological-characteristics-of-breast-cancer-patients
#10
M L Filipenko, N A Os'kina, I A Oskorbin, O V Mishukova, L K Ovchinnikova, E S Gershtein, N E Kushlinskii
The presence of activating somatic mutations in codons 542 and 545 of exon 9 (p.E542K c.1624G>A and p.E545K c.1633G>A) and in codon 1047 of exon 20 (p.H1047R c.3140A>G and p.H1047L c.3140A>T) of PIK3CA gene encoding catalytic p110α-subunit of phosphatidylinositol-3-kinase was studied in tumors of 473 breast cancer patients by multiplex allele-specific real-time PCR. Fifty-eight (12.3%) different mutations were found. An increase in the frequency of PIK3CA gene mutations with disease progression (from 2...
June 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28725277/sabcs-2016-systemic-therapy-for-metastatic-breast-cancer
#11
REVIEW
Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial...
2017: Memo
https://www.readbyqxmd.com/read/28718916/the-genetic-landscape-of-endometrial-clear-cell-carcinomas
#12
Deborah F DeLair, Kathleen A Burke, Pier Selenica, Raymond S Lim, Sasinya N Scott, Sumit Middha, Abhinita S Mohanty, Donavan T Cheng, Michael F Berger, Robert A Soslow, Britta Weigelt
Clear cell carcinoma of the endometrium is a rare type of endometrial cancer generally associated with an aggressive clinical behavior. Here we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs) and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs...
July 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28706137/assessment-of-pancreatic-neuroendocrine-tumor-cytologic-genotype-diversity-to-guide-personalized-medicine-using-a-custom-gastroenteropancreatic-next-generation-sequencing-panel
#13
Ferga C Gleeson, Jesse S Voss, Benjamin R Kipp, Sarah E Kerr, John S Van Arnam, John R Mills, Cherisse A Marcou, Amber R Schneider, Zheng Jin Tu, Michael R Henry, Michael J Levy
BACKGROUND: Recent genetic studies have highlighted that alterations in MEN1, chromatin remodeling genes, and mammalian target of rapamycin (mTOR) pathway genes are the most frequent molecular events identified in pancreas neuroendocrine tumors (pNETs). The prognostic or predictive impact of these biomarkers and other less frequently observed aberrations, i.e. PTEN, TSC2 and PIK3CA are relatively unknown. The aims of this targeted next generation sequencing (NGS) study were to assess tumor cytology genotype diversity, to survey for potential adverse prognostic biomarkers and the prevalence of mTOR pathway variants...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700273/pik3ca-oncogenic-mutations-in-neoadjuvant-treatments-for-breast-cancer
#14
Giovanni Corso, Paolo Veronesi, Mattia Intra, Virgilio Sacchini, Viviana Galimberti
No abstract text is available yet for this article.
July 2017: Biomarkers in Medicine
https://www.readbyqxmd.com/read/28698100/adenosquamous-gallbladder-carcinoma-multigene-hotspot-mutational-profiling-reveals-a-monoclonal-origin-of-the-two-components
#15
Francesca Galuppini, Roberta Salmaso, Elisa Valentini, Cristiano Lanza, Isacco Maretto, Donato Nitti, Massimo Rugge, Matteo Fassan
Adenosquamous carcinoma (ASC) of the gallbladder is a rare malignant tumor that is characterized by a coexisting of glandular and squamous components. In a case of ASC, we performed hotspot multigene mutational profiling of 164 hotspot regions of eleven cancer-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53) in the two microdissected components. Both tumor phenotypes resulted characterized by a p.E542K point mutation in the PIK3CA gene, whereas adenocarcinoma component revealed also a TP53 Q331* homozygous stop mutation...
August 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28694672/benefit-of-everolimus-in-treatment-of-an-intrahepatic-cholangiocarcinoma-patient-with-a-pik3ca-mutation
#16
Ji-Lai Bian, Mei-Mei Wang, En-Juan Tong, Jing Sun, Ming Li, Zhi-Bo Miao, Yan-Lin Li, Bai-Hong Zhu, Jia-Jia Xu
Intrahepatic cholangiocarcinoma (ICC) is a relatively rare form of liver cancer with a poor prognosis. The therapeutic options for patients with advanced ICC are limited and usually ineffective. There is currently no approved targeted therapy for ICC, although accumulating evidence supports inhibition of the PI3K/Akt/mTOR signaling pathway as a promising therapeutic strategy in the treatment of ICC. Here, we report a patient with stage IV ICC harboring a PIK3CA mutation who responded well to the mTOR inhibitor everolimus...
June 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28694015/predicting-treatment-resistance-and-relapse-through-circulating-dna
#17
Emma Beddowes, Stephen J Sammut, Meiling Gao, Carlos Caldas
The use of circulating DNA(ctDNA) to provide a non-invasive, personalised genomic snapshot of a patients' tumour has huge potential. Over the past five years this area of research has gained huge momentum. A number of studies in metastatic breast cancer have shown the potential of ctDNA to predict prognosis and treatment response using ctDNA. Further developments have included deeper sequencing using whole exome and shallow whole genome approaches which has the potential to identify new mutations and chromosomal copy number changes which appear upon resistance to treatment...
July 7, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28693246/genetic-alterations-in-japanese-extrahepatic-biliary-tract-cancer
#18
Rei Noguchi, Kiyoshi Yamaguchi, Tsuneo Ikenoue, Yumi Terakado, Yasunori Ohta, Naohide Yamashita, Osamu Kainuma, Sana Yokoi, Yoshiaki Maru, Hiroki Nagase, Yoichi Furukawa
Biliary tract cancer (BTC) is one of the most devastating types of malignant neoplasms worldwide. However, the mechanisms underlying the development and progression of BTC remain unresolved. BTC includes extrahepatic bile duct carcinoma (EBDC), gallbladder carcinoma (GBC) and ampulla of Vater carcinoma (AVC), named according to the location of the tumor. Although genetic alterations of intrahepatic cholangiocarcinoma have been investigated, those of EBDC, GBC and AVC have not yet been fully understood. The present study analyzed somatic mutations of 50 cancer-associated genes in 27 Japanese BTC cells, including: 11 EBDC, 14 GBC and 2 AVC...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28692045/impact-of-histone-demethylase-kdm3a-dependent-ap-1-transactivity-on-hepatotumorigenesis-induced-by-pi3k-activation
#19
T Nakatsuka, K Tateishi, Y Kudo, K Yamamoto, H Nakagawa, H Fujiwara, R Takahashi, K Miyabayashi, Y Asaoka, Y Tanaka, H Ijichi, Y Hirata, M Otsuka, M Kato, J Sakai, M Tachibana, H Aburatani, Y Shinkai, K Koike
Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28688230/mutation-landscape-and-intra-tumor-heterogeneity-of-two-manecs-of-the-esophagus-revealed-by-multi-region-sequencing
#20
Wenqing Yuan, Zhen Liu, Wanjun Lei, Li Sun, Haijun Yang, Yu Wang, Shweta Ramdas, Xiao Dong, Ruiping Xu, Hong Cai, Jun Z Li, Yang Ke
Mixed adenoneuroendocrine carcinoma (MANEC) in the esophagus is an infrequent but highly malignant cancer with few known genomic alterations. We conducted whole-exome sequencing and whole-genome SNP genotyping for 4-6 tumor subregions and 5-6 adjacent normal tissue sites and 1-3 lymph node metastases in two esophageal MANECs to detect somatic mutations and copy number alterations, and to explore their spatial heterogeneity and underlying clonal structure. TP53 mutation, RB1 deletion or LOH, and PIK3CA, PTEN, KRAS, SOX2, DVL3, TP63 amplification appeared in all regions in both tumors...
June 27, 2017: Oncotarget
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