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Molecular Oncology

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https://www.readbyqxmd.com/read/29160958/prognostic-value-of-an-immunohistochemical-signature-in-patients-with-esophageal-squamous-cell-carcinoma-undergoing-radical-esophagectomy
#1
Jin Meng, Junhua Zhang, Yingjie Xiu, Yan Jin, Jiaqing Xiang, Yongzhan Nie, Shen Fu, Kuaile Zhao
Here, we aimed to identify an immunohistochemical (IHC)-based classifier as a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC). A cohort of 235 patients with ESCC undergoing radical esophagectomy (with complete clinical and pathological information) were enrolled in the study. Using the least absolute shrinkage and selection operator (LASSO) regression model, we extracted six IHC features associated with progression-free survival (PFS) and then built a classifier in the discovery cohort (n=141)...
November 21, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29130642/dual-inhibition-of-dnmts-and-ezh2-can-overcome-both-intrinsic-and-acquired-resistance-of-myeloma-cells-to-imids-in-a-cereblon-independent-manner
#2
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Emil Hermansen, Casey O'Connel, Peter Gimsing, Gangning Liang, Kirsten Grønbaek
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide- (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29130628/characterization-of-genetic-intratumor-heterogeneity-in-colorectal-cancer-and-matching-patient-derived-spheroid-cultures
#3
Sigrid Salling Árnadóttir, Maria Jeppesen, Philippe Lamy, Jesper Bertram Bramsen, Iver Nordentoft, Michael Knudsen, Søren Vang, Mogens Rørbaek Madsen, Ole Thastrup, Jacob Thastrup, Claus Lindbjerg Andersen
Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, the other half was used for DNA and RNA purification...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29124875/emerging-functions-of-the-egfr-in-cancer
#4
REVIEW
Sara Sigismund, Daniele Avanzato, Letizia Lanzetti
The physiological function of the Epidermal Growth Factor Receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms have also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, since its amplification or secondary mutations have been found to arise under drug pressure...
November 10, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29120535/mirna-profiling-identifies-deregulated-mirnas-associated-with-osteosarcoma-development-and-time-to-metastasis-in-two-large-cohorts
#5
Gitte Brinch Andersen, Alice Knudsen, Henrik Hager, Lise Lotte Hansen, Jörg Tost
Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays...
November 9, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29117471/tumor-adjacent-tissue-co-expression-profile-analysis-reveals-pro-oncogenic-ribosomal-gene-signature-for-prognosis-of-resectable-hepatocellular-carcinoma
#6
O V Grinchuk, S P Yenamandra, R Iyer, M Singh, H K Lee, K H Lim, P K H Chow, V A Kuznetsov
Currently, molecular markers are not used whilst determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). Here, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT), and adjacent non-malignant tissues (AT), that typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods...
November 8, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29112787/dabrafenib-inhibits-the-growth-of-braf-wt-cancers-through-cdk16-and-nek9-inhibition
#7
Manali Phadke, Lily L Remsing Rix, Inna Smalley, Annamarie T Bryant, Yunting Luo, Harshani R Lawrence, Braydon J Schaible, Y Ann Chen, Uwe Rix, Keiran S M Smalley
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival...
November 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29094484/degradation-of-ampk-%C3%AE-1-sensitizes-braf-inhibitor-resistant-melanoma-cells-to-arginine-deprivation
#8
Ying-Ying Li, Chunjing Wu, Sumedh S Shah, Shu-Mei Chen, Medhi Wangpaichitr, Macus T Kuo, Lynn G Feun, Xiaoqing Han, Miguel Suarez, Jeffrey Prince, Niramol Savaraj
Melanomas harboring BRAF mutation (V600E) are known to recur frequently following treatment with BRAF inhibitors (BRAFi) despite a high initial response rate. Our previous study has uncovered that BRAFi-resistant melanoma (BR) cells are vulnerable to arginine deprivation. It has been reported that naïve melanoma cells undergo autophagy and re-express argininosuccinate synthetase 1 (ASS1) to enable them to synthesize arginine for survival when encountering arginine deprivation. Abolishing these two factors in BR cells confers sensitivity to arginine deprivation...
November 2, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29094504/a-link-between-the-fibroblast-growth-factor-axis-and-the-mir-16-family-reveals-potential-new-treatment-combinations-in-mesothelioma
#9
Karin Schelch, Michaela B Kirschner, Marissa Williams, Yuen Yee Cheng, Nico van Zandwijk, Michael Grusch, Glen Reid
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with very limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth. Several FGFs and FGF receptors (FGFRs) are predicted targets of the miR-15/16 family, which is downregulated in MPM. The aim of this study was to explore the link between the miR-15/16 family and the FGF-axis in MPM. Expression analyses via RT-qPCR showed downregulation of the FGF-axis after transfection with miR-15/16 mimics...
November 1, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29080283/tcf21-hypermethylation-regulates-renal-tumor-cell-clonogenic-proliferation-and-migration
#10
S L Gooskens, T D Klasson, H Gremmels, I Logister, R Pieters, E J Perlman, R H Giles, M M van den Heuvel-Eibrink
We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor. TCF21 is a transcription factor involved in tubular epithelial development of the kidney and is a candidate tumor suppressor. As there are no in vitro models of CCSK, we employed a well-established clear cell renal cell carcinoma (ccRCC) cell line, 786-O, which also manifests high methylation at the TCF21 promoter, with consequent low TCF21 expression...
October 27, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29063679/estrogen-receptor-mutations-and-splice-variants-determined-in-liquid-biopsies-from-metastatic-breast-cancer-patients
#11
Nick Beije, Anieta M Sieuwerts, Jaco Kraan, Ngoc M Van, Onstenk Wendy, Silvia R Vitale, Michelle van der Vlugt-Daane, Luc Y Dirix, Anja Brouwer, Paul Hamberg, Felix E de Jongh, Agnes Jager, Caroline M Seynaeve, Maurice P H M Jansen, John A Foekens, John W M Martens, Stefan Sleijfer
Mutations and splice variants in the estrogen receptor (ER) gene, ESR1, may yield endocrine resistance in metastatic breast cancer (MBC) patients. These putative endocrine resistance markers are likely to emerge during treatment and therefore its detection in liquid biopsies, such as circulating tumor cells (CTCs) and cell-free DNA (cfDNA), is of great interest. This research aimed to determine if ESR1 mutations and splice variants occur more frequently in CTCs of MBC patients progressing on endocrine treatment...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29063678/molecular-profiling-and-combinatorial-activity-of-cct068127-a-potent-cdk2-and-cdk9-inhibitor
#12
Steven R Whittaker, Clare Barlow, Mathew P Martin, Caterina Mancusi, Steve Wagner, Annette Self, Elaine Barrie, Robert Te Poele, Swee Sharp, Nathan Brown, Stuart Wilson, Wayne Jackson, Peter M Fischer, Paul A Clarke, Michael I Walton, Edward McDonald, Julian Blagg, Martin Noble, Michelle D Garrett, Paul Workman
Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29063676/xiap-inhibition-sensitizes-acute-myeloid-leukemia-cells-response-to-trail-and-chemotherapy-through-potentiated-induction-of-pro-apoptotic-machinery
#13
Jianbiao Zhou, Xiao Lu, Tuan Zea Tan, Wee-Joo Chng
Acute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5-year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X-Linked Inhibitor of Apoptosis (XIAP), one of the inhibitor of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (abbreviation: RO-BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29032615/regulation-of-the-prometastatic-neuregulin-mmp13-axis-by-src-family-kinases-therapeutic-implications
#14
Ana Orive-Ramos, Samuel Seoane, Alberto Ocaña, Atanasio Pandiella, Juan Carlos Montero
Metastatic dissemination of tumor cells is responsible for the fatal outcome of breast cancer. Therefore, understanding the mechanisms involved in dissemination is essential for the development of new therapeutic strategies to prevent metastasis. One mechanism involved in metastatic dissemination of breast cancer cells is dependent on control of the production of matrix metalloproteinases by the neuregulins (NRGs). The NRGs are polypeptide factors that act by binding to the ErbB/HER subfamily of receptor tyrosine kinases...
October 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29024497/a-mission-oriented-approach-to-cancer-in-europe-a-joint-mission-vision-2030
#15
Julio E Celis, Dainius Pavalkis
By combining innovative prevention and treatment strategies in a sustainable state-of-the-art virtual European cancer centre/infrastructure, it will be possible by 2030 to achieve a long-term survival of 3 out of 4 cancer patients in countries with well-developed healthcare systems. Furthermore, the proposed concerted actions will pave the way to handling the economic and social inequalities in countries with less developed systems. These efforts will also ensure that in the long-run, science-driven and social innovations reach patients across the healthcare systems in Europe...
October 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29024380/cell-to-cell-communication-micrornas-as-hormones
#16
REVIEW
Recep Bayraktar, Katrien Van Roosbroeck, George A Calin
Mammalian cells can release different types of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies. Accumulating evidence suggests that EVs play a role in cell-to-cell communication within the tumor microenvironment. EVs' components, such as proteins, non-coding RNAs [microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)], messenger RNAs (mRNAs), DNA, and lipids, can mediate paracrine signaling in the tumor microenvironment. Recently, miRNAs encapsulated in secreted EVs have been identified in the extracellular space...
October 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28981199/microrna-661-modulates-redox-and-metabolic-homeostasis-in-colon-cancer
#17
Marta Gómez de Cedrón, Rebeca Acín Pérez, Ruth Sánchez-Martínez, Susana Molina, Jesús Herranz, Jaime Feliu, Guillermo Reglero, Jose Antonio Enríquez, Ana Ramírez de Molina
Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA-661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. miR661 induces a global increase in reactive oxygen species (ROS), specifically in mitochondrial superoxide anions (SO(-) ), which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration...
October 5, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28972307/role-of-brf1-interaction-with-er%C3%AE-and-significance-of-its-overexpression-in-human-breast-cancer
#18
Zeng Fang, Yunfeng Yi, Ganggang Shi, Songqi Li, Songlin Chen, Ying Lin, Zhi Li, Zhimin He, Wen Li, Shuping Zhong
TFIIB-related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase-dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC...
October 3, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28972304/dr5-cbl-b-c-cbl-traf2-complex-inhibits-trail-induced-apoptosis-by-promoting-traf2-mediated-polyubiquitination-of-caspase-8-in-gastric-cancer-cells
#19
Ling Xu, Ye Zhang, Xiujuan Qu, Xiaofang Che, Tianshu Guo, Ce Li, Rui Ma, Yibo Fan, Yanju Ma, Kezuo Hou, Danni Li, Xuejun Hu, Bofang Liu, Ruoxi Yu, Hongfei Yan, Jing Gong, Yunpeng Liu
Ubiquitination of caspase-8 regulates TNF-related apoptosis-inducing ligand (TRAIL) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase-8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL-triggered apoptosis is unclear. In this study, DR5, casitas B-lineage lymphoma-b (Cbl-b)/c-Cbl, and TRAF2 formed a complex in TRAIL-resistant gastric cancer cells, and Cbl-b and c-Cbl were the critical adaptors linking DR5 and TRAF2...
October 3, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28922540/ape1-ref-1-knockdown-in-pancreatic-ductal-adenocarcinoma-characterizing-gene-expression-changes-and-identifying-novel-pathways-using-single-cell-rna-sequencing
#20
Fenil Shah, Emery Goossens, Nadia M Atallah, Michelle Grimard, Mark R Kelley, Melissa L Fishel
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1 knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA Sequencing to identify differentially expressed genes in relation to APE1 protein levels within the cell...
September 18, 2017: Molecular Oncology
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