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Tuhina Mazumdar, Lauren A Byers, Patrick Kwok Shing Ng, Gordon B Mills, Shaohua Peng, Lixia Diao, You-Hong Fan, Katherine Stemke-Hale, John V Heymach, Jeffrey N Myers, Bonnie S Glisson, Faye M Johnson
The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose of this study was to extend recent discoveries regarding the PI3K/AKT/mTOR pathway in HNSCC by more broadly examining potential biomarkers of response, by examining pathway inhibitors with a diverse range of targets, and by defining mechanisms of resistance and potential combination therapies...
November 2014: Molecular Cancer Therapeutics
Ian R Watson, Liren Li, Peter K Cabeceiras, Mozhdeh Mahdavi, Tony Gutschner, Giannicola Genovese, Guocan Wang, Zhuangna Fang, James M Tepper, Katherine Stemke-Hale, Kenneth Y Tsai, Michael A Davies, Gordon B Mills, Lynda Chin
Following mutations in BRAF and NRAS, the RAC1 c.85C>T single-nucleotide variant (SNV) encoding P29S amino acid change represents the next most frequently observed protein-coding hotspot mutation in melanoma. However, the biologic and clinical significance of the RAC1 P29S somatic mutation in approximately 4% to 9% of patients remains unclear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (vemurafenib and dabrafenib). Enforced expression of RAC1 P29S in sensitive BRAF-mutant melanoma cell lines confers resistance manifested by increased viability, decreased apoptosis, and enhanced tumor growth in vivo upon treatment with RAF inhibitors...
September 1, 2014: Cancer Research
Rachel Eyre, Ian Harvey, Katherine Stemke-Hale, Thomas W J Lennard, Alison Tyson-Capper, Annette P Meeson
The majority of deaths in ovarian cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self-renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA-binding dye Hoechst 33342 through ATP-binding cassette (ABC) transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers...
October 2014: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kimberly C Wiegand, Bryan T Hennessy, Samuel Leung, Yemin Wang, Zhenlin Ju, Mollianne McGahren, Steve E Kalloger, Sarah Finlayson, Katherine Stemke-Hale, Yiling Lu, Fan Zhang, Michael S Anglesio, Blake Gilks, Gordon B Mills, David G Huntsman, Mark S Carey
BACKGROUND: Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC...
2014: BMC Cancer
Sangjo Shim, Katherine Stemke-Hale, Jamileh Noshari, Frederick F Becker, Peter R C Gascoyne
The number of circulating tumor cells (CTCs) found in blood is known to be a prognostic marker for recurrence of primary tumors, however, most current methods for isolating CTCs rely on cell surface markers that are not universally expressed by CTCs. Dielectrophoresis (DEP) can discriminate and manipulate cancer cells in microfluidic systems and has been proposed as a molecular marker-independent approach for isolating CTCs from blood. To investigate the potential applicability of DEP to different cancer types, the dielectric and density properties of the NCI-60 panel of tumor cell types have been measured by dielectrophoretic field-flow fractionation (DEP-FFF) and compared with like properties of the subpopulations of normal peripheral blood cells...
2013: Biomicrofluidics
Sangjo Shim, Katherine Stemke-Hale, Apostolia M Tsimberidou, Jamileh Noshari, Thomas E Anderson, Peter R C Gascoyne
Circulating tumor cells (CTCs) are prognostic markers for the recurrence of cancer and may carry molecular information relevant to cancer diagnosis. Dielectrophoresis (DEP) has been proposed as a molecular marker-independent approach for isolating CTCs from blood and has been shown to be broadly applicable to different types of cancers. However, existing batch-mode microfluidic DEP methods have been unable to process 10 ml clinical blood specimens rapidly enough. To achieve the required processing rates of 10(6) nucleated cells/min, we describe a continuous flow microfluidic processing chamber into which the peripheral blood mononuclear cell fraction of a clinical specimen is slowly injected, deionized by diffusion, and then subjected to a balance of DEP, sedimentation and hydrodynamic lift forces...
2013: Biomicrofluidics
Greg Feldman, Emily Dunn, Carrie Stemke, Kelly Bell, Jeff Greeson
Distress tolerance (DT) is a proposed transdiagnostic factor in psychopathology, yet sources of individual differences in DT are largely unknown. The present study examined mindfulness and rumination facets as predictors of persistence on a standardized DT task (mirror tracing). Acting with awareness (a facet of mindfulness) and reflection (a potentially adaptive form of rumination) predicted increased DT. Increased task-induced skin conductance reactivity predicted decreased DT. These results held after controlling for task skill and subjective and heart rate reactivity...
January 1, 2014: Personality and Individual Differences
Kosuke Yoshihara, Maria Shahmoradgoli, Emmanuel Martínez, Rahulsimham Vegesna, Hoon Kim, Wandaliz Torres-Garcia, Victor Treviño, Hui Shen, Peter W Laird, Douglas A Levine, Scott L Carter, Gad Getz, Katherine Stemke-Hale, Gordon B Mills, Roel G W Verhaak
Infiltrating stromal and immune cells form the major fraction of normal cells in tumour tissue and not only perturb the tumour signal in molecular studies but also have an important role in cancer biology. Here we describe 'Estimation of STromal and Immune cells in MAlignant Tumours using Expression data' (ESTIMATE)--a method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples. ESTIMATE scores correlate with DNA copy number-based tumour purity across samples from 11 different tumour types, profiled on Agilent, Affymetrix platforms or based on RNA sequencing and available through The Cancer Genome Atlas...
2013: Nature Communications
Michael J Overman, Jiexin Zhang, Scott Kopetz, Michael Davies, Zhi-Qin Jiang, Jiang Zhi-Qin, Katherine Stemke-Hale, Petra Rümmele, Christian Pilarsky, Robert Grützmann, Stanley Hamilton, Rosa Hwang, James L Abbruzzese, Gauri Varadhachary, Bradley Broom, Huamin Wang
BACKGROUND: Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis. METHODS: We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2...
2013: PloS One
Jérôme Lane, Paul J McLaren, Lucy Dorrell, Kevin V Shianna, Amanda Stemke, Kimberly Pelak, Stephen Moore, Johannes Oldenburg, Maria Teresa Alvarez-Roman, Anne Angelillo-Scherrer, Francoise Boehlen, Paula H B Bolton-Maggs, Brigit Brand, Deborah Brown, Elaine Chiang, Ana Rosa Cid-Haro, Bonaventura Clotet, Peter Collins, Sara Colombo, Judith Dalmau, Patrick Fogarty, Paul Giangrande, Alessandro Gringeri, Rathi Iyer, Olga Katsarou, Christine Kempton, Philip Kuriakose, Judith Lin, Mike Makris, Marilyn Manco-Johnson, Dimitrios A Tsakiris, Javier Martinez-Picado, Evelien Mauser-Bunschoten, Anne Neff, Shinichi Oka, Lara Oyesiku, Rafael Parra, Kristiina Peter-Salonen, Jerry Powell, Michael Recht, Amy Shapiro, Kimo Stine, Katherine Talks, Amalio Telenti, Jonathan Wilde, Thynn Thynn Yee, Steven M Wolinsky, Jeremy Martinson, Shehnaz K Hussain, Jay H Bream, Lisa P Jacobson, Mary Carrington, James J Goedert, Barton F Haynes, Andrew J McMichael, David B Goldstein, Jacques Fellay
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals...
May 1, 2013: Human Molecular Genetics
Katherine Stemke-Hale, Kristy Shipman, Isidora Kitsou-Mylona, David G de Castro, Vicky Hird, Robert Brown, James Flanagan, Hani Gabra, Gordon B Mills, Roshan Agarwal, Mona El-Bahrawy
Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform, we investigated 160 mutations/polymorphisms in 33 genes involved in cell signaling, apoptosis, angiogenesis, cell cycle regulation and cellular senescence. Of 52 tumors analyzed, 33 were serous, 18 mucinous and 1 endometrioid...
April 2013: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Peter R C Gascoyne, Sangjo Shim, Jamileh Noshari, Frederick F Becker, Katherine Stemke-Hale
Although dielectrophoresis (DEP) has great potential for addressing clinical cell isolation problems based on cell dielectric differences, a biological basis for predicting the DEP behavior of cells has been lacking. Here, the dielectric properties of the NCI-60 panel of tumor cell types have been measured by dielectrophoretic (DEP) field-flow fractionation, correlated with the exterior morphologies of the cells during growth, and compared with the dielectric and morphological characteristics of the subpopulations of peripheral blood...
April 2013: Electrophoresis
Han Liang, Lydia W T Cheung, Jie Li, Zhenlin Ju, Shuangxing Yu, Katherine Stemke-Hale, Turgut Dogruluk, Yiling Lu, Xiuping Liu, Chao Gu, Wei Guo, Steven E Scherer, Hannah Carter, Shannon N Westin, Mary D Dyer, Roeland G W Verhaak, Fan Zhang, Rachel Karchin, Chang-Gong Liu, Karen H Lu, Russell R Broaddus, Kenneth L Scott, Bryan T Hennessy, Gordon B Mills
Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis...
November 2012: Genome Research
Eran Hodis, Ian R Watson, Gregory V Kryukov, Stefan T Arold, Marcin Imielinski, Jean-Philippe Theurillat, Elizabeth Nickerson, Daniel Auclair, Liren Li, Chelsea Place, Daniel Dicara, Alex H Ramos, Michael S Lawrence, Kristian Cibulskis, Andrey Sivachenko, Douglas Voet, Gordon Saksena, Nicolas Stransky, Robert C Onofrio, Wendy Winckler, Kristin Ardlie, Nikhil Wagle, Jennifer Wargo, Kelly Chong, Donald L Morton, Katherine Stemke-Hale, Guo Chen, Michael Noble, Matthew Meyerson, John E Ladbury, Michael A Davies, Jeffrey E Gershenwald, Stephan N Wagner, Dave S B Hoon, Dirk Schadendorf, Eric S Lander, Stacey B Gabriel, Gad Getz, Levi A Garraway, Lynda Chin
Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations...
July 20, 2012: Cell
Justin M Balko, Rebecca S Cook, David B Vaught, María G Kuba, Todd W Miller, Neil E Bhola, Melinda E Sanders, Nara M Granja-Ingram, J Joshua Smith, Ingrid M Meszoely, Janine Salter, Mitch Dowsett, Katherine Stemke-Hale, Ana M González-Angulo, Gordon B Mills, Joseph A Pinto, Henry L Gómez, Carlos L Arteaga
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status...
July 2012: Nature Medicine
Libero Santarpia, Yuan Qi, Katherine Stemke-Hale, Bailiang Wang, Elliana J Young, Daniel J Booser, Frankie A Holmes, Joyce O'Shaughnessy, Beth Hellerstedt, John Pippen, Tatiana Vidaurre, Henry Gomez, Vicente Valero, Gabriel N Hortobagyi, W Fraser Symmans, Giulia Bottai, Angelo Di Leo, Ana M Gonzalez-Angulo, Lajos Pusztai
The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers. These tumor specimens typically consisted of >80% neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology...
July 2012: Breast Cancer Research and Treatment
K M Britton, R Eyre, I J Harvey, K Stemke-Hale, D Browell, T W J Lennard, A P Meeson
Recurrent metastatic breast cancer may arise in part due to the presence of drug resistant adult stem cells such as Side Population (SP) cells, whose phenotype has been demonstrated to be due to the expression of ABCG2. We hypothesised that SP may be identified in Fine Needle Aspirates (FNAs) and their presence may be determined by expression of ABCG2 in breast tumours. SP and non-side population cells (NSP) were isolated using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux and analysed for expression of ABCG2 and chemoresistance...
October 1, 2012: Cancer Letters
Siqing Fu, Bryan T Hennessy, Chaan S Ng, Zhenlin Ju, Kevin R Coombes, Judith K Wolf, Anil K Sood, Charles F Levenback, Robert L Coleman, John J Kavanagh, David M Gershenson, Maurie Markman, Kristine Dice, Adrienne Howard, Jane Li, Yang Li, Katherine Stemke-Hale, Mary Dyer, Edward Atkinson, Ed Jackson, Vikas Kundra, Razelle Kurzrock, Robert C Bast, Gordon B Mills
OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies...
July 2012: Gynecologic Oncology
Nayoung Kim, Ningning He, Changsik Kim, Fan Zhang, Yiling Lu, Qinghua Yu, Katherine Stemke-Hale, Joel Greshock, Richard Wooster, Sukjoon Yoon, Gordon B Mills
A systematic understanding of genotype-specific sensitivity or resistance to anticancer agents is required to provide improved patient therapy. The availability of an expansive panel of annotated cancer cell lines enables comparative surveys of associations between genotypes and compounds of various target classes. Thus, one can better predict the optimal treatment for a specific tumor. Here, we present a statistical framework, cell line enrichment analysis (CLEA), to associate the response of anticancer agents with major cancer genotypes...
November 15, 2012: International Journal of Cancer. Journal International du Cancer
Névine Eltonsy, Vivian Gabisi, Xuesong Li, K Blair Russe, Gordon B Mills, Katherine Stemke-Hale
Cell lines are an important tool in understanding all aspects of cancer growth, development, metastasis and tumor cell death. There has been a dramatic increase in the number of cell lines and diversity of the cancers they represent; however, misidentification and cross-contamination of cell lines can lead to erroneous conclusions. One method that has gained favor for authenticating cell lines is the use of short tandem repeats (STR) to generate a unique DNA profile. The challenge in validating cell lines is the requirement to compare the large number of existing STR profiles against cell lines of interest, particularly when considering that the profiles of many cell lines have drifted over time and original samples are not available...
September 15, 2012: International Journal of Cancer. Journal International du Cancer
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