Avera Cancer Institute
Avera Cancer Institute
Dey N.,Avera Cancer Institute |
Dey N.,University of South Dakota |
Williams C.,Avera Cancer Institute |
Williams C.,University of South Dakota |
And 3 more authors.
Cancer Treatment Reviews | Year: 2017
As a genetic disease  cancer dysregulates key oncogenic pathways that influence cell growth, proliferation, survival, angiogenesis, and metastasis. Among the major determinants that enable cancer cells to acquire malignant traits are genomic diversity and instability. In the post human genome project era, cancer-specific genomic maps are redesigning tumor taxonomy. The treatment modalities, as well as the overall management of cancer as a disease in today's clinic, have started depending heavily on the molecular pathology of the individual tumor(s) in addition to the fundamental classification of cancers by histopathology. The enrichment tumor taxonomy by genomic morphology has also opened up the possibilities for genomics-driven drug development. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control tumorigenic pathways. One primary goal of precision cancer medicine is to make clinical decisions based on genomic/proteomic data, which can identify a target or targets for therapy, and subsequent inevitable development of therapeutic resistance to the drug. The ability to exploit tumor genetic information for its full clinical potential has only recently become evident. Over the last decade, the convergence of discovery, technology, and therapeutic development has created an unparalleled opportunity to test the hypothesis that systematic knowledge of genomic and proteomic information from individual tumor(s) may significantly improve clinical outcomes for many patients with unmanageable tumor burden. This review presents the signaling logic behind the ground rules for the rational approach to the genomics-driven precision medicine. © 2017 Elsevier Ltd
Blais E.M.,University of Virginia |
Rawls K.D.,University of Virginia |
Dougherty B.V.,University of Virginia |
Li Z.I.,University of Virginia |
And 5 more authors.
Nature Communications | Year: 2017
The laboratory rat has been used as a surrogate to study human biology for more than a century. Here we present the first genome-scale network reconstruction of Rattus norvegicus metabolism, iRno, and a significantly improved reconstruction of human metabolism, iHsa. These curated models comprehensively capture metabolic features known to distinguish rats from humans including vitamin C and bile acid synthesis pathways. After reconciling network differences between iRno and iHsa, we integrate toxicogenomics data from rat and human hepatocytes, to generate biomarker predictions in response to 76 drugs. We validate comparative predictions for xanthine derivatives with new experimental data and literature-based evidence delineating metabolite biomarkers unique to humans. Our results provide mechanistic insights into species-specific metabolism and facilitate the selection of biomarkers consistent with rat and human biology. These models can serve as powerful computational platforms for contextualizing experimental data and making functional predictions for clinical and basic science applications. © The Author(s) 2017.
Willis S.,Avera Cancer Institute |
Byrd G.,North Carolina State University |
Johnson B.D.,Arizona State University
Computer | Year: 2017
Challenges and competitions offer a compelling platform for engaging students and lifelong learners in new technologies and skill development. This special issue explores a sampling of challenge-based approaches to education and community outreach. © 1970-2012 IEEE.
Willis S.,Avera Cancer Institute
Computer | Year: 2017
New editor Scooter Willis reflects on his journey to becoming an electrical engineer and how we can promote the work of students who've found their passion. © 2017 IEEE.
Willis S.,Avera Cancer Institute
Computer | Year: 2017
Recent advances in deep learning for image recognition have spawned numerous challenge-based learning competitions in which participants can use a low-cost GPU graphics card to accomplish goals that required expensive resources in the recent past. Students are encouraged to explore this exciting new field of research by entering these competitions. © 1970-2012 IEEE.
De P.,Avera Cancer Institute |
De P.,University of South Dakota |
Sun Y.,Avera Cancer Institute |
Carlson J.H.,Avera Cancer Institute |
And 5 more authors.
Neoplasia (United States) | Year: 2014
Phosphoinositide 3-kinase (PI3K) pathway, in addition to its pro-proliferative and antiapoptotic effects on tumor cells, contributes to DNA damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mammalian target of rapamycin (mTOR) inhibitor, would induce an efficient antitumor effect in BRCA-competent triple negative breast cancer (TNBC) model when combined with ABT888 and carboplatin. Mechanism-based in vitro studies demonstrated that GDC-0980 treatment alone or in combination led to DNA damage (increased pγH2AXS139; Western blot, immunofluorescence), gain in poly ADP-ribose (PAR), and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin with a time-dependent 1) decrease in proliferation signals (pAKTT308/S473, pP70S6KT421/S424, pS6RPS235/236), PAR/poly(ADP-ribose) polymerase (PARP) ratios, PAR/pγH2AX ratios, live/dead cell ratios, cell cycle progression, and three-dimensional clonogenic growths and 2) increase in apoptosis markers (cleaved caspases 3 and 9, a pro-apoptotic BH3-only of Bcl-2 family (BIM), cleaved PARP, annexin V). The combination was effective in vitro in BRCA-wild-type PIK3CA-H1047R-mutated BT20 and PTEN-null HCC70 cells. The combination blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, CD31, phosphorylated vascular endothelial growth factor receptor, pS6RPS235/236, and p4EBP1T37/46 as well as an increase in cleaved caspase 3 immunohistochemistry (IHC) levels. Interestingly, a combination with GDC-0941, a pan-PI3K inhibitor, failed to block the tumor growth in MDA-MB231. Results demonstrate that the dual inhibition of PI3K and mTOR regulates DDR. In a BRCA-competent model, GDC-0980 enhanced the antitumor activity of ABT888 plus carboplatin by inhibiting both tumor cell proliferation and tumor-induced angiogenesis along with an increase in the tumor cell apoptosis. This is the first mechanism-based study to demonstrate the integral role of the PI3K-AKTmTOR pathway in DDR-mediated antitumor action of PARP inhibitor in TNBC. © 2014 Neoplasia Press, Inc. All rights reserved.
Chastain M.,Washington State University |
Zhou Q.,Washington State University |
Shiva O.,Washington State University |
Whitmore L.,Washington State University |
And 7 more authors.
Cell Reports | Year: 2016
The telomeric CTC1/STN1/TEN1 (CST) complex has been implicated in promoting replication recovery under replication stress at genomic regions, yet its precise role is unclear. Here, we report that STN1 is enriched at GC-rich repetitive sequences genome-wide in response to hydroxyurea (HU)-induced replication stress. STN1 deficiency exacerbates the fragility of these sequences under replication stress, resulting in chromosome fragmentation. We find that upon fork stalling, CST proteins form distinct nuclear foci that colocalize with RAD51. Furthermore, replication stress induces physical association of CST with RAD51 in an ATR-dependent manner. Strikingly, CST deficiency diminishes HU-induced RAD51 foci formation and reduces RAD51 recruitment to telomeres and non-telomeric GC-rich fragile sequences. Collectively, our findings establish that CST promotes RAD51 recruitment to GC-rich repetitive sequences in response to replication stress to facilitate replication restart, thereby providing insights into the mechanism underlying genome stability maintenance. © 2016 The Author(s)
Abramovitz M.,Avera Cancer Institute
Current Opinion in Oncology | Year: 2016
PURPOSE OF REVIEW: In this review, we summarize recent and current biomarkers and assays that are being considered in the selection of suitable patients with estrogen receptor-positive early breast cancer for extended (years 5–10) adjuvant endocrine therapy (AET). RECENT FINDINGS: Women with estrogen receptor-positive early-stage breast cancer (65% of cases) continue to have late risk for distant recurrence extending beyond 5 years from surgery. Recent large trials have consistently demonstrated improvement for prolonging endocrine therapy. However, endocrine therapy can cause women bothersome side effects and can negatively impact quality of life. Determining which patients remain at risk for disease recurrence and predicting which of these patients would derive the most benefit from the addition of extended AET are key issues faced by patients and oncologists today. A number of predictive molecular assays have been developed and are being considered as tools to be used in guiding the implementation of adjuvant systemic therapy. SUMMARY: The future holds much promise and as more information and understanding is acquired, treatment regimens will increasingly incorporate clinically validated biomarker assays in the decision-making process that will be of great benefit to these patients. Proving clinical utility, though, will ultimately decide their implementation. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Whitmore L.S.,Washington State University |
Ye P.,Washington State University |
Ye P.,Avera Cancer Institute
PLoS ONE | Year: 2015
Metabolic pathways are increasingly postulated to be vital in programming cell fate, including stemness, differentiation, proliferation, and apoptosis. The commitment to meiosis is a critical fate decision for mammalian germ cells, and requires a metabolic derivative of vitamin A, retinoic acid (RA). Recent evidence showed that a pulse of RA is generated in the testis of male mice thereby triggering meiotic commitment. However, enzymes and reactions that regulate this RA pulse have yet to be identified. We developed a mouse germ cellspecific metabolic network with a curated vitamin A pathway. Using this network, we implemented flux balance analysis throughout the initial wave of spermatogenesis to elucidate important reactions and enzymes for the generation and degradation of RA. Our results indicate that primary RA sources in the germ cell include RA import from the extracellular region, release of RA from binding proteins, and metabolism of retinal to RA. Further, in silico knockouts of genes and reactions in the vitamin A pathway predict that deletion of Lipe, hormone-sensitive lipase, disrupts the RA pulse thereby causing spermatogenic defects. Examination of other metabolic pathways reveals that the citric acid cycle is the most active pathway. In addition, we discover that fatty acid synthesis/oxidation are the primary energy sources in the germ cell. In summary, this study predicts enzymes, reactions, and pathways important for germ cell commitment to meiosis. These findings enhance our understanding of the metabolic control of germ cell differentiation and will help guide future experiments to improve reproductive health. Copyright: © 2015 Whitmore, Ye.
Buchwald D.,University of Washington |
Muller C.,University of Washington |
Bell M.,University of South Dakota |
Bell M.,Sanford Health |
And 2 more authors.
Health Education and Behavior | Year: 2013
Background. American Indian women in the Northern Plains have a high incidence of cervical cancer. We assessed attitudes on vaccination against human papillomavirus (HPV) in this population. Method. In partnership with two tribal communities, from 2007 to 2009, we surveyed women 18 to 65 years old attending two reservation clinics (n = 118 and n = 76) and an urban clinic in the same region serving primarily White women (n = 158) on HPV knowledge, vaccine familiarity, and willingness to vaccinate children against HPV. We used chi-square tests and binary logistic regression to compare groups and identify correlates of willingness to vaccinate. Results. American Indian women were less knowledgeable about HPV than White women (p <.001), especially its role in cervical cancer. Willingness to vaccinate children was differentially distributed across the three clinic samples (p <.001), but this association did not persist after adjusting for demographics and HPV knowledge. Among all samples, more correct answers to HPV knowledge questions was the only factor positively correlated with willingness to vaccinate (odds ratios = 1.2-1.5; p <.00-.05). Conclusions. These findings underscore the importance of locally relevant educational interventions to increase HPV vaccination rates among American Indian women. © 2013 Society for Public Health Education.