tbuckley/cabot-search huggingface dataset:
Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17
Authors: Dong G. Hu, Luke A. Selth, Gerard A. Tarulli, Robyn Meech, Dhilushi Wijayakumara, Apichaya Chanawong, Roslin Russell, Carlos Caldas, Jessica L.L. Robinson, Jason S. Carroll, Wayne D. Tilley, Peter I. Mackenzie, Theresa E. Hickey
Journal: Cancer Research (2016)

Abstract Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3′ to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα+ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881–93. ©2016 AACR.
Abstract 4526: Proscillaridin A effects on chromatin modifications and oncogene degradation in acute lymphoblastic leukemia
Authors: Gregory Armaos, Simon Jacques-Ricard, Elodie Da Costa, Annie Beaudry, Noël J-M Raynal.
Journal: Cancer Research (2016)

Abstract Acute lymphoblastic leukemia (ALL) represents approximately 25% of all pediatric cancers diagnosed every year. In about 80% of cases, pediatric patients will attain an event-free 5-year survival. Unfortunately, patients who are resistant to treatment or who relapse have a poor prognosis. Hence, novel therapeutic approaches are necessary to increase survival rates. Epigenetic alterations, such as DNA methylation and histone modifications, are involved in disease development, progression, and in particular, resistance to treatment. These reversible alterations represent additional targets in ALL. Recently, we discovered candidate epigenetic drugs in FDA-approved drug libraries. We hypothesize that one drug in particular, the cardiac glycoside proscillaridin A, has both epigenetic and anti-cancerous properties in preclinical models of ALL and can therefore be repositioned for the treatment of the disease. To test our hypothesis, we treated two ALL cell lines Nalm-6 (pre-B ALL) and Molt-4 (T-ALL) in vitro with clinically relevant concentrations of proscillaridin A and analyzed cell growth, cell cycle, gene expression and chromatin modifications. We observed dose-dependent growth inhibition in all cell lines, with IC50 values of 3.0 and 2.3 nM in Nalm-6 and Molt-4, respectively. Our results using BrdU staining indicate a block in the G2/M phase of the cell cycle. By western blot, we detected a reduction in histone acetylation levels and in histone modifying enzymes CBP and Tip60, as well as the c-myc oncogene. These promising results illustrate the perspective of using the cardiac glycoside proscillaridin A as a novel epigenetic drug for the treatment of relapsed or refractory ALL. Citation Format: Gregory Armaos, Simon Jacques-Ricard, Elodie Da Costa, Annie Beaudry, Noël J-M Raynal. Proscillaridin A effects on chromatin modifications and oncogene degradation in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4526.
Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells
Authors: Yu Wang, Dilani C. Dehigaspitiya, Paul M. Levine, Adam A. Profit, Michael Haugbro, Keren Imberg-Kazdan, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian
Journal: Cancer Research (2016)

Abstract Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure–activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator–peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124–32. ©2016 AACR.
Dietary Diversity, Diet Cost, and Incidence of Type 2 Diabetes in the United Kingdom: A Prospective Cohort Study
Authors: Annalijn I. Conklin, Pablo Monsivais, Kay-Tee Khaw, Nicholas J. Wareham, Nita G. Forouhi
Journal: PLoS Medicine (2016)

Background Diet is a key modifiable risk factor for multiple chronic conditions, including type 2 diabetes (T2D). Consuming a range of foods from the five major food groups is advocated as critical to healthy eating, but the association of diversity across major food groups with T2D is not clear and the relationship of within-food-group diversity is unknown. In addition, there is a growing price gap between more and less healthy foods, which may limit the uptake of varied diets. The current study had two aims: first, to examine the association of reported diversity of intake of food groups as well as their subtypes with risk of developing T2D, and second, to estimate the monetary cost associated with dietary diversity. Methods and Findings A prospective study of 23,238 participants in the population-based EPIC-Norfolk cohort completed a baseline Food Frequency Questionnaire in 1993–1997 and were followed up for a median of 10 y. We derived a total diet diversity score and additional scores for diversity within each food group (dairy products, fruits, vegetables, meat and alternatives, and grains). We used multivariable Cox regression analyses for incident diabetes (892 new cases), and multivariable linear regression for diet cost. Greater total diet diversity was associated with 30% lower risk of developing T2D (Hazard ratio [HR] 0.70 [95% CI 0.51 to 0.95]) comparing diets comprising all five food groups to those with three or fewer, adjusting for confounders including obesity and socioeconomic status. In analyses of diversity within each food group, greater diversity in dairy products (HR 0.61 [0.45 to 0.81]), fruits (HR 0.69 [0.52 to 0.90]), and vegetables (HR 0.67 [0.52 to 0.87]) were each associated with lower incident diabetes. The cost of consuming a diet covering all 5 food groups was 18% higher (£4.15/day [4.14 to 4.16]) than one comprising three or fewer groups. Key limitations are the self-reported dietary data and the binary scoring approach whereby some food groups contained both healthy and less healthy food items. Conclusions A diet characterized by regular consumption of all five food groups and by greater variety of dairy, fruit, and vegetable subtypes, appears important for a reduced risk of diabetes. However, such a diet is more expensive. Public health efforts to prevent diabetes should include food price policies to promote healthier, more varied diets.
Abstract SY28-01: Immunotherapy in combination with neoadjuvant therapy and immune-related adverse events
Authors: Mark J. Smyth, Jing Liu, Stephen J. Blake, Michele WL Teng.
Journal: Cancer Research (2016)

Abstract Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with conventional therapies, such as surgery, has not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice to compare the therapeutic power of neoadjuvant versus adjuvant immunotherapies in the context of primary tumor resection. Therapies, including Treg depletion, anti-PD-1 or anti-PD1/anti-CD137 combinations were evaluated. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAEs) in humans. Prolonged T regulatory cell (Treg) depletion in tumor bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab treated patients, while transient Treg depletion and anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily provoked following treatment with additional immunomodulatory antibodies. This platform has been used to compare a number of promising immunotherapies. Citation Format: Mark J. Smyth, Jing Liu, Stephen J. Blake, Michele WL Teng. Immunotherapy in combination with neoadjuvant therapy and immune-related adverse events. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY28-01.
Successful ex-vivo normothermic machine perfusion and viability testing of discarded human donor livers
Authors: Sanna Op den Dries, Negin Karimian, Michael E. Sutton, Andrie Westerkamp, Maarten Nijsten, Annette S. Gouw, Janneke Wiersema-Buist, Ton Lisman, Henri G. Leuvenink, Robert J. Porte
Journal: Hepatology (2012)
Expression of anaplastic lymphoma kinase (ALK) in patients with non-small cell lung cancer (NSCLC) in the South of Russia.
Authors: Inna Arnoldovna Novikova, Evgeniya M. Nepomnyashchaya, Aleksey Yurievich Maksimov, Elena Petrovna Ulianova, Yury N. Lazutin, Pavel A. Anistratov, Sergey P. Pyltsin
Journal: Journal of Clinical Oncology (2015)

e18536 Background: The purpose of the study was to analyze the effectiveness of immunohistochemistry (IHC) in detecting ALK in tissues of NSCLC. Methods: 50 patients with NSCLC living in the South of Russia, aged 46-78 years (mean age 56±2.4), were recruited. Rabbit Monoclonal Primary Antibodies VENTANA anti-ALK (D5F3) were used to detect ALK expression. Staining was performed using VENTANA BenchMark GX immunostainer and tissue samples of primary NSCLC patients, including material from resections and bronchial biopsy, formalin-fixed and paraffin-embedded using OptiView DAB IHC Detection Kit and OptiView Amplification Kit. ALK-status was considered positive when an intense granular cytoplasmic staining was detected (any percentage of positive tumor cells). Results: The study was performed in NSCLC tissue samples after tumor was confirmed to be EGFR-negative by molecular genetic study. An even intense granular cytoplasmic staining was detected in 4% (2 of 50 patients). 6% (3 of 50 patients) – heterogeneous staining, intense in some areas and weak staining or its absence in the others. We considered these cases as ALK-positive ones. The tumors were sent for the FISH test to confirm their positive status. Absence of staining was detected in 90% of the cases (45 of 50 patients), ALK-status was determined as negative. Conclusions: The rate of ALK detection in NSCLC patients in the South of Russia by IHC was 10%. Thus, the method is sensitive and specific enough for determining ALK-status of tumor and can serve as an alternative to the FISH test for administration of targeted agents to NSCLC patients.
Abstract 5223: A novel molecular inversion probe (MIP) system for the streamlined identification of germline and somatic sequence variants in cancer
Authors: Keynttisha Jefferson, Heather Halvensleben, Dawn Green, Ryan Bannen, Michael Brockman, Todd Richmond, Daniel Burgess
Journal: Cancer Research (2016)

Abstract Characterization of the somatic sequence variations that accrue in cells is critical for understanding the pronounced cellular and clinical heterogeneity observed in cancer. The ability to efficiently detect variations in tumors can help to identify biomarkers which may be relevant to clinical trials, support more accurate prognosis, and help guide more effective choices of therapy. Next-generation sequencing (NGS) has become a valuable tool for discovering somatic mutations in cancers. Here we present an alternative approach to current methodologies for addressing these needs. HEAT-Seq (High Efficiency Amplification of Targets for Sequencing) is a targeted NGS method based on optimized, multiplexed molecular inversion probes (MIPs). This is a convenient, sensitive and cost-effective target enrichment technology for SNP discovery and SNP validation in cancer-related genes. HEAT-Seq probes target both DNA strands and were designed to facilitate bioinformatic error correction. Molecule identifiers (UIDs) incorporated into the probes tag PCR duplicates and support ultra-sensitive detection of low frequency variants, reduction of false positives, and accurate assessment of molecular complexity free of amplification bias. Sensitivities for allele detection have been measured to below 1%. The HEAT-Seq workflow from input DNA to sequence-ready sample can be completed in ≤8 hours without any requirement for a separate library preparation step, which saves both time and cost. Additionally, the capture, amplification and sample clean up steps are performed in a single reaction tube. This eliminates the need to transfer samples to subsequent reaction tubes, preserves sample identity, prevents cross contamination, limits sample loss, and makes the HEAT-Seq protocol easy to automate. A comparison of current PCR-based targeted sequencing with the new HEAT-Seq technology indicates significant advantages for HEAT-Seq in the accurate quantification of low frequency cancer variants. In summary, HEAT-Seq technology offers a rapid, convenient, automatable option to identify genomic DNA variants and enable advances in cancer research. Citation Format: Keynttisha Jefferson, Heather Halvensleben, Dawn Green, Ryan Bannen, Michael Brockman, Todd Richmond, Daniel Burgess. A novel molecular inversion probe (MIP) system for the streamlined identification of germline and somatic sequence variants in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5223.
A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)
Authors: Shyamala C. Navada, Lewis R. Silverman, Katherine P. Hearn, Rosalie Odchimar-Reissig, Erin P. Demakos, Yesid Alvarado, Naval Daver, Courtney DiNardo, Marina Konopleva, Gautam Borthakur, Naveen Pemmaraju, Tapan Kadia, Pierre Fenaux, Steve Fruchtman, Nozar Azarnia, Guillermo Garcia-Manero
Journal: Blood (2015)
Abstract 2878: The tumor-permissive role of KHSRP in colorectal cancer: Mechanistic insights from a gene expression study
Authors: Francesco Caiazza, Robert Power, Kate Killick, Des Higgins, Walter Kolch, Laura Breen, Sinead Aherne, Sudipto Das, Darran O’Connor, Miriam Tosetto, Blathnaid Nolan, David Fennelly, Kieran Sheahan, Glen Doherty, Elizabeth J. Ryan
Journal: Cancer Research (2016)

Abstract Inflammation plays a key role in the development of Colorectal Cancer (CRC), but the underlying regulatory mechanisms are yet to be fully elucidated. The K-homology splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein which regulates translation of transcripts containing ARE sequences in their 3’-UTR, affecting RNA fate at different levels. KHSRP has been implicated in different functions associated with cancer cell biology, such as inflammation and cell-fate determination. Importantly, KHSRP regulates expression of pro-tumorigenic and anti-inflammatory cytokines, potentially impacting on the tumor microenvironment. We have previously shown that knockdown of KHSRP expression in CRC cell lines regulates cell proliferation and clonogenic survival. KHSRP is also required for the secretion of the pro-angiogenic cytokines, IL-8 and VEGF, impacting on endothelial tube formation. To understand the global impact of KHSRP in regulation of CRC cell function we used Affimetrix Human Transcriptome array to investigate gene expression upon KHSRP silencing in SW480 CRC cells. A total of 210 genes were differentially expressed, 155 of which were up-regulated (100 coding and 55 non-coding genes) and 55 were down-regulated (34 coding and 21 non-coding genes). Among these were genes involved in RNA biology, inflammation, immunity, cell signaling and tumor-stroma interaction, shedding light on the potential mechanisms of action of KHSRP in epithelial cells. Representative targets have been selected for validation and further mechanistic studies. These data builds upon our previous findings suggesting a role for KHSRP in creating a tumor-permissive microenvironment in CRC. Citation Format: Francesco Caiazza, Robert Power, Kate Killick, Des Higgins, Walter Kolch, Laura Breen, Sinead Aherne, Sudipto Das, Darran O’Connor, Miriam Tosetto, Blathnaid Nolan, David Fennelly, Kieran Sheahan, Glen Doherty, Elizabeth J. Ryan. The tumor-permissive role of KHSRP in colorectal cancer: Mechanistic insights from a gene expression study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2878.
Changes in circulating tumor cell counts during the course of chemotherapy in women with high-risk early breast cancer.
Authors: Marie Lena Johanna Tzschaschel, Brigitte Kathrin Rack, Ulrich Andergassen, Thomas W. P. Friedl, Andreas Schneeweiss, Volkmar Müller, Tanja N. Fehm, Klaus Pantel, Jörg Gade, Ralf Lorenz, Mahdi Rezai, Hans Tesch, Ulrike Soeling, Elisabeth Katharina Trapp, Sven Mahner, Christian Schindlbeck, Werner Lichtenegger, Matthias W. Beckmann, Peter A. Fasching, Wolfgang Janni
Journal: Journal of Clinical Oncology (2016)

11529 Background: The presence of circulating tumor cells (CTCs) before chemotherapy (CTX) is an independent prognostic marker for reduced survival in early breast cancer (EBC). In addition, recent results suggest that persisting CTCs immediately after adjuvant CTX indicate poor prognosis. There is a lack of data regarding the best use of CTC numbers for risk stratification. Here, we evaluated different methods to calculate changes in CTC counts during the course of CTX and their prognostic value with respect to overall survival (OS). Methods: The German SUCCESS A trial is a phase III study in which patients with high-risk EBC were first randomized to adjuvant CTX treatment with 3 cycles of epirubicin-fluorouracil-cyclophosphamide followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. CTC enumeration was performed using the FDA-approved CellSearch System (Janssen Diagnostics, LLC). Patient outcome in terms of OS was analyzed using univariate log-rank tests and Cox regression models. Information on CTC status before and after CTX was available for 1507 (40.1 %) of 3754 randomized patients. Results: Overall, 311 patients had at least one CTC before CTX (median 1 CTC, range 1 – 827) and were included in the analyses. 79 (25.4%) of these patients had at least one CTC after CTX (median 1, range 1 – 124). A quantitative assessment with the change in number of CTCs (before and after CTX) as continuous variable significantly predicted OS (hazard ratio [HR] 0.995, 95% confidence interval [CI] 0.992-0.998, p = 0.002). Surprisingly CTC clearance (no vs. yes) was not significantly associated with OS (HR 1.508, 95% CI 0.783- 2.904, p = 0.216). However, patients that showed an increase in CTC number from before to after CTX had significantly shorter OS than patients with no such increase (HR 3.545, 95% CI 1.490- 8.434, p = 0.004). Conclusions: Both a quantitative assessment in terms of changes in CTC numbers from before to after CTX and a qualitative measure according to whether or not there was an increase in CTC number showed a significant association with overall survival in EBC patients. Clinical trial information: NCT02181101.