tbuckley/cabot-search huggingface dataset:
Abstract 3314: Targeting Hsp90 affects stem cell signaling in triple negative breast cancer
Authors: Prabhu Ramamoorthy, Parthasarathy Rangarajan, Roy Jensen, Shrikant Anant
Journal: Cancer Research (2016)

Abstract Background: Triple Negative Breast Cancer (TNBC) exhibit dismal survival rates due to their propensity to develop distant metastases. Heat shock protein 90 (Hsp90) is a molecular chaperone that aids in the folding and maturation of various proteins involved in breast cancer progression and resistance to therapy. Many studies have also suggested that breast cancer's ability to proliferate, progress, and spread is due to the presence of a rare subpopulation of cancer stem cells. The aim of this study is to investigate the efficacy of HSP90 inhibitors celastrol and triptolide (from the Chinese herb “Thunder God of Vine” (Tripterygium wilfordii) on stem cells as a novel therapy for TNBC. Methods: We performed in vitro studies using the TNBC cell lines BT20 and MDA-MB-231. We performed mammosphere assays to determine self-renewal capacity. For in vivo, we injected BT20 cells into flanks of athymic nude mice and treated with celastrol and triptolide at 3 mg/Kg bw and 0.25 mg/Kg bw, respectively. Results: Both celastrol and triptolide significantly suppressed mammosphere size and number. Furthermore, expression of breast cancer stem cell markers DCLK1, ALDH1 and CD133 were significantly reduced in the two cell lines following treatment. Flow cytometry also suggested a significant reduction in DCLK1+, ALDH+ and CD133+ cells. Recently, Notch signaling has been shown to be critical for self-renewal of cancer stem cells. In cells treated with either celastrol or triptolide, there was a significant reduction in activated Notch intracellullar domain (NICD), and its downstream target Hes-1. However, in cells where we ectopically overexpressed NICD, neither compound was as potent as control, vector transfected cells in reducing 2D cell proliferation or 3D mammosphere formation, suggesting the direct role for inhibiting Notch activation as a mechanism of action for the two compounds. Furthermore, inhibition of Notch signaling pathway by using Υ-secretase inhibitor DAPT shows further reduction in mammosphere formation and Notch and its downstream target gene. We confirmed these finding in vivo using BT20 tumor xenografts grown in athymic nude mice. There was a reduction in the size and weight of tumors in mice treated with celastrol or triptolide. Western blot data showed that there is a decrease in activated Notch-1 protein and stem cell marker, DCLK1+ and ALDH+ in celastrol and triptolide treated xenograft tissue. Conclusion: Taken together these data suggest that both celastrol and triptolide affect cancer stem cells in TNBC, in part through inhibition of Notch signaling. Citation Format: Prabhu Ramamoorthy, Parthasarathy Rangarajan, Roy Jensen, Shrikant Anant. Targeting Hsp90 affects stem cell signaling in triple negative breast 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 3314.
Abstract 1984: A regulatory triad consisting of BMI1, let-7i miRNA and ERK3 kinase in controlling cancer cell invasiveness
Authors: Lobna Elkhadragy, Minyi Chen, Weiwen Long
Journal: Cancer Research (2016)

Abstract Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase, whose biological activity is tightly regulated by its cellular abundance. ERK3 expression is upregulated in multiple cancer types, including head and neck cancers. Importantly, our recent finding revealed a critical role for ERK3 in promoting cancer cell invasiveness. However, little is known about the molecular regulation of ERK3 level in cancers. Here we identify a pathway which regulates ERK3 expression and cell invasiveness of head and neck cancers, comprising the oncogenic polycomb group protein BMI1 and the tumor suppressive miRNA let-7i. To study the regulation of ERK3, we performed several loss-of-function and gain-of-function assays in head and neck cancer cell lines, including OECM1 and Fadu. Stable knockdown of BMI1 greatly reduced ERK3 protein level, whereas overexpression of BMI1 significantly increased ERK3 level, demonstrating a positive regulation of ERK3 by BMI1. Interestingly, we found that this regulation is mediated by the miRNA let-7i, whose transcription is repressed by BMI1, a component of the polycomb repressive complex 1. ERK3 mRNA is directly targeted by let-7i miRNA, which was demonstrated by the assay using a luciferase reporter containing the 3’UTR of ERK3 mRNA downstream of luciferase gene. Mutation of the let-7i binding site in ERK3 3’UTR abolished the negative regulation of let-7i on ERK3. Further, let-7i mimic decreased ERK3 expression and let-7i inhibitor increased ERK3 expression in head and neck cancer cells. To determine the functional significance of this regulation, we investigated their role in cancer cell invasiveness by performing trans-well migration/invasion assays. Importantly, ERK3 depletion abolished BMI1-induced increase in cancer cell migration and invasion, so was by let-7i mimic. Finally, we examined by immunohistochemistry the expression of both BMI1 and ERK3 in head and neck tumor specimens and found that ERK3 expression is positively correlated with BMI1. All together, we unravel a novel regulatory mechanism for ERK3 by the BMI1/let-7i axis, which together controls head and neck cancer cell invasiveness. Citation Format: Lobna Elkhadragy, Minyi Chen, Weiwen Long. A regulatory triad consisting of BMI1, let-7i miRNA and ERK3 kinase in controlling cancer cell invasiveness. [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 1984.
Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans
Authors: Min Kyung Sung, Juneil Jang, Kang Seon Lee, Cheol-Min Ghim, Jung Kyoon Choi
Journal: Genome biology (2016)

Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions.The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise.This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans.
EPID-08ISOCITRATE DEHYDROGENASE (IDH) MUTATION AND METHYL-GUANINE METHYL TRANSFERASE (MGMT) PROMOTER METHYLATION STATUS IN GLIOBLASTOMA: RESULTS OF A PROSPECTIVE MOLECULAR GLIOBLASTOMA REGISTRY
Authors: Clark Chen, Tao Jiang
Journal: Neuro-Oncology (2015)

BACKGROUND:The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood.METHODS: We investigated the association between methMGMT and mIDH with progression free survival (PFS) and overall survival (OS) in a prospectively collected molecular registry of 274 glioblastoma patients.RESULTS: For glioblastoma patients who underwent concurrent Temozolomide and Radiation Therapy (TMZ + RT), OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS (mOS): 35.8 mo, median PFS (mPFS):27.5mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo).For patients with wtIDH glioblastomas, TMZ + RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo; PFS: 9.9 mo v 6.5 mo).While TMZ + RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ + RT or RT group.These results suggest that mIDH1 conferred resistance to TMZ.Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3-10 fold increase in TMZ resistance after long-term passage.CONCLUSION: Our study demonstrates that IDH and MGMT promoter methylation status independently associate with favorable outcome in TMZ + RT treated glioblastoma patients.However, these biomarkers differentially impact clinical TMZ response.
Soluble Human Interleukin-2 Receptor (SIL-2R) as a Potential Predictor for Central Nervous System Relapse In Patients with Diffuse Large B-Cell Lymphoma In Rituximab Era: A 4.4-Year Follow up Analysis.
Authors: Noriko Nishimura, Masahiro Yokoyama, Kengo Takeuchi, Eriko Nara, Kenji Nakano, Kentaro Nasu, Kazuhito Suzuki, Kyoko Ueda, Yuko Mishima, Sakura Sakajiri, Shunji Takahashi, Yasuhito Terui, Kiyohiko Hatake
Journal: Blood (2010)
Age-Adjusted Co-Morbidity Score - but Not Revised Disease Risk Index - Is Associated with Progression-Free Survival after Intermediate Intensity Double Unit CBT in Adults with Hematologic Malignancies
Authors: Satyajit Kosuri, Patrick Hilden, Sean Devlin, Yeon Yoo, Emily Lauer, Jonathan Peled, Dahi B. Parastoo, Sergio A. Giralt, Boglarka Gyurkocza, Hugo Castro-Malaspina, Ann A. Jakubowski, Esperanza B Papadopoulos, Miguel-Angel Perales, Craig S. Sauter, Brian C Shaffer, Roni Tamari, James W. Young, Andromachi Scaradavou, Doris M Ponce, Juliet N. Barker
Journal: Blood (2015)
Abstract 736: Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC
Authors: Yuhong Lu, Peter M. Glazer
Journal: Cancer Research (2016)

Abstract The development of small molecule inhibitors specific for epidermal growth factor receptors (EGFR) with activating mutations has led to a dramatic shift in the treatment of non-small cell lung cancer (NSCLC) patients. Patients with NSCLC carrying such EGFR mutations often show prolonged responses when treated with first or second generation EGFR tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance to EGFR TKIs. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis. Studies have linked hypoxia to therapy resistance, including radiation therapy and chemotherapy. In this study, we show that long-term, moderate hypoxia induces gefitinib resistance in the NSCLC cell line, HCC827, that harbors an activating EGFR mutation. The hypoxia-induced gefitinib resistance is associated with reduced BIM induction after gefitinib treatment when compared to normoxic HCC827 cells. In addition, in hypoxic HCC827 cells, gefitinib treatment induces N-cadherin expression, a mesenchymal marker, accompanied by downregulation of E-cadherin, an epithelial maker. These results suggest that epithelial-mesenchymal transition (EMT) may be involved in hypoxia induced gefitinib resistance. Wound healing migration assays further support that hypoxia induces HCC827 cell migration after gefitinib treatment. These results suggest that hypoxia may be a driving force for EGFR TKIs resistance potentially through EMT in NSCLC. Citation Format: Yuhong Lu, Peter M. Glazer. Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC. [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 736.
Biased Engraftment of Retrovirus-Transduced Marrow in Murine X-CGD Following Submyeloablative Conditioning.
Authors: Mohammed Sadat, Sara Dirscherl, Nancy Pech, Robert Getty, Scott Cross, Cecilia Barese, W. Scott Goebel, Mervin C. Yoder, Sean Mooney, Manuel Grez, Kenneth Cornetta, Mary C. Dinauer
Journal: Blood (2006)
On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
Authors: Igor Theurl, Ingo Hilgendorf, Manfred Nairz, Piotr Tymoszuk, David Haschka, Malte Asshoff, Shun He, Louisa M S Gerhardt, Tobias A W Holderried, Markus Seifert, Sieghart Sopper, Ashley M Fenn, Atsushi Anzai, Sara Rattik, Cameron McAlpine, Milan Theurl, Peter Wieghofer, Yoshiko Iwamoto, Georg F Weber, Nina K Harder, Benjamin G Chousterman, Tara L Arvedson, Mary McKee, Fudi Wang, Oliver M D Lutz, Emanuele Rezoagli, Jodie L Babitt, Lorenzo Berra, Marco Prinz, Matthias Nahrendorf, Guenter Weiss, Ralph Weissleder, Herbert Y Lin, Filip K Swirski
Journal: Nature Medicine (2016)
Abstract 2809: ROS signaling by NADPH oxidase 5 (Nox5) modulates proliferation of human melanoma UACC-257 cells and prolongs growth in the absence of serum or growth factors
Authors: Smitha Antony, Yongzhong Wu, Diana C. Haines, Guojian Jiang, Jennifer L. Meitzler, Agnes Juhasz, Jiamo Lu, Krishnendu K. Roy, James H. Doroshow
Journal: Cancer Research (2016)

Abstract Reactive oxygen species (ROS) produced by the NADPH oxidase (Noxs) homologs participate in signaling cascades regulating proliferation. Recently, we have reported substantial overexpression of Nox5 in several human cancers including those of prostate, ovary and melanomas. Despite being upregulated in many human cancers and implicated in promoting cell proliferation, the molecular mechanisms modulated by Nox5 are poorly understood. In this study, the functional significance of Nox5 was assessed in human UACC-257 and WM-852 melanoma cells by generating Nox5-overexpressing and knockdown cells. Stable overexpression of Nox5 in UACC-257 cells resulted in enhanced cell growth, increased BrdU positive cells and decreased protein tyrosine phosphatase activity. Additionally, these cells had increased normoxic Hif-1α expression and decreased p27Kip1 expression. Conversely, knockdown of endogenous Nox5 in UACC-257 cells resulted in decreased cell growth, decreased BrdU positive cells, decreased Hif-1α expression and increased p27Kip1 expression. Likewise, in human WM-852 melanoma cells, transient overexpression of Nox5 decreased p27Kip1 expression and knockdown of endogenous Nox5 resulted in increased p27Kip1 and gamma-H2AX expression with decreased cell growth. Cadherin switch, loss of E-cadherin expression and upregulation of N-cadherin was observed in UACC-257 Nox5 overexpressing cells indicative of an invasive phenotype; conversely, an upregulation of E-cadherin expression in Nox5 knockdown cells was noted. Cell invasion assay through matrigel-coated membranes also demonstrated enhanced invasion by Nox5 overexpressing cells. Additionally, 3D cultures of Nox5 overexpressing UACC-257 cells exhibit an amoeboid morphology compared to that of the Nox5 knockdown cells that were mesenchymal, suggestive of an amoeboid - mesenchymal (AMT) transition. Strikingly, UACC-257 cells that overexpress Nox5 were able to proliferate in serum-free conditions for over a month. In summary, our findings suggest that ROS signaling by Nox5 in human melanoma could modulate multiple signaling networks that regulate Hif-1α and p27Kip1 expression, contributing in part, to cell proliferation and the ability to grow in the absence of serum or growth factors. Citation Format: Smitha Antony, Yongzhong Wu, Diana C. Haines, Guojian Jiang, Jennifer L. Meitzler, Agnes Juhasz, Jiamo Lu, Krishnendu K. Roy, James H. Doroshow. ROS signaling by NADPH oxidase 5 (Nox5) modulates proliferation of human melanoma UACC-257 cells and prolongs growth in the absence of serum or growth factors. [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 2809.
P-189 Correlation between of expression of the enzyme topoisomerase I and p53 and result of irinotecan based therapy in patients with metastatic colorectal cancer
Authors: A. Pasic, S. Beslija, A. Djuran, I. Sefic-Pasic, M. Banjin, T. Ceric, A. Rasic, B. Hasanbegovic, A. Jalovcic, E. Kapisazovic
Journal: Annals of Oncology (2015)
PWE-437 The effectiveness of a collaborative educational programme between 2 centres for newly appointed screening specialist practitioners (ssps)?: Abstract PWE-437 Table 1
Authors: M Mbuyongha, E Smith, L Lisa, G Fitzgerald, N Taggart, S Sarkar
Journal: Gut (2015)

<h3>Introduction</h3> Within the Bowel cancer screening programme- Specialist Screening practitioner have a pivot role. Training new SSPs can take up 1 year and include gaining competencies in pre-assessment clinics for patients on the FOBT programme and compulsory attendance and attainment of the JMU course. The introduction of bowel scope has led to the significant increase in recruitment of SSP to cope with the programme. <h3>Method</h3> Two separate BCSP programmes in the Northwest and Cheshire, recruited 8 new SSP to deal with the demand of bowel scope. They collaborated to deliver a multidisciplinary weekly educational programme between 2 sites to help accelerate training of the new SSPs. After the course, the SSPs were asked to complete an anonymous feedback questionnaire on the effectiveness of the course rating 0–10 (10-best score). <h3>Results</h3> Tutorial lasted 1–2 h and covered: SSP role, colonoscopy and assessment, documentation, 3x sessions on complex cases, pathology and cancer datasets, AVI reporting, lesion recognition, EMR, Difficult pathways on open Exeter, management of new anticoagulants. Tutors include clinical director, lead colonscopists, Associate specialist, lead Specialist Screening Practitioner (Nurse) and a Programme Manager On average seven SSP between the 2 sites attended each tutorial. <h3>Conclusion</h3> Collaboration between two sites can lead to an effective delivery of educational programme for SSPs. <h3>Disclosure of interest</h3> None Declared.
Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis
Authors: Kaori Mukai, Nicolas Gaudenzio, Sheena Gupta, Nora Vivanco, Sean C. Bendall, Holden T. Maecker, Rebecca S. Chinthrajah, Mindy Tsai, Kari C. Nadeau, Stephen J. Galli
Journal: Journal of Allergy and Clinical Immunology (2016)
Dual targeting of the androgen receptor and hypoxia-inducible factor-1α pathways to synergistically inhibit castrate-resistant prostate cancer.
Authors: William Douglas Figg, Elena V. Fernandez, Kelie M Reece, Ariel M Ley, Sarah M Troutman, Tristan M. Sissung, Douglas K. Price, Cindy H. Chau
Journal: Journal of Clinical Oncology (2015)

270 Background: Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). While enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and HIF-1α are key regulators of these processes, dual targeting of both signaling axis represents an attractive therapeutic approach. Methods: Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. Cells were stimulated with dihydrotestosterone (DHT) or the hypoxia mimetic cobalt chloride. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. Results: In prostate cancer cells, gene expressions of AR targets (KLK3, FKBP5, TMPRSS2) were repressed by HIF-signaling; conversely, HIF-1α target expressions (VEGF, ENO1, LDHA) were induced by DHT-mediated AR signaling. Treatment of CRPC cells with enzalutamide and chetomin or HIF-1α siRNA attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells. Additionally, HIF-1α siRNA synergistically increased enzalutamide-induced apoptosis. Conclusions: Combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene specific HIF-dependent expression, prostate cancer cell growth, and apoptosis.
Basal-like breast cancer: Single-institution study of the incidence, risk factors, and clinical characteristics in a predominantly minority population.
Authors: A. Padmanabhan, R. Sterling, X. Zhang, M. Bromberg
Journal: Journal of Clinical Oncology (2010)

e12008 Background: Basal-like breast tumors are characterized by an aggressive course in young, African-American women - a prevalent subset in our community. This study aims to define characteristics of this subset to help improve outcomes. Methods: Medical records of female breast cancer patients (BC) at Temple University Hospital (January 2003 to December 2008) were reviewed. Basal-like subset was defined as negative Immunohistochemical staining for estrogen-receptor, progesterone-receptor and HER2/neu and expression of cytokeratin 5/6 and/or EGFR. Clinical parameters were examined using chi square and univariate analysis. Results: Of the 467 patients (BC), 44 had triple-negative cancer and 37 (8%) were of basal-like subtype (BLS). 40% (15/37) BLS were ≤ 50 y vs. 26% (122/467) BC; 59% (22/37) BLS were ≥ 50 y vs. 74% (345/467) BC (p = 0.05). 84% (31/37) BLS were African-American vs. 62% (291/441) BC; 16% (6/37) BLS were Caucasian vs. 32% (150/441) BC (p = 0.03). 26 patients did not belong to either category. Prior breast cancer history was seen in 16% (6/37) BLS. 5% (2/37) were nulliparous, 49% (18/37) multiparous, 17 unknown. 62% (23/37) had ≥ 2 medical conditions (HTN, DM, COPD). 51% (19/37) had smoking history. Patients had more right verse left sided tumors (51% vs. 35%); 49% (18/37) had lymph node involvement (LN), 41% (15/37) negative LN, 11% (4/37) unknown; 78% (29/37) had high-grade disease, 3% (1/37) intermediate, 19% (7/37) unknown. On comparing stages, 41% (15/37) BLS had Stage I/II vs. 70% (325/467) BC; 59% (22/37) BLS had stage III/ IV vs. 30% (142/467) BC (p = 0.000283). Metastatic disease was seen in 22% (8/37) patients (3 bone, 3 lung, 1 brain, and 1 mediastinum). 37% oncology appointments and 32% chemotherapy sessions were missed. 78% (29/37) continue followup; 22% (8/37) are deceased. Conclusions: Compared with the total breast cancer population, the basal like subgroup had younger, more African American women, with higher stage/grade disease and more nodal involvement. Majority had comorbid conditions and many were noncompliant. In addition to the newer targeted therapies, increased social support would likely improve our patient outcomes No significant financial relationships to disclose.