tbuckley/cabot-search huggingface dataset:
Abstract 1155: Inhibitory effect of CYP1B1 on antitumor activities induced by dysregulated CDC20 and DAPK1 in renal cell carcinoma
Authors: Yozo Mitsui, Inik Chang, Shinichiro Fukuhar, Hiroshi Hirata, Ryan Kenji Wong, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Saini Sharanjot, Shahana Majid, Hiroaki Shiina, Rajvir Dahiya, Yuichiro Tanaka
Journal: Cancer Research (2016)

Abstract Introduction and Objective: Cytochrome P450 1B1 (CYP1B1) has been shown to be up-regulated in many types of cancer including renal cell carcinoma (RCC). Several reports have shown that CYP1B1 can influence the regulation of tumor development; however, its role in RCC has not been well investigated. The aim of the present study was to determine the functional effects of CYP1B1 gene on tumorigenesis in RCC. Methods: Expression of CYP1B1 was determined in RCC cell lines, and tissue microarrays of 96 RCC and 25 normal tissues. To determine the biological significance of CYP1B1 in RCC progression, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses. Results: First, we confirmed that CYP1B1 protein expression was significantly higher in RCC cell lines compared to normal kidney tissue. This trend was also observed in RCC samples (p&amp;lt;0.01). Interestingly, CYP1B1 expression was associated with tumor grade and stage. Next, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses to determine the biological significance of CYP1B1 in RCC progression. Inhibition of CYP1B1 expression resulted in decreased cell proliferation, migration and invasion of RCC cells. In addition, reduction of CYP1B1 induced cellular apoptosis in Caki-1. We also found that these anti-tumor effects on RCC cells caused by CYP1B1 depletion may be due to alteration of CDC20 and DAPK1 expression based on gene microarray and confirmed by real-time PCR. Interestingly, CYP1B1 expression was associated with CDC20 and DAPK1 expression in clinical samples. Conclusions: CYP1B1 may promote RCC development by inducing CDC20 expression and inhibiting apoptosis through the down-regulation of DAPK1. Our results demonstrate that CYP1B1 can be a potential tumor biomarker and a target for anticancer therapy in RCC. Citation Format: Yozo Mitsui, Inik Chang, Shinichiro Fukuhar, Hiroshi Hirata, Ryan Kenji Wong, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Saini Sharanjot, Shahana Majid, Hiroaki Shiina, Rajvir Dahiya, Yuichiro Tanaka. Inhibitory effect of CYP1B1 on antitumor activities induced by dysregulated CDC20 and DAPK1 in renal cell carcinoma. [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 1155.
Abstract 989: A novel function of LncRNA AK023948—regulation of PI3K signaling
Authors: Pratirodh Koirala, Yin Yuan Mo
Journal: Cancer Research (2016)

Abstract The human genome expresses a large number of long non-coding RNAs (lncRNAs) and increasing evidences suggest their physiological functions.However, the roles vast majority of lncRNAs are elusive in breast cancer. In the present study, we identified a set of lncRNAs that were differentially expressed in breast cancer tissues as compared to normal tissue. AK023948 is one of such lncRNAs which is up-regulated in breast cancer tissue and in breast cancer cell lines. Ectopic expression of AK023948 in breast cancer MCF-7 cells promotes proliferation and anchorage independent cell growth along with activation of AKT phosphorylation. On the other hand, knockdown or knockout of AK023948 in MCF-7 cells reduces the proliferation of cells and phosphorylation of AKT. Furthermore, there is a positive correlation between AK023948 and pAKT expression in breast cancer tissue microarray. To determine the underlying mechanism of AK023948-mediated activation of AKT, we performed RNA precipitation assays using biotin-labeled AK023948 RNA probe combined with mass spectrometry analysis and identified that ATP dependent RNA helicase A (RHA/DHX9) is AK023948. The interaction of AK023948 with DHX9 was confirmed by Western blot and RNA immunoprecipitation (IP), respectively. Co-IP indicated that DHX9 interacts with PI3K regulatory subunit p85. Further characterization revealed that AK023948 works as scaffold for p85-DHX9 interaction, which is essential for stability of p85 and AKT activity. Finally, we showed that AK023948 is essential to AKT activation induced by growth factors and acidosis, but it has no effect on activation of ERK phosphorylation, suggesting that AK023948 specifically regulate AKT signaling via PI3K. Together, these results suggest that AK023948 contributes to breast cancer pathogenesis by activating AKT and AK023948 may serve as a novel target for breast cancer therapy. Citation Format: Pratirodh Koirala, Yin Yuan Mo. A novel function of LncRNA AK023948—regulation of PI3K signaling. [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 989.
Abstract 83: MicroRNAs associated with the p53 tumor suppressor signaling network are differentially expressed in triple negative breast cancer cell lines
Authors: Malcolm M. Moses, Sherette S. Godfrey, Niageria Q. Lusk, Checo J. Rorie
Journal: Cancer Research (2016)

Abstract “Triple-negative” breast cancer (TNBC) is an aggressive subtype of breast cancer that appears prevalently in African American women below the age of 35, and has no known biomarker that can be targeted for drug therapy. This aggressive breast cancer phenotype is due to its high mitotic index and high metastatic potential, and may be due to the fact that up to 80% of TNBC has a mutation in the p53 tumor suppressor gene. The p53 tumor suppressor gene signaling pathway can be mediated by microRNAs (miRNAs) which are short sequences of RNA (∼22nt) that target protein coding mRNA and mark them for degradation. Characterization of the miRNA profiles in TNBC cells compared to normal breast cell lines may provide potential targets in treating TNBC. In this study, microarray analysis was performed on TNBC cell lines HCC1806, HCC70, and MB157 and the normal breast cells AG11132. The expression levels of miRNAs found to play a role in the p53 tumor suppressor gene signaling pathway were compared between the normal and TNBC cell lines. The miRNAs let-7b, let-7a, miR-29a, miR-100, let-7f, miR-34a, miR-15b, miR-21, miR-16, and miR-22 displayed the greatest differences in expression levels between the normal and TNBC cell lines, thereby implicating them as potential biomarkers for TNBC and potential drug treatment targets. These miRNAs can be studied further to determine their role in mediating the p53 tumor suppressor gene signaling pathway in these cells for their potential use in the diagnosis and treatment of TNBC. Citation Format: Malcolm M. Moses, Sherette S. Godfrey, Niageria Q. Lusk, Checo J. Rorie. MicroRNAs associated with the p53 tumor suppressor signaling network are differentially expressed in triple negative breast cancer cell lines. [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 83.
Composition of the Sepsis Definitions Task Force
Authors: Charles R. Wira, Kai E. Swenson
Journal: JAMA (2016)

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Long-term results of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer.
Authors: Fumiyoshi Ohyanagi, Nobuyuki Yamamoto, Atsushi Horiike, Takeshi Horai, Takuyo Kozuka, Haruyasu Murakami, Hideyuki Harada, Toshiaki Takahashi, Yukiko Nakamura, Makoto Nishio
Journal: Journal of Clinical Oncology (2013)

7556 Background: Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). S-1 has been shown to be significant efficacious for treating advanced NSCLC. Our previous phase II study reported short-term outcomes of cisplatin (CDDP)/S-1 chemoradiotherapy. Because CDDP/S-1 chemoradiotherapy is considered to have advantages over others in overall survival (OS) and toxicity, we analyzed its long-term outcomes by following up patients included in the phase II study. Methods: Forty-eight patients (aged &lt;75 years) with unresectable stage III NSCLC were evaluated. They were treated with CDDP (60 mg/m 2 on day 1) intravenously and oral S-1 (40 mg/m 2 twice daily on days 1–14); this regimen was repeated every 4 weeks for four cycles. A 60-Gy thoracic radiation dose was delivered in 30 fractions beginning on day 2. Results: After a median follow-up of 6.3 years (range, 5.7–7.4 years), the median OS was 2.8 years [95% confidence interval (CI); 1.04–4.63 years], and the 3- and 5-year OS rates were 49.7% (95% CI: 35.6%–63.8%) and 33.0% (95% CI: 20.0%–46.6%), respectively. Out of the several variables evaluated as predictors of OS, including gender, age, stage, histology, and performance status (PS), only PS proved to be a statistically significant predictor in both univariate and multivariate analyses. Conclusions: CDDP/S-1 concurrent thoracic radiotherapy is clinically feasible and highly efficacious. Despite our relatively small sample size, the benefits of this regimen revealed in this study warrant further research.
Abstract 4522: Epstein-Barr virus infection suppresses the DNA repair mechanisms in nasopharyngeal epithelial cells via reduction of the H3K4me3 mark
Authors: Maria L. Lung, Arthur KL Cheung, Wei Dai, Merrin ML Leong, George SW Tsao.
Journal: Cancer Research (2016)

Abstract Introduction: Epstein-Barr Virus (EBV) is an oncovirus, which contributes to development of various cancers, including nasopharyngeal carcinoma (NPC). EBV latent proteins play critical roles in modulation host cell histone modifications in order to regulate its signaling pathways. However, the role of EBV in regulation histone modifications in epithelia cell system is still not very clear. Further studies are necessary to characterize the functional role of EBV in regulating epithelial cell modifications. Aim: in this current study, we aim to investigate the role of EBV infection in regulating a promoter and transcription activation histone marker, H3K4me3, in the host cell genome. Methodologies: Chromatin immunoprecipitation sequencing (ChIPseq) was performed by using the next-generation sequencing approach. The ChIP reactions were prepared by utilizing the antibody targeting the H3K4me3 mark in two pairs of immortalized non-tumorigenic nasopharyngeal epithelial (NPE) cell lines, which were artificially infected with (550, 550-EBV, 361, and 361-EBV). The ChIPseq results were validated by the ChIP-QPCR and RT-QPCR. Results: A total of 1747 genes show losses of H3K4me3 in both sets of EBV-infected NPE cell lines. Among them, 628 (36%) genes show losses of H3K4me3 in promoter regions. Interestingly, a total of 18 DNA damage repair signaling members in the base excision repair (BER), homologous recombination, non-homologous end-joining, and the mismatch repair pathways showed significant losses of H3K4me3 in EBV-infected NPE cells. Based on utilizing the DAVID annotation tool for pathway analysis, members in the BER pathway were significantly enriched (FDR = 0.0709, cut-off&amp;lt;0.1). The ChIPseq results were validated by ChIP- and RT-QPCR and showed significant losses of the H3K4me3 and expression of the BER members in both sets of EBV-infected NPE cell lines. The clinical significances were further confirmed by detection of significant down-regulation of the BER members in NPC paired biopsies. Conclusion: EBV infection induces changes of host cell H3K4me3 levels and results in down-regulation of the BER members. Acknowledgement: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China: Grant number AoE/M-06/08 to MLL and the Seed Funding Programme for Basic Research of the University of Hong Kong: Grant number 201308159003 to AKLC. Citation Format: Maria L. Lung, Arthur KL Cheung, Wei Dai, Merrin ML Leong, George SW Tsao. Epstein-Barr virus infection suppresses the DNA repair mechanisms in nasopharyngeal epithelial cells via reduction of the H3K4me3 mark. [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 4522.
P0245 : The IL-6/SIL6R and STAT3 axis is crucial for hepatoprotection and suppression of liver cancer in female mice with chronic liver injury
Authors: J.H. Axelrod, T. Lanton, A. Shriki, A. Sonnenblick, R. Abramovitch, O. Pappo, A. Peled, S. Rose-John, E. Galun
Journal: Journal of Hepatology (2015)
A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with capecitabine and trastuzumab, in HER2+ metastatic breast cancer (MBC).
Authors: Erika Paige Hamilton, Denise A. Yardley, Gabriel N. Hortobagyi, Luke N. Walker, Virginia F. Borges, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2014)

TPS663 Background: ONT-380 is a selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities. In preclinical studies, ONT-380 demonstrated greater than additive activity with trastuzumab, and was active in models of CNS metastases. In a single-agent phase 1 study in 50 patients (pts) with metastatic HER2+ cancer, the MTD was 600 mg BID, with DLT consisting of reversible gr 3 ALT/AST in 2/4 pts at 800 mg. In 22 HER2+ breast cancer pts treated at doses ≥ 600 mg BID, the clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) was 27%. Based on data supporting dual blockade of HER2, as well as preclinical activity of ONT-380 in the CNS, ONT-380 is now being evaluated in combination with capecitabine and trastuzumab. Methods: The study objectives are to determine the MTD/Phase 2 dose and preliminary anti-tumor activity of ONT-380 given with capecitabine alone, trastuzumab alone, and both capecitabine and trastuzumab in pts with and without CNS metastases. The study population includes adult pts with HER2+ MBC who have received trastuzumab and ado-trastuzumab emtansine (T-DM1) but not capecitabine for metastatic disease. A 3+3 design will evaluate up to three dose levels of ONT-380 (starting at 300 mg PO BID) given in combination with either capecitabine (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) or trastuzumab (8 mg/kg IV loading dose; 6 mg/kg IV once every 21 days). If both combinations are tolerable, ONT-380 will be evaluated with both capecitabine and trastuzumab. Expanded cohorts of pts with and without CNS metastases may be enrolled for either doublet or triplet combinations. Tumor response will be evaluated using RECIST 1.1. CNS response will be also evaluated by modified RECIST 1.1 and volumetric criteria. Potential biomarkers of response, including p95 HER2 and HER2 mutations, will be assessed in archived tumor biopsies. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal of consent. Clinical trial information: NCT02025192.
Effectiveness of direct egfr mutations research at time of diagnostic biopsy for lung cancer: a single institution outcome research
Authors: L. Ghilardi, G. Massazza, L. Bonomi, G. Ciaravino, G. Michetti, B. Oprandi, A. Lucianetti, E. Candiago, C. Bertuletti, A. Gianatti, C.A. Tondini, R. Labianca, A.C. Bettini
Journal: Annals of Oncology (2015)
A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia
Authors: Natalie Dimier, Paul Delmar, Carol Ward, Rodica Morariu-Zamfir, Gunter Fingerle-Rowson, Jasmin Bahlo, Kirsten Fischer, Barbara F. Eichhorst, Valentin Goede, Jacques J.M. van Dongen, Matthias Ritgen, Sebastian Böttcher, Anton W. Langerak, Michael Kneba, Michael Hallek
Journal: Blood (2015)
Abstract 3698: The effect of epigenetic silencing and p53 mutation on DLL4 expression in human cancer stem cell disorder: The Li-Fraumeni syndrome
Authors: Zhixing Yao, Zaki A. Sherif
Journal: Cancer Research (2016)

Abstract Tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome that can provide powerful insights into our understanding of the somatic mutations present in sporadic cancers. LFS is currently linked to heterozygous mutation in the tumor suppressor gene p53 (TP53), which encodes a transcription factor that responds to diverse cellular stresses through the regulation of target genes that induce apoptosis, cell cycle arrest, DNA repair, and senescence. We previously showed a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes DLL4, (Delta-like ligand 4; locus at 15q15.1), a Notch ligand that is a key target in tumor vasculature. DLL4 regulates T-cell lineage thymopoiesis and further affects cancer immunosurveillance. In the breakpoint region of chromosome 15q15, we examined THBS1, DNAJC17, Rad51, DLL4, CHAC1 and INO80 gene expression levels. We found that specifically DLL4 is abrogated in all the LFS cell lines as well as MDA231 breast cancer cell line, and drastically down-regulated in MCF7 breast and IMR32 brain cancer cell lines and several human organ-specific tumor samples. Furthermore, DNA methylation studies revealed that DLL4 promoter is silenced only in MCF7 and MDA231 but not in LFS cell lines. ChIP and siRNA knockdown assays demonstrated that p53 binds to DLL4 promoter through its association with CTCF, a chromosomal networking protein CCCTC binding factor. These results imply a possible karyotype-phenotype correlation with respect to DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in normal skin fibroblasts of LFS patients as well as breast and brain cancer cells is significant and supports the concept that this ligand may also play a role in cancer immune-surveillance; and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. Citation Format: Zhixing Yao, Zaki A. Sherif. The effect of epigenetic silencing and p53 mutation on DLL4 expression in human cancer stem cell disorder: The Li-Fraumeni syndrome. [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 3698.
Abstract 2722: Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy
Authors: Emma G. Sturgill, Ryoma Ohi
Journal: Cancer Research (2016)

Abstract Mitosis serves as a powerful opportunity for therapeutic intervention in the treatment of neoplastic diseases like cancer. Anti-mitotic pharmacological agents tame the proliferative capacity of tumor cells by interfering with proper function of the mitotic spindle. Several next generation anti-mitotics target kinesins involved in assembling the mitotic spindle. Of these mitotic kinesins, the kinesin-5 Eg5 (also known as KSP) is perhaps the most compelling because of its primacy during spindle assembly in animal cells. Indeed, Eg5-inhibitors (K5Is) induce a potent and lethal mitotic arrest in cell culture and murine xenografts; however, K5Is failed to induce tumor regression during Phase II trials. This devastating clinical performance has halted further development of K5I monotherapies and motivated investigation into the underlying reason(s) for K5I inefficacy. We previously showed that tumor cells in culture are capable of acquiring K5I resistance by employing parallel spindle assembly pathways. By studying a limited number of K5I-resistant cell lines, we showed that resistance involved the kinesin-12 Kif15; however, the generality of this finding was unclear. In this study we capitalize on the latest methodologies in targeted genome editing to study mechanisms of K5I resistance on a broader cell population level. We find that cells require Kif15 in all cases of K5I resistance, and that rescue is sensitive to the timing and extent of Kif15 expression. We propose that K5Is steer cells into an evolutionary bottleneck that requires Kif15, and that adaptive changes occur during passage through the bottleneck that enable populations to recover and diversify. These findings prompt a search for pharmacological inhibitors of Kif15 to test in combination with K5Is as an anti-mitotic chemotherapeutic regimen. Citation Format: Emma G. Sturgill, Ryoma Ohi. Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy. [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 2722.