bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3766: Identifying rational combination therapies with rapamycin for the treatment of epithelial cancers
Authors: Dawood Moez , Lu Yiling , Mills Gordon 
Published: August 2015

Abstract
Targeted therapies are designed to inhibit specific pathways driving the malignant phenotype while concurrently decreasing side effects on normal cells. However, very frequently, inhibition of the targeted pathway activates compensatory mechanisms designed to bring the pathway back into equilibrium allowing for cancer cell survival, a mechanism known as adaptive drug resistance. The purpose of this project is to identify and abrogate the adaptive drug resistance of epithelial cancers to rapamycin, an allosteric inhibitor of mTOR (mammalian target of rapamycin), and to rapamycin analogs in the PI3K (phosphoinositide-3-kinase) pathway, the most commonly dysregulated pathway in epithelial cancers. Using 3D- cultures, rapamycin-induced morphology changes and cell death were recorded. Changes in protein levels due to rapamycin-induced adaptive signaling were detected using reverse phase protein arrays (RPPA), verified by western blotting, and analyzed to determine potential adaptive mechanisms. Based on screening results from RPPA, rapamycin was combined with rationally selected drugs designed to thwart adaptive drug resistance to rapamycin. This co-extinction approach reinforced rapamycin into an effective inducer of cell death, ultimately bypassing drug resistance mechanisms and precluding the emergence of future therapeutic resistance. Successful combinations will be forwarded into animal studies to demonstrate in vivo efficacy for the treatment of epithelial cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Moez Dawood, Yiling Lu, Gordon Mills. Identifying rational combination therapies with rapamycin for the treatment of epithelial cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3766. doi:10.1158/1538-7445.AM2015-3766
Abstract 3770: The spindle assembly checkpoint requires phosphatase activity
Authors: Foss Kristen , Zhang Liguo , Robeson Alexander C. , Kornbluth Sally 
Published: August 2015

Abstract
The spindle assembly checkpoint (SAC) prevents activation of the anaphase-promoting complex (APC/C) until all chromosomes are correctly attached to the mitotic spindle. A defective SAC contributes to errors in chromosome segregation, which promotes aneuploidy and may eventually lead to cancer. Early in mitosis, the mitotic checkpoint complex (MCC) inactivates the APC/C by binding the APC/C activating protein cdc20 until the chromosomes are properly aligned, at which point the MCC dissociates and releases cdc20 to activate the APC/C. Once the APC/C is activated, it targets many substrates for degradation, including cyclin B and securin, and the cell progresses into anaphase. The precise molecular mechanisms regulating SAC inactivation are still poorly understood. We sought to determine the role of mitotic phosphatases in the SAC. To address this question, we treated mitotic cells with various phosphatase inhibitors to examine their effect on APC/C activation. Using this approach we identified two inhibitors, calyculin A and okadaic acid (1uM), that cause MCC dissociation and APC/C activation leading to cyclin A and cyclin B degradation in nocodazole-arrested cells. Although the cells are able to degrade cyclin B, they do not exit mitosis as evidenced by high levels of cdk1 substrate phosphorylation and chromosome condensation. Our results demonstrate that a calyculin A and okadaic acid (1uM) sensitive phosphatase is required for SAC activation.
Citation Format: Kristen Foss, Liguo Zhang, Alexander C. Robeson, Sally Kornbluth. The spindle assembly checkpoint requires phosphatase activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2015-3770
Abstract 3798: KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway
Authors: Kong Yanjie , Chen Ceshi 
Published: August 2015

Abstract
Triterpenoids extracted from Cimicifuga foetida were reported to inhibit cancers by inducing cell cycle arrest and apoptosis. In this study, KHF16 (24-acetylisodahurinol-3-O-b-D-xylopyranoside), a new cycloartane triterpenoid isolated from the rhizomes of Cimicifuga foetida, showed potent anti-cancer activity in multiple ERa/PR/HER2 triple-negative breast cancer (TNBC) cell lines. KHF16 significantly induces cell cycle G2/M phase arrest and apoptosis in both MDA-MB-468 and SW527 TNBC cell lines. KHF16 reduces the expression levels of XIAP, Mcl-1, Survivin, Bcl-2 and Cyclin B1/D1 proteins. Importantly, KHF16 inhibits TNFα-induced IKKa/b phosphorylation, IKBa phosphorylation, p65 nuclear translocation and NF-κB downstream target gene induction in TNBC cells. These results suggest that KHF16 may inhibit TNBC through blocking the NF-κB signaling pathway.
Citation Format: Yanjie Kong, Ceshi Chen. KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3798. doi:10.1158/1538-7445.AM2015-3798
Abstract 380: Capture of EpCAM-negative circulating tumor cells (CTCs) with a “Universal CTC-Chip”
Authors: Yoneda Kazue , Chikaishi Yasuhiro , Kawashima Eri , So Tomoko , Uramoto Hidetaka , Ohnaga Takashi , Tanaka Fumihiro 
Published: August 2015

Abstract
Background: Circulating tumor cell (CTC) can be a potentially useful clinical marker in early diagnosis and monitoring therapeutic effects for patients with malignant tumors. Our previous study showed that CTC detected by an EpCAM (epithelial cell adhesion molecule) based immuno-magnetic separation system “CellSearch” was useful in the diagnosis of malignant pleural mesothelioma (MPM), and also useful in the prognosis of epithelioid type MPM (Yoneda K, et al. Ann Surg Oncol. 2013). However, EpCAM-negative tumor cells cannot be principally captured with the system. Therefore, we have developed EpCAM-independent “Universal CTC-Chip System”, and assessed its capture capability.
Methods: PC-9 (lung cancer cell line) was employed as EpCAM-positive cells, ACC-MESO-1 and ACC-MESO-4 (mesothelioma cell lines) were employed as EpCAM-negative cells. The expression of cell surface antigen was confirmed by flow cytometry. A microfluidic devices made of resin was coated in two steps with bridging antibody and capture antibody. It is possible to use any antibody to capture. In this study, we use anti-EpCAM antibody, anti-podoplain antibody, anti-mesothelin antibody, and isotype control. First, we verified capture capability of this system using samples which were spiked tumor cells labeled with CFSE in PBS containing 5% BSA. Then, we measured in the same manner by adding the cells to the blood of healthy donor, and calculated capture rate.
Results: The expression analysis of cell surface antigens, PC-9 was EpCAM-positive, podoplanin, mesothelin were negative. On the other hand, MESO-1, 4 was EpCAM negative, podoplanin, mesothelin were positive. The capture efficiency in PBS containing 5% BSA with each cell using anti-EpCAM antibody, anti-podoplanin antibody and anti-mesothelin were PC-9: 101.1% / 2.3% / 2.9%, MESO-1: 3.5% / 52.7% / 4.3%, MESO-4: 3.0% / 78.3% / 5.4%, respectively. In the study of blood, each of the capture rate using anti-EpCAM antibody and anti-podoplanin antibody were PC-9: 88.0/ 6.9%, MESO-1: 4.0%/ 12.7%, MESO-4: 2.2%/ 38.4%, respectively.
Conclusions: The capture efficiency using this device depends on the expression intensity of cell surface antigens. In experiments with PBS samples, it was possible to capture targeting specific cell surface antigen. Mesothelioma cells in the blood ware captured with combination of this CTC-Chip system and anti-podoplanin antibody.
Citation Format: Kazue Yoneda, Yasuhiro Chikaishi, Eri Kawashima, Tomoko So, Hidetaka Uramoto, Takashi Ohnaga, Fumihiro Tanaka. Capture of EpCAM-negative circulating tumor cells (CTCs) with a “Universal CTC-Chip”. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2015-380
Abstract 3807: Capsazepine attenuates JAK/STAT3 signaling pathway, proliferation, survival of prostate carcinoma DU145 cells through induction of the protein tyrosine phosphatase epsilon (PTP-epsilon)
Authors: Lee Jong Hyun , Kim Chulwon , Lee Seok-Geun , Lee Junhee , Lee Jung-woo , Ahn Kwang Seok 
Published: August 2015

Abstract
Constitutive activation of signal transducers and activators of transcription (STAT) 3 is a major distinguishing feature of various human cancer cells and its activation leads to survival, proliferation, and metastasis of tumor cells. Whether the anti-proliferative, pro-apoptotic, and anti-invasive effects of capsazepine (Capz), a synthetic analog of capsaicin, are linked to its capability to inhibit STAT3 activation was investigated. We found that Capz suppressed both constitutive and IL-6-inducible STAT3 activation in human prostate carcinoma cells. Capz also suppressed nuclear translocation and DNA binding activity of STAT3. The suppression was mediated through the inhibition of activation of the upstream kinases JAK1/2 and c-Src. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate treatment reversed the Capz-induced down-regulation of STAT3, thereby suggesting the involvement of a PTP. Capz induced the expression of PTPϵ protein and mRNA. Moreover, knockdown of PTPϵ by small interfering RNA suppressed the induction of PTPϵ, reversed the inhibition of STAT3 activation, suggesting the critical role of PTPϵ in its possible mechanism of action. Capz downregulated the expression of STAT3-regulated proliferative, antiapoptotic, angiogenetic, and metastatic gene products; and this correlated with suppression of cell proliferation and invasion, the accumulation of cells in sub-G1 phase of cell cycle, and induction of apoptosis. Overexpression of phosphorylated STAT3 led to the attenuation of Capz-mediated cleavage of PARP as compared to the control. Thus, overall, our results suggest that Capz is a novel inhibitor of STAT3 activation and thus may have a potential in negative regulation of growth, metastasis, and angiogenesis of tumor cells.
Citation Format: Jong Hyun Lee, Chulwon Kim, Seok-Geun Lee, Junhee Lee, Jung-woo Lee, Kwang Seok Ahn. Capsazepine attenuates JAK/STAT3 signaling pathway, proliferation, survival of prostate carcinoma DU145 cells through induction of the protein tyrosine phosphatase epsilon (PTP-epsilon). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3807. doi:10.1158/1538-7445.AM2015-3807
Abstract 3824: Human pan-cancer variomes and their epigenetic profiles: Extending beyond the coding region
Authors: Torcivia-Rodriguez John P. , Mazumder Raja 
Published: August 2015

Abstract
The identification on different cancer lines of non-synonymous single nucleotide variations (nsSNVs) has exploded as sequencing technology has improved and decreased in expense. The impact of these variations on specific genes is being widely studied thanks to efforts to unify fragmented information about sequence functional sites into comprehensive databases. In additional to sequence functional sites, DNA functional elements have been found throughout the genome - estimates by the ENCODE project of upwards of 80% of the genome - and account for at least some of the biological complexity of life. In this study, we investigate the frequency of cancer related nsSNVs on tissue-independent DNA functional element sites comprised of 14 different functional elements. Out of 1 651 364 cancer related nsSNVs that matched one or more of 5 680 308 total DNA elements collected, we identified a number of variations that significantly affect a broad range of DNA functional elements. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across several different cancer types led to the identification of nsSNVs located in functional elements found in 3 or more cancer types.
Citation Format: John P. Torcivia-Rodriguez, Raja Mazumder. Human pan-cancer variomes and their epigenetic profiles: Extending beyond the coding region. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3824. doi:10.1158/1538-7445.AM2015-3824
Abstract 3870: Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer
Authors: Hirashima Kyotaro , Seimiya Hiroyuki 
Published: August 2015

Abstract
The end replication problem of linear chromosome DNA causes telomere shortening and eventual senescence of normal cells. Cancer cells reactivate telomerase to maintain their telomere length and exhibit an infinite replicative potential. However, telomerase activation does not necessarily increase the average telomere length in cancer cells. Actually, cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. We previously demonstrated that forced telomere elongation in cancer cells promotes their differentiation in a xenograft tumor and represses innate immune genes that are upregulated in various human cancers. This implies that short telomeres of cancer cells contribute to their malignancy. However, it is completely unknown how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated human cancer cells. Using three different cancer cell lines, including those from prostate, breast and stomach, we found that telomere elongation by hTERT overexpression up-regulates TERRA signals, which were detected by northern blot analysis, and down-regulates innate immune genes such as STAT1, ISG15, and OAS3 in vivo. These changes were caused by telomere elongation and not by enhanced telomerase activity or hTERT overexpression per se. Down-regulation of the innate immune genes was also observed in the telomere-elongated cells under three-dimensional (3D) culture conditions, which mimicked the tumor microenvironment in vivo. Introduction of TERRA oligonucleotides repressed the innate immune genes even in cells with short telomeres under 3D culture conditions. Intriguingly, this gene repression appeared to occur from the action of the non-canonical nucleic acid structure called G-quadruplex (G4) in TERRA, because non-telomeric (i.e., non-G4-forming) control oligonucleotides had no effect whereas another non-telomeric but G4-forming oligonucleotide phenocopied the TERRA oligonucleotides. Transcriptome analysis revealed that telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various human cancers. Taken together, these observations suggest that the telomeric non-coding RNA G4 counteracts cancer malignancy through suppression of innate immune genes, and give a new insight into our understanding of telomere shortening in human cancer.
Citation Format: Kyotaro Hirashima, Hiroyuki Seimiya. Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3870. doi:10.1158/1538-7445.AM2015-3870
Abstract 3909: Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer
Authors: Harmon Tia L. , Harbuzariu Adriana , Yang Lily , Gonzalez-Perez Ruben R. 
Published: August 2015

Abstract
Background:
Leptin is a cytokine secreted by adipose tissue that binds its receptor, OB-R, leading to increased growth and survival of cancer cells. High levels of leptin have been correlated with poorer outcomes in breast cancer patients, particularly those afflicted with triple negative breast cancer (TNBC).
We have created a leptin peptide receptor antagonist, LPrA2, which has been shown to block leptin signaling in several cancer types. To increase its effectiveness, LPrA2 was coupled to iron oxide nanoparticles (IONPs).
We aim to determine if IONP-LPrA2 will serve as an adjuvant treatment, when combined with chemotherapeutics, for human TNBC and mouse TNBC-like (Tamoxifen-resistant) breast cancer cells E0771-TAM.
Methods:
Conjugation of LPrA2 to IONPs was confirmed by Western Blot and inhibition assays. To evaluate the effects of IONP-LPrA2 in mouse TNBC-like cells, the E0771 cell line (progesterone receptor and HER2 negative) was made insensitive to estrogen stimuli by long-term treatment with Tamoxifen (TAM). Human TNBC and E0771 cells, both responsive and unresponsive to estrogen (E0771-TAM), were treated with recombinant leptin and culture medium containing fetal bovine serum plus chemotherapeutics and IONP-LPrA2.
Cell cycle progression, cell viability and apoptosis were analyzed using the Cellometer Vision Image Cytometer ®.
Results:
IONP-LPrA2 was found to cause significant decrease in DNA synthesis during the S phase of the cell cycle in TNBC and TNBC-like cells when compared to E0771 cells. Additionally, IONP-LPrA2 showed additive effects on reduction of cell viability and apoptosis when combined with chemotherapeutics.
Conclusion:
These findings indicate that IONP-LPrA2 may be useful in the treatment and prevention of TNBC. Further, IONP-LPrA2 treatment may increase the effectiveness and allow for reduction of the dosage of chemotherapeutics. This will in turn attenuate undesired side effects of chemotherapy. These results may be beneficial for breast cancer patients, particularly those with TNBC who are overweight or obese lacking targeted therapy thus suffering the poorest outcomes.
Citation Format: Tia L. Harmon, Adriana Harbuzariu, Lily Yang, Ruben R. Gonzalez-Perez. Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3909. doi:10.1158/1538-7445.AM2015-3909
Abstract 3915: Inhibition of cdc2 is linked to PMA-induced cell differentiation
Authors: Vasilyeva Daria , Dolinsky Pairat , Fielder Shashana , Nakasone Alice , Packert Gerhild , Hu Xiaotang 
Published: August 2015

Abstract
The critical role of cdc2 (CDK1) in G2-M transition of the cell cycle control in mammalian cells has been well documented. Recent studies have also demonstrated that cdc2 is capable of driving G1 progress and G1-S transition via association with multiple interphase cyclins and through the interactions with Rb proteins. However, whether this pluripotent CDK regulates cell differentiation is unclear. Thus, the effect of phorbol 12-myristate 13-acetate (PMA) on cell differentiation and the expression of cdc2 in a human myeloid leukemia cell line, TF-1a, was investigated. When TF-1a cells were treated with 10−5, 10−6, and 10−7 PMA for 48 and 72h, they showed marked (≥50%) macrophage-like changes, evidenced by significant decrease in nucleus/cytoplasm ratio and increase (1-3 folds) in the expression of IL-1β, a macrophage marker. PMA treatment also caused time-dependent inhibition of cdc2 in both cytosol and nucleus of the cells, with a maximal inhibition being observed by 48 and 72h, which paralleled with the cell differentiation course. In contrast, there was no significant cell differentiation and inhibition of cdc2 being observed in control human myeloid leukemia TF-1 cells treated with PMA. Previous studies suggest that prolonged activation of MAPK pathway is linked to cell differentiation. PMA treatment also rapidly induced phosphorylation of MAPK kinases (MEK and ERK), which persisted for 24h, after which phosphorylated MEK and ERK were returned to base level, while the expression of cdc2 was still significantly downregulated, as compared with the control cells treated with DMSO. Pretreatment of TF-1a cells with sense cdc2 oligo nucleotides partially inhibited PMA-induced differentiation and upregulation of IL-1β. Taken together, our data suggest that MAPK pathway may be responsible for initiation of cell differentiation whereas inhibition of cdc2 is required for late differentiation of TF-1a cells in response to PMA stimulation. Whether activation of the MAPK pathway inhibits expression of cdc2 is currently under investigation (Supported by Faculty Incentive Grant and NIH-NIGMS MBRS RISE: R25 GM059244-13, Barry University).
Note: This abstract was not presented at the meeting.
Citation Format: Daria Vasilyeva, Pairat Dolinsky, Shashana Fielder, Alice Nakasone, Gerhild Packert, Xiaotang Hu. Inhibition of cdc2 is linked to PMA-induced cell differentiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2015-3915