bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 203: Visualization of drug delivery by using high resolution microscopic mass spectrometry
Authors: Yasunaga Masahiro , Furuta Masaru , Ogata Koretsugu , Koga Yoshikatsu , Matsumura Yasuhiro 
Published: August 2015

Abstract
Pharmacokinetic (PK) and pharmacodynamic (PD) studies are important to evaluate the efficacy and toxicity of the drugs. In these analyses, tissue homogenates are generally used for the quantification by high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LC-MS). However, they lack the information regarding the drug distribution in a specific anatomical area. The information of the drug distribution allows us to optimize the drug design enabling more efficient targeted delivery. We studied the tissue distribution of paclitaxel (PTX) and its micellar formulation (NK105) using a microscopic mass spectroscopy (MMS). A MMS in which a microscope is coupled with an atmospheric pressure matrix-assisted laser desorption/ionization (MALDI) and quadruple ion trap time-of-flight (TOF) analyser was used. The matrix-coated drug sample is ionised and then separated on the basis of its mass-to-charge ratio (m/z). Images were acquired from imaging mass spectrometry (IMS) or tandem mass spectrometry (MS/MS) data. (1) We established the drug imaging system with enhanced resolution and sensitivity. In the analysis, MS and MS/MS were used for quantification and validation, respectively. (2) NK105 showed much stronger antitumor effects on a human pancreatic cancer BxPC3 xenograft than PTX. In the drug imaging, we demonstrated that NK105 delivered more PTX to the whole tumor tissue (including the center lesion). In the mouse model, PTX caused the peripheral neurotoxicity but NK105 did not. Multiple high drug-signal areas surrounding and inside the caudal nerve were observed in the case of PTX, whereas the signals after NK105 injection were significantly low. We succeeded in visualising the EPR (Enhanced Permeability and Retention) effect using MMS. The data obtained by the drug imaging may be useful for facilitating DDS-drug design.
The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution. Sci Rep. 3:3050. 2013.
Citation Format: Masahiro Yasunaga, Masaru Furuta, Koretsugu Ogata, Yoshikatsu Koga, Yasuhiro Matsumura. Visualization of drug delivery by using high resolution microscopic mass spectrometry. [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 203. doi:10.1158/1538-7445.AM2015-203
Abstract 2042: Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma
Authors: Jeon MinJi , Kim Won Gu , Lim Seonhee , Jang Eun Kyung , Kim Tae Yong , Shong Young Kee , Kim Won Bae 
Published: August 2015

Abstract
Context: Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors are identified as key regulators of many cancers. One genome-wide liknage analysis suggested Slit-Robo Rho GTPase activating protein 1 gene as a candidate gene in papillary thyroid carcinoma (PTC) susceptibility.
Objective: To identify the role of Slit-Robo signaling in PTC.
Results : Slits(Slit 1-3) and Robos (Robo 1-4) were expressed in all of thyroid cancer cells and Slit2, Slit3, Robo1 and Robo4 presented higher expression than others. The mRNA expression of Slits and Robos was higher in fresh frozen PTC tissues than matched normal tissues. When we conducted immunohistochemical staining of Slit2 and Robo1 in thyroid tissues, the positivity of Slit2 and Robo1 were higher in PTC tissues than benign or normal tissues. However, negative Slit2 expression was significantly associated with cervical lymph node (LN) metastasis, distant metastasis and cervical recurrence of PTC (P &lt;.001) irrespective of BRAF mutation status. In cellular assays, Slit2 treatment inhibited proliferation of thyroid cancer cells as dose dependent manner and also significantly suppressed cell migration by inhibiting activation of beta-catenin and inducing E-cadherin. Slit2 treatment also significantly suppressed beta-catenin activation induced by Wnt3A in luciferase reporter assay.
Conclusions : Low expression of Slit2 was associated with poor prognostic factors in PTC. This present study demonstrated the potential of Slit2 as a novel prognostic and therapeutic factor in PTC.
Citation Format: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma. [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 2042. doi:10.1158/1538-7445.AM2015-2042
Abstract 2049: Characterization of a novel BRCA1-EGR1 interaction
Authors: Dickson Naomi A. , Crawford Nyree T. , Mullan Paul B. 
Published: August 2015

Abstract
The tumor suppressor protein BRCA1 orchestrates DNA repair and cell cycle arrest following DNA damage, with transcriptional regulation integral to these processes. We have identified a novel, DNA-damage responsive, interaction between BRCA1 and the zinc-finger transcription factor EGR1. EGR1 is rapidly and transiently expressed in response to a wide variety of stress stimuli and growth factors, and like BRCA1, decreased expression of EGR1 correlates with tumor formation in mammary cell lines and tissues.
The stress response gene, NDRG1, was identified as a transcriptional target of BRCA1 by microarray analysis and subsequent RQ-PCR validation. NDRG1 is a known suppressor of breast cancer metastasis and we have observed a significant reduction of NDRG1 expression in breast cancer cell lines (relative to normal cell lines). Promoter analyses identified EGR1 binding motifs within the NDRG1 proximal promoter region, and EGR1 was confirmed as the transcription factor of interest by promoter assays. Downregulation of either BRCA1 or EGR1 (using a siRNA approach) resulted in a reduction in both basal and DNA-damage induced NDRG1 promoter activity, suggesting a co-regulatory mechanism. Indeed, recruitment of BRCA1 and EGR1 to the NDRG1 promoter was confirmed by ChIP assays.
GST-fused BRCA1 deletion constructs showed that EGR1 specifically interacts with a C-terminal region of BRCA1 (which contains both BRCT domains). However, following DNA damage, we observed EGR1 interaction along the entire length of the BRCA1 protein, suggesting that both BRCA1 and EGR1 reside within a larger transcriptional complex upon DNA damage. In agreement with this, siRNA knockdown of either BRCA1 or EGR1 in breast cell lines (i) induced endogenous DNA damage signalling, (ii) increased intracellular ROS generation and (iii) upregulated numerous stress-response genes.
To investigate transcriptional regulation downstream of this interaction we performed analyses of publically available ChIP-Seq data for both BRCA1 and EGR1, and identified a list of genomic locations (corresponding to gene promoters) at which both proteins localise. We will use these findings, in combination with our own ChIP-Seq experiments performed in the non-tumorigenic mammary cell line, 184A1, to investigate the roles of this novel complex in the maintenance of genomic stability and within normal breast biology.
Citation Format: Naomi A. Dickson, Nyree T. Crawford, Paul B. Mullan. Characterization of a novel BRCA1-EGR1 interaction. [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 2049. doi:10.1158/1538-7445.AM2015-2049
Abstract 2058: RHOA inactivation enhances Wnt signaling and promotes colorectal cancer
Authors: Rodrigues Paulo , Macaya Irati , Bazzocco Sarah , Andretta Elena , Mazzolini Rocco , Dopeso Higinio , Mateo-Lozano Silvia , Bilic Josipa , Cartón-García Fernando , Nieto Rocio , Suárez-López Lucia , Afonso Elsa , Landolfi Stefania , Hernandez-Losa Javier , Kobayashi Kazuto , Ramón y Cajal Santiago , Tabernero Josep , Tebbutt Niall C. , Mariadason John M. , Schwartz Jr Simo , Arango Diego 
Published: August 2015

Abstract
Activation of the small GTPase RHOA has strong oncogenic effects in many tumor types, although its role in colorectal cancer remains unclear. We show that RHOA inactivation contributes to colorectal cancer progression/metastasis, largely through the activation of Wnt/β-catenin signaling. RhoA inactivation in the murine intestine accelerates the tumorigenic process and in human colon cancer cells leads to the redistribution of β-catenin from the membrane to the nucleus and enhanced Wnt/β-catenin signaling, resulting in increased proliferation, invasion and de-differentiation. In mice, RHOA inactivation contributes to colon cancer metastasis and reduced RHOA levels were observed at metastatic sites compared to primary human colon tumors. Therefore, we have identified a new mechanism of activation of Wnt/β-catenin signaling and characterized the role of RHOA as a novel gene with tumor suppressor activity in colorectal cancer. These results constitute a shift from the current paradigm and demonstrate that RHO GTPases can suppress tumor progression and metastasis.
Citation Format: Paulo Rodrigues, Irati Macaya, Sarah Bazzocco, Elena Andretta, Rocco Mazzolini, Higinio Dopeso, Silvia Mateo-Lozano, Josipa Bilic, Fernando Cartón-García, Rocio Nieto, Lucia Suárez-López, Elsa Afonso, Stefania Landolfi, Javier Hernandez-Losa, Kazuto Kobayashi, Santiago Ramón y Cajal, Josep Tabernero, Niall C. Tebbutt, John M. Mariadason, Simo Schwartz Jr, Diego Arango. RHOA inactivation enhances Wnt signaling and promotes colorectal 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 2058. doi:10.1158/1538-7445.AM2015-2058
Abstract 2064: GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha
Authors: Thidil Puliyappadamba Vineshkumar , Thudi Nanda Kumar , Bredel Markus 
Published: August 2015

Abstract
Recently we demonstrated that the gene NFKBIA is deleted in most of the nonclassic sub types of Glioma. We have also shown that the over-expression of NFKBIA causes sensitization of the cancer cells towards various chemotherapeutic agents. We further extended our study to investigate the mechanism behind this chemo-sensitization by using temazolamide and and BAY 11-7082. We used two glioma cell lines U251, LN229 and one breast cancer cell line MDAMB231. Very interestingly we found that over expression of NFKBIA itself results in the down regulation of two major anti apoptotic proteins Mcl1 and Bcl-XL respectively. Next we treated the cells with Temozolamide and BAY 11-7082 separately and analysed the protein profile by western blotting. We have seen a strong down regulation of Mcl1 in all the cell lines and BCL-xl in two cell lines. But we didn't see any difference in the abundance of another related anti apoptotic protein Bcl2. We have seen enhanced apoptotic signal corresponding with the Mcl1 degradation. So it is clear from the study that the down regulation of Mcl1 by NFKBIA makes cells more susceptible towards the chemotherapeutic drugs.
Interestingly we also found that the protein beta-catetnine, a major component of a Wnt signaling pathway, is up regulated with the IκBα over expression and remain unchanged with the chemotherapeutic drugs in all the cell lines. Mcl1 degradation was mediated by the phosphorylation of GSK3 and the phosphorylated GSK3 prevent the usual proteasomal degradation of the beta-catetnine leading to it's accumulation in the cell. Thus we can conclude that NFKBIA paly an important role in the phosphorylation of GSK3 and results in the regulation of Mcl-1 and beta catenine.
Citation Format: Vineshkumar Thidil Puliyappadamba, Nanda Kumar Thudi, Markus Bredel. GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha. [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 2064. doi:10.1158/1538-7445.AM2015-2064
Abstract 2069: Stromal-epithelial crosstalk of Mig-6 has an important role for tumor suppression via progesterone in endometrial cancer
Authors: Kim Tae Hoon , Kim Byung Gak , Yoo Jung-Yoon , Lee Jae Hee , Castrillon Diego H. , Jeong Jae-Wook 
Published: August 2015

Abstract
Endometrial cancer is the most common malignancy of the female genital tract. This disease is commonly caused by an imbalance of progesterone (P4) and estrogen (E2) action that E2 stimulates proliferation of uterine epithelial cells while P4 is inhibitory to estrogen-mediated proliferation of the epithelium. Endometrial hyperplasia is also associated with endometrial cancer, which is a proliferative process in epithelium by E2. Responsiveness of progesterone is required to treat endometrial cancer and preserve the fertility of patients. Furthermore, PR expression in the uteri of patients with endometrial cancer has been used as an indicator for a first-rate prognosis. However, more than 30% of patients do not respond to progesterone treatment as a result of progesterone resistance and the mechanism of progesterone resistance is still unknown. Thus, identifying the mechanism of progesterone in endometrial cancer is essential to improve the therapy of this disease. Mitogen-inducible gene 6 (Mig-6) is an important mediator of progesterone receptor (PR) action in the murine uterus. As P4 achieves the inhibition of proliferation by coordinating stromal-epithelial cross-talk, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Sprr2f-cre mice (Sprr2fcre+ Mig-6f/f) to understand the role of epithelial Mig-6 in the uterus. Sprr2fcre+ Mig-6f/f mice displayed endometrial hyperplasia upon 10 weeks of age and develop endometrial cancer by E2 treatment for 3 months. Interestingly, the hyperplasia exhibited by Sprr2fcre+ Mig-6f/f mice was prevented by P4 treatment for 1 week in morphological and histological analysis. Proliferation decreased in the glandular epithelium of Sprr2fcre+ Mig-6f/f mice by P4, and apoptotic signal was also reduced. The expressions of stromal PR and its target genes were induced in Sprr2fcre+ Mig-6f/f mice after P4 treatment, indicating that P4-induced stromal Mig-6 can prevent the hyperplasia via regulating steroid hormonal signaling. This study suggested that stromal-epithelial communication of Mig-6 is critical in tumor suppressor function via regulating steroid hormonal signaling by progesterone. (This work was supported by American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.)
Citation Format: Tae Hoon Kim, Byung Gak Kim, Jung-Yoon Yoo, Jae Hee Lee, Diego H. Castrillon, Jae-Wook Jeong. Stromal-epithelial crosstalk of Mig-6 has an important role for tumor suppression via progesterone in endometrial 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 2069. doi:10.1158/1538-7445.AM2015-2069
Abstract 2081: The CCCTC-binding factor (CTCF) functions to downregulate the transcription of MGMT gene in human glioblastoma cells
Authors: Srivenugopal Kalkunte S. , Al-Obaide Mohammed Ibrahim 
Published: August 2015

Abstract
The O6-methylguanine-DNA methyltransferase (MGMT) gene located at chromosome 10q26 encodes a DNA repair protein that abrogates the therapeutic effects of alkylating agents by preventing the formation of mutagenic lesions or cytotoxic DNA crosslinks. MGMT is highly expressed in human gliomas and its transcriptional regulation has emerged as a major translational focal point in neuro-oncology, because the epigenetic silencing of the MGMT gene which occurs in a subset of these malignancies confers improved treatment responses to both chemo and radiation therapies. While the promoter methylation and its contribution to glioma therapy has been much studied, the regulation of MGMT transcription per se, proteins accessory to the process and the chromatin structure thereof are not well understood. The CCCTC-binding transcription factor (CTCF) is one such multifunctional protein involved not only in DNA methylation but also with transcriptional activation/repression, and induction of short or long range chromatin looping. CTCF, an 11 zinc-finger containing protein is more frequently known for its insulating effects by binding diverse nucleotide sequences and restricting the function of transcriptional enhancers. Our bioinformatic analysis of the human MGMT gene showed an unusually high (7-10 sites) congregation of CTCF-binding sites distal to the promoter in human cancer cell lines. Given these considerations, we used CTCF siRNA to eliminate the transcription factor in two MGMT-proficient GBM cell lines (SF180 and GBM10). A specific reduction of CTCF protein by individual and pooled siRNAs was consistently accompanied by increased MGMT protein and mRNA levels. Furthermore, the DNA repair activity of MGMT was increased by 50%, which correlated with a proportional reduction of the CTCF protein in siRNA-exposed cells. Currently, we are investigating the effect of CTCF on MGMT reactivation in cells with methylation, MGMT promoter activity in CTCF silenced cells and the effect of enforced CTCF expression on MGMT transcription. Our results for the first time highlight the involvement of multivalent CTCF in MGMT expression. Since CTCF is tightly linked with DNA methylation, further studies should reveal its role in silencing of MGMT in human GBMs (supported by CPRIT RP130266 and NIH RO3CA125872 grants to KSS).
Citation Format: Kalkunte S. Srivenugopal, Mohammed Ibrahim Al-Obaide. The CCCTC-binding factor (CTCF) functions to downregulate the transcription of MGMT gene in human glioblastoma cells. [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 2081. doi:10.1158/1538-7445.AM2015-2081
Abstract 2082: Control and function of the PROX1 transcription factor in malignant glioma
Authors: Goudarzi Kaveh M. , Elsir Tamador , Nistér Monica , Lindström Mikael S. 
Published: August 2015

Abstract
Malignant gliomas remain to be fatal and highly resistant to therapy. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. PROX1 is highly relevant to study in relation to brain tumors due to its role in normal CNS development, where it leads to progenitor cell differentiation and initiation of neurogenesis. We have previously shown that PROX1 is expressed in human gliomas where there is a positive and statistically significant correlation between PROX1 expression and glioma tumor grade. We have also evaluated the prognostic value of PROX1 in a cohort of patients with grade II gliomas and found that a high number of PROX1 positive cells correlated significantly with poor outcome, a clinically important finding, as such predictors do not exist at present. The mechanism behind PROX1 overexpression in high-grade glioma and its functional consequences remain unclear. To this end we set out to study PROX1 effects on the behavior of glioma cells. We found that glioma cell lines in general expressed only low levels of PROX1 protein and mRNA. However, PROX1 was readily detected in the U343MGa Cl2:6 glioma cell line. This cell line also expresses GFAP and SOX2 and has features in common with glioma stem cells. Depletion of PROX1 in U343MGa Cl2:6 cells using siRNA had a marginal positive effect on cell proliferation in a short term assay. Furthermore, ectopic PROX1 impaired the ability of glioma cells to proliferate as indicated by reduced colony formation and decreased BrdU incorporation. We present experimental evidence showing that PROX1 induces p27. By regulating p27, PROX1 may block the activity of Cdk2/Cyclin E complex, and thus inhibit cell cycle progression. The functional consequences of PROX1 expression on the stemness, migration, and invasion phenotypes of glioma cells remain to be further investigated and preliminary results will be presented.
Citation Format: Kaveh M. Goudarzi, Tamador Elsir, Monica Nistér, Mikael S. Lindström. Control and function of the PROX1 transcription factor in malignant glioma. [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 2082. doi:10.1158/1538-7445.AM2015-2082
Abstract 2092: FOXO1/Sprouty2 pathway regulates vascular tumor growth
Authors: Ayyaswamy Sriram , Du Wa , Anderson Christopher , Phung Thuy L. 
Published: August 2015

Abstract
Vascular tumors are endothelial cell neoplasms with a wide spectrum of clinical presentations, ranging from benign infantile hemangiomas in children to low-grade malignant hemangioendotheliomas and highly aggressive angiosarcomas in adults. To date, the molecular basis of vascular tumor pathogenesis is poorly understood and standard therapy for these tumors have limited clinical efficacy.
Forkhead box protein O1 (FOXO1) is a transcription factor with tumor suppressor function and is dysregulated in human cancer. In this study, we showed that FOXO1 suppressed vascular tumor growth, and mechanistically, the inhibitory effects of FOXO1 were mediated by Sprouty2. FOXO1 expression was reduced in a variety of human vascular tumors examined (infantile hemangioma, hemangioendothelioma and angiosarcoma) as compared with normal blood vessels as determined by western blotting and immunohistochemical stains. Knockdown of FOXO1 gene expression with short hairpin RNA resulted in increased vascular tumor cell migration and proliferation in vitro and in vivo. Conversely, over-expression of constitutively active FOXO1 in these cells suppressed cell growth. We observed that FOXO1 interacted with Sprouty2 promoter in situ in chromatin immunoprecipitation assay and increased Sprouty2 gene expression in tumor cells. Similar to FOXO1, Sprouty2 expression was reduced in vascular tumors. Over-expression of Sprouty2 decreased tumor cell growth and migration. Conversely, knockdown of Sprouty2 increased tumor growth in vitro and in vivo. Knockdown of Sprouty2 in cells with over-expression of constitutively active FOXO1 resulted in reduced tumor growth and “rescued” the FOXO1 phenotype, indicating that Sprouty2 is an important mediator of the biological effects of FOXO1. Microarray gene expression profiling of human angiosarcoma cells with Sprouty2 knockdown together with network data integration using bioinformatics analysis and validated by quantitative PCR revealed important Sprouty2-regulated genes that are involved in angiogenesis, apoptosis and growth signal transduction pathways, including the collagen gene family, Notch signaling pathway and the GTPase IMAP family members.
In summary, these findings demonstrate important growth regulatory role of the FOXO1/Sprouty2 pathway in vascular tumors and highlight the potential roles of novel pathways downstream of Sprouty2 in these tumors.
Citation Format: Sriram Ayyaswamy, Wa Du, Christopher Anderson, Thuy L. Phung. FOXO1/Sprouty2 pathway regulates vascular tumor growth. [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 2092. doi:10.1158/1538-7445.AM2015-2092