bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2964: The codon 47 Pro47Ser polymorphism influences p53 phosphorylation and apoptotic function
Authors: Jennis Matthew , Hollstein Monica , Murphy Maureen E. 
Published: May 2015

Abstract
The p53 tumor suppressor protein is a central signaling protein in response to oncogenic, genotoxic and metabolic stress. Single nucleotide polymorphisms (SNPs) in p53 can have a marked impact on p53 tumor suppressor function, and have been associated with increased cancer risk. Amino acid 47 of p53 is a conserved residue, located within the second transactivation domain of this protein. In wild type p53, this residue is proline (P47, or WT). Importantly, this proline is critical for the ability of proline-directed kinases to phosphorylate p53 on the adjacent residue, serine 46. Phosphorylation of serine 46 of p53 greatly enhances the ability of p53 to transactivate certain target genes, and to induce apoptosis. In some Africans and African Americans, amino acid 47 of p53 encodes serine (S47) instead of proline. We have shown that the S47 polymorphism eliminates phosphorylation on serine 46, and reduces p53's ability to induce apoptosis by at least 3-fold. We have created mice that contain the humanized p53 gene (Hupki) for either the S47 or WT alleles of p53. In new data, we show that tissues from these mice have significantly decreased apoptosis after gamma radiation. We also show that apoptosis induced by cisplatin is markedly defective in S47 mice and cell lines. Further, MEFs from S47 mice have a 15-fold increase in IC50 for cisplatin, indicating that this polymorphism will impact the efficacy of cisplatin therapy in Africans and African Americans. Finally, we have identified two critical p53 target genes, GLS2 (metabolism) and NOXA (apoptosis), which show significantly impaired transactivation by S47. The long-term objective of this research is to further characterize the function of the S47 variant, and to identify the contribution of this variant to cancer risk and progression in Africans and African Americans.
Citation Format: Matthew Jennis, Monica Hollstein, Maureen E. Murphy. The codon 47 Pro47Ser polymorphism influences p53 phosphorylation and apoptotic function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2964. doi:10.1158/1538-7445.AM2014-2964
Abstract 2975: The pluripotency factor LIN28 promotes colorectal tumorigenesis and tumor progression
Authors: Schwitalla Sarah , Tu Ho-Chou , Viswanathan Srinivas , Zhu Hao , Qian Zhirong , Shah Samar , Ogino Shuji , Daley George Q. 
Published: May 2015

Abstract
LIN28A and LIN28B are RNA-binding protein paralogs expressed in embryonic stem cells and in early developing tissues. Through blocking the terminal processing of let-7 miRNAs and regulating the translation of a number of mRNA binding targets, LIN28 controls an array of targets that mediate proliferation, pluripotency, differentiation and metabolism. While highly expressed in the early embryos, the levels of LIN28A/B are downregulated as differentiation and development proceed. However, aberrant overexpression of LIN28 is often observed in human malignancies especially those with poor prognosis. We have demonstrated that LIN28 promotes cellular transformation in vitro, yet it is unknown how LIN28 regulates tumorigenesis in vivo. Here, we investigate the role of LIN28 in colorectal cancer (CRC) in humans and in mouse models. We first investigated the status of LIN28A/B in 1000 CRC patients and observed 35-60% of the cancer samples express LIN28A and/or LIN28B. Furthermore, we generated intestinal-specific LIN28 overexpressing mice, and observed intestinal adenoma as well as invasive adenocarcinoma that highly resemble the histology of human CRCs. Moreover, in Apcmin/+ animals, additional LIN28 expression significantly increased tumor incidence and accelerated disease onset, as their tumors are poorly differentiated and more invasive compared with Apcmin/+ tumors. Together, our study shows that LIN28 drives intestinal tumorigenesis and further promotes tumor progression in vivo. CRC is one of the major contributors to cancer-related mortality; however, current mouse models seldom progress to later stages of the disease, which greatly impedes efforts to developing more effective therapies. Based on the knowledge gained from this research, we hope to provide novel insights into designing therapeutics targeting late-stage CRC.
Citation Format: Sarah Schwitalla, Ho-Chou Tu, Srinivas Viswanathan, Hao Zhu, Zhirong Qian, Samar Shah, Shuji Ogino, George Q. Daley. The pluripotency factor LIN28 promotes colorectal tumorigenesis and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2975. doi:10.1158/1538-7445.AM2014-2975
Abstract 2992: Zoledronic acid inhibits angiogenesis through Rac1 inactivation in ovarian cancer
Authors: Gonzalez-Villasana Viany , Rodriguez-Aguayo Cristian , Fuentes-Mattei Enrique , Pradeep Sunila , Ivan Cristina , Sood Anil K. , Lopez-Berestein Gabriel 
Published: May 2015

Abstract
Background Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex and crucial process for tumor growth and development of metastasis. Rac1, a member of the Rho GTPase family, plays a central role in angiogenesis through regulation of endothelial cell migration, tube formation, adhesion, invasion, and proliferation. In this study we hypothesized that zoledronic acid (ZA) inhibits ovarian cancer angiogenesis through the inactivation of Rac1. Methods We treated HeyA8 MDR and Ovcar-5 cells with ZA to assess its effects on cell invasion, proliferation, expression of matrix metalloproteinases (MMPs; Milliplex assay) and angiogenic factors. We also determined Rac1 activation by pull-down assay. HeyA8 MDR and Ovcar-5 orthotopic murine models of ovarian cancer were assessed for expression of CD31 and Ki-67, Rac1 activation, and apoptosis by immunohistochemistry after treatment with ZA, nanoparticle, albumin-bound paclitaxel (nab-paclitaxel), or a combination. Results In vitro, we observed inhibition of HeyA8 MDR and Ovcar-5 cell invasion and proliferation by ZA. Moreover, ZA decreased the secretion of MMP-7 and vascular endothelial growth factor C (VEGF-C) in HeyA8 MDR cells and MMP-9, MMP-10, VEGF-C, granulocyte-colony stimulating factor, endothelin-1, follistatin, interleukin-8, placenta growth factor, fibroblast growth factor-1, and hepatocyte growth factor in Ovcar-5 cells. Furthermore, ZA inactivated Rac1 in both cells lines. In vivo, ZA decreased the number of nodules and tumor weight, inhibited angiogenesis and cell proliferation, and increased apoptosis in both HeyA8 MDR and Ovcar-5 animal models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel. Conclusion ZA inhibits ovarian cancer angiogenesis through the inactivation of Rac1, suggesting that ZA combined with paclitaxel could be a novel therapeutic approach to ovarian cancer angiogenesis.
Citation Format: Viany Gonzalez-Villasana, Cristian Rodriguez-Aguayo, Enrique Fuentes-Mattei, Sunila Pradeep, Cristina Ivan, Anil K. Sood, Gabriel Lopez-Berestein. Zoledronic acid inhibits angiogenesis through Rac1 inactivation in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2992. doi:10.1158/1538-7445.AM2014-2992
Abstract 3008: Effects of HSPG on inhibition of chemokine-induced angiogenesis
Authors: Ju Donghong , Speyer Cecelia , Gorski David , Kosir Mary A. 
Published: May 2015

Abstract
PURPOSE: The purpose of the study is to inhibit angiogenesis by using using specific inhibitors to the CXCR2 receptor that binds angiogenic CXC chemokines, while varying the concentration of heparan sulfate proteoglycan (HSPG), an important molecule for multiple angiogenesis factors.
METHODS: Using endothelial tubule formation assays on Matrigel, human umbilical vascular endothelial cells were treated with either antibody to CXCR2 or a small selective non-peptide inhibitor SB225002 (N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl)urea at varying concentrations and compared to control creating a dose-response curve. Experiments were repeated using Growth Factor Reduced (GFR) Matrigel which has 40-50% less HSPG. After 4 hours incubation, endothelial tubule formation was quantified by counting tubule numbers in four random microscopic fields using the microscope camera software NIS-Elements AR 3.10 in triplicate and compared to control.
RESULTS: There was a significant and dose-dependent inhibition of endothelial tubule formation on Matrigel by SB225002 at concentrations ranging from 0.56 µM to 11 µM (p=0.04 to 0.004). The IC50 was 5.2 µM. There was also significant inhibition of tubule formation with anti-CXCR2 antibody at 20-40 µg/ml in a dose-dependent manner (p=0.001 and 0.00003), with IC50 of 33.6 µg/ml on Matrigel. However, on GFR Matrigel, the IC50 for SB225002 inhibition of endothelial tubule formation was lower at 0.61 µM with a significant dose-dependent inhibition from 0.56 µM to 11 µM (p=0.0004 to 0.00001). Anti-CXCR2 antibody inhibition of tubule formation was also significant on GFR Matrigel at 20 µg/ml (p=0.006) with IC50 of 18.6 µg/ml.
CONCLUSION: A selective non-peptide inhibitor of CXCR2 (SB225002) inhibited endothelial tubule formation with 8.5 times a lower dose when HSPG concentrations were reduced using GFR Matrigel. Angiogenesis factors such as VEGFA, FGF-2 and CXC chemokines require HSPGs on the cell surface of endothelial cells, so optimal control of angiogenesis may require control of HSPGs as well. The inhibition of transmembrane CXCR2 is important for emerging therapies for inflammation and malignancy, and associated angiogenesis.
Citation Format: Donghong Ju, Cecelia Speyer, David Gorski, Mary A. Kosir. Effects of HSPG on inhibition of chemokine-induced angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3008. doi:10.1158/1538-7445.AM2014-3008
Abstract 3012: Converging effectors of airway lineage specification and metastasis in lung cancer
Authors: Nguyen Don X. 
Published: May 2015

Abstract
Lung adenocarcinoma (LUAD) is a deadly and heterogeneous subtype of non-small cell lung cancer. During LUAD progression, the emergence of alternate cell lineage traits in primary tumors correlates with poor outcome. The underlying mechanisms and biological consequences of these phenomena are poorly understood.
Using an integrated approach, we examined the molecular relationship between cell differentiation states, lung cancer subtypes, and clinical outcome, to discover a role for lineage-restricted genes in the pathogenesis of LUAD (1). Specifically, we identified two airway selective lineage transcription factors, GATA6 and HOPX, as inhibitors of metastatic progression. Down-regulation of their expression in a subset of human tumors correlates with aberrant tumor differentiation and relapses. GATA6 and HOPX cooperatively restrict the metastatic potential of LUAD cells, by modulating converging transcriptional programs of airway epithelial differentiation and malignant invasion.
Our findings demonstrate that perturbation of intrinsic cell lineage pathways is a determinant of metastasis in specific lung cancers. The implications of these findings for the origin(s) and treatment of LUAD metastasis will be discussed.
(1) Cancer Cell, 23 (6): 725-738. 2013.
Citation Format: Don X. Nguyen. Converging effectors of airway lineage specification and metastasis in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3012. doi:10.1158/1538-7445.AM2014-3012
Abstract 3058: Bone marrow hematopoietic stem cell niche activation and mobilization fosters the metastatic niche
Authors: Giles Amber J. , Murgai Meera , Vicioso Yorleny , Highfil Steven , Mackall Crystal , Wexler Leonard , Lyden David , Kaplan Rosandra Natasha 
Published: May 2015

Abstract
Metastasis remains the main cause of mortality for patients with cancer. The process whereby a localized tumor becomes metastatic remains poorly understood. Metastasis was previously thought to be a late-stage, unidirectional migration of cells from the primary tumor to a distant site, due to acquired genetic mutations that conferred necessary metastatic attributes to the cell. However, current research demonstrates that dissemination is not a late phenomenon and although loss of metastasis suppressor genes or gain of acquired mutations can contribute to the metastatic phenotype, the cross-talk between the tumor and its microenvironment has proven to be a major driver of this process. We have found that recruited bone marrow-derived cells and changes in resident stromal cells form a microenvironment that is conducive to metastatic progression, termed the pre-metastatic niche. The recruited and resident cells that form this microenvironment are active areas of investigation. Because the bone marrow is the source for most of the recruited cell types in these distant tissue sites, we postulated that activation of the bone marrow's hematopoietic compartment plays a key role in metastatic progression. We sought to profile the changes that occur within the hematopoietic stem cell niche of the bone marrow and subsequent changes in hematopoiesis in the setting of tumor development. Within the bone marrow of tumor bearing mice we found increased proliferation of hematopoietic stem and progenitor cells. These cells are also increased in the circulation of both tumor bearing mice and patients with malignancy. Furthermore, we have determined that elevated levels of circulating hematopoietic progenitor cells can be predictive of metastatic risk, as those patients with the highest levels at diagnosis developed metastases. This biomarker may be useful in stratifying therapy for patients with localized disease who have the highest metastatic risk. Better understanding of the steps and individual factors required to establish a metastatic microenvironment can lead to novel adjuvant therapies to target this process.
Citation Format: Amber J. Giles, Meera Murgai, Yorleny Vicioso, Steven Highfil, Crystal Mackall, Leonard Wexler, David Lyden, Rosandra Natasha Kaplan. Bone marrow hematopoietic stem cell niche activation and mobilization fosters the metastatic niche. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3058. doi:10.1158/1538-7445.AM2014-3058
Abstract 3069: Radial flow microfluidic device for high-throughput affinity-based isolation of circulating tumor cells
Authors: Murlidhar Vasudha , Reddy Rishindra M. , Zeinali Mina , Grabauskiene Svetlana , Ghannad-Rezaie Mostafa , Wicha Max S. , Simeone Diane M. , Ramnath Nithya , Nagrath Sunitha 
Published: May 2015

Abstract
Circulating tumor cells (CTCs) are believed to play an important role in metastasis, a process accounting for the majority of cancer-related deaths. They offer a non-invasive biopsy technique to study tumors and are shown to be useful prognostic indicators. Because of their rarity in the bloodstream, microfluidic isolation techniques are complex and time-consuming, and provide yields of CTCs insufficient or non-viable for studies other than enumeration. Additionally, due to the low processing speeds, the volumes of blood processed remain limited and can be a hindrance to obtaining higher yields of CTCs and their potential use as biomarkers of early diagnosis. Here we report a novel high throughput microfluidic technology, the OncoBean Chip, employing radial flow that introduces a varying shear profile across the device and enables efficient cell capture by affinity at high flow rates. The cell recovery from whole blood was validated with cancer cell lines H1650 and MCF7, and the OncoBean Chip achieved an efficiency &gt;80% at a throughput of 10 mL/hr, a flow rate yet achieved only in physical size based separation techniques. A cell viability of 92.91% shows that the cells recovered at high throughput could still be used for downstream analysis. Clinical competence was demonstrated in blood specimens from breast, pancreatic and lung cancer patients. The OncoBean Chip thus holds potential applications in the diagnosis of early stage cancers, where the low numbers of CTCs could be enriched using this novel device.
Citation Format: Vasudha Murlidhar, Rishindra M. Reddy, Mina Zeinali, Svetlana Grabauskiene, Mostafa Ghannad-Rezaie, Max S. Wicha, Diane M. Simeone, Nithya Ramnath, Sunitha Nagrath. Radial flow microfluidic device for high-throughput affinity-based isolation of circulating tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3069. doi:10.1158/1538-7445.AM2014-3069
Abstract 3099: Dual targeting of mTOR and Notch disrupts growth and promotes apoptosis in diffuse intrinsic pontine glioma
Authors: Taylor Isabella C. , Hutt-Cabezas Marianne , Weingart Melanie , Warren Kathy , Chang Howard , Nazarian Javad , Eberhart Charles G. , Raabe Eric H. 
Published: May 2015

Abstract
Diffuse intrinsic pontine gliomass (DIPGss) account for 10% of pediatric brain tumors and have a universally poor prognosis. Our laboratory has shown that targeting the NOTCH pathway in glioblastoma (GBM) with gamma secretase inhibitors (GSI), inhibits the growth and viability of tumor neurospheres. Primary DIPG as well as DIPG cell lines express have very high levels of NOTCH activity as measured by western blot and qPCR assays. AKT amplification is observed in primary DIPG, and TORC1/TORC2 activation occurs in DIPG cell lines as measured by western blot. The mTOR and NOTCH pathways are known to interact and alter cancer stem cell growth, stemness, and metabolism. We hypothesized that dual targeting of NOTCH and mTOR in DIPG would lead to decreased proliferation and increased apoptosis compared to targeting either pathway in isolation. In established DIPG cell lines, we observed that GSI treatment decreases NOTCH activity in a dose dependent manner as evidenced by decreased expression of NOTCH targets expression of Hes1 and Hey1 via as measured by western blot and qPCR assays. We also observed a dose-dependent reduction in DIPG proliferation and growth after gamma-secretase inhibition as measured by BrdU (Day 7, DMSO to 5 uM MRK003 had p value &lt;0.05) and MTT assays (Day 5 and Day 7, DMSO to 2 uM and 5 uM MRK003 p value &lt;0.05). However, inhibition of growth and increased apoptosis were not complete. We observed a similar decrease in proliferation and increase in apoptosis using the dual TORC1/TORC2 inhibitor PPT242. Combination therapy with MRK003 and PP242 led to significantly increased apoptosis compared to either treatment alone (cell cycle Sub-G1: DMSO 13.2% vs 1000nM PP242-5uM M003 28.9%). This data suggest that dual targeting of the mTOR and NOTCH pathways with GSI will decrease DIPG cell growth and proliferation, increase cell death, and reduce tumorigenicity.
Citation Format: Isabella C. Taylor, Marianne Hutt-Cabezas, Melanie Weingart, Kathy Warren, Howard Chang, Javad Nazarian, Charles G. Eberhart, Eric H. Raabe. Dual targeting of mTOR and Notch disrupts growth and promotes apoptosis in diffuse intrinsic pontine glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3099. doi:10.1158/1538-7445.AM2014-3099
Abstract 3100: Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies
Authors: Bolin Sara M. , Lau Jasmine , Chen Justin , Savov Vasil , Persson Anders I. , Hede Sanna-Maria , Weiss William A. , Swartling Fredrik 
Published: May 2015

Abstract
MYCN-amplified medulloblastoma is a poor-prognosis childhood brain tumor with unknown cellular origin. Recently, we showed how MYCN overexpression could generate tumors with high penetrance from a glutamate transporter (GLT1) promoter in a transgenic model (GTML) of medulloblastoma. By using Rosa26-lsl-LacZ reporters we also showed that GLT1-positive neural stem cells represent presumed cells of tumor origin.
Transgenic GTML mice generate SHH-independent medulloblastoma 2-3 months after birth. Before tumor onset GTML mice presented significantly more proliferation in thalamic forebrain cells and in Bergmann glia in the cerebellum as compared to corresponding normal brain. Strikingly, adult GTML mice also show proliferative capacity in the Bergmann glia cell population in response to MYCN oncogene activity, further connecting this population to medulloblastoma development. Retroviral tagging using the RCAS/tv-a system marked BLBP- or GFAP-positive tumor initiating cells and expression analysis could further determine genetic profiles of glial origin.
Interestingly, MYCN levels and early proliferation of brain tumors could be reduced by specific CDK2-inhibition by Milciclib or by using the bromodomain inhibitor JQ1. Treatment studies revealed a need for sustained treatment over 7-10 days to effectively abolish tumor cell proliferation. Both treatment strategies induced tumor cell senescence as seen by SA-beta-gal staining and by downregulated levels of Lamin B1. Our data suggest that tumors generated arise from radial glia or Bergmann glia in this medulloblastoma model and that dual inhibition of CDK2 and bromodomains suppresses tumor growth by targeting MYCN.
Citation Format: Sara M. Bolin, Jasmine Lau, Justin Chen, Vasil Savov, Anders I. Persson, Sanna-Maria Hede, William A. Weiss, Fredrik Swartling. Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2014-3100