bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4874: CXCR2 signaling axis- a helping hand to KRAS(G12D) mutation in pancreatic cancer initiation
Authors: Purohit Abhilasha , Varney Michelle , Rachagani Satya , Ouellette Michel , Batra Surinder K. , Singh Rakesh K. 
Published: May 2015

Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States. The high mortality can be accredited to late clinical presentation and early metastasis. Somatic mutations in oncogene KRAS(G12D) are the most common and earliest events during development of PC, suggesting their crucial role in tumor initiation; however, the precise functional molecular mechanism(s) of action remains unclear. CXCR2, a CXC chemokine receptor, and its ligands have also been found to be important in regulating inflammation, angiogenesis, and metastasis in various cancers. The purpose of the current study was to test the functional role of CXCR2 signaling in KRAS(G12D)-induced PC development. Immunohistochemical analysis of tumors derived from PDX-cre-LSL-kras(G12D) mice demonstrated significantly higher expression of Cxcr2 and its ligands Cxcl1 and -3. Expression of Cxcr2 and its ligands Cxcl1 and -3 was observed as early as 10 weeks and increased consistently as the lesions advanced. We demonstrated the direct link between KRAS(G12D) mutation and CXCR2 signaling using cell line models hTERT-HPNE and hTERT-HPNE -E6-E7-st with or without exogenously expressed KRAS(G12D). Real time PCR, ELISA and western blot analysis of these cells revealed that KRAS (G12D) up-regulates the expression of CXCR2 and its ligands at both the transcriptional and protein levels. In order to delineate the significance of CXCR2 in KRAS(G12D) induced autocrine growth, we treated the cell line models with various concentrations of SCH-527123 (CXCR2 antagonist) or CXCR2 neutralizing antibody. Our data shows that KRAS(G12D) bearing cells show significantly (P ≤ 0.05) greater percent inhibition in cell growth in comparison to their control counterparts. Next to evaluate the role of CXCR2 autocrine signaling in KRAS(G12D) induced cell migration, we performed a scratch assay by treating the hTERT-HPNE -E6/E7-st- KRAS(G12D) cells with SCH-527123 for 24 hours. Our data demonstrated a significant inhibition of cell migration in CXCR2 antagonist treated cultures. Together, our data demonstrate that KRAS(G12D) mutation up regulates CXCR2 and its ligands, which, in turn, play key roles in the autocrine regulation of cellular growth and migration in PC.
Note: This abstract was not presented at the meeting.
Citation Format: Abhilasha Purohit, Michelle Varney, Satya Rachagani, Michel Ouellette, Surinder K. Batra, Rakesh K. Singh. CXCR2 signaling axis- a helping hand to KRAS(G12D) mutation in pancreatic cancer initiation. [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 4874. doi:10.1158/1538-7445.AM2014-4874
Abstract 4884: Determination of sphingosine-1-phosphate levels in tissue interstitial fluid and lymphatic fluid utilizing novel collection techniques
Authors: Nagahashi Masayuki , Yamada Akimitsu , Miyazaki Hiroshi , Allegood Jeremy C. , Aoyagi Tomoyoshi , Huang Wei-Ching , Terracina Krista P. , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: May 2015

Abstract
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates many processes of cancer progression including angiogenesis. Among the two sphingosine kinases (SphK1 and SphK2), S1P generated by SphK1 inside cells is secreted and exerts its functions by binding to specific G protein-coupled receptors outside the cells. It is known that S1P levels in circulation of SphK1-/- mice are low and SphK2 -/- mice are high compared from controls. Utilizing SphK2 -/- mice, we have recently reported that S1P links inflammation and cancer in colitis-associated colon cancer. Further, we have shown that secreted S1P plays critical roles in tumor microenvironment by stimulating both angiogenesis and lymphangiogenesis. Although it is well established that S1P plays important roles in lymphatic fluid and interstitial fluid (IF), no methodology has been available to date to measure S1P levels in those fluid. Here we introduce for the first time the newly developed methods and measurements of levels of sphingolipids including S1P in IF and lymphatic fluid in both SphK1 -/- and SphK2 -/- mice. We found that S1P levels in the lymphatic fluid and IF are generally low in SphK1-/- mice and high in SphK2-/- mice. Interestingly, however, S1P levels in IF of the colon in SphK2-/- mice are significantly lower compared with wild type mice, where levels in downstream mesenteric lymph nodes and lymphatic fluid are higher, which is in agreement with the previous notion that lymphatic endothelial cells contribute to the S1P levels in the lymphatic fluid. Measurement of sphingolipids in IF and lymphatic fluid will provide new insights into mechanism of their actions in lymphatic progression of cancer.
M.N. is a Japan Society for the Promotion of Science Postdoctoral Fellow. S.S. is supported by NIH R37GM043880, and K.T. by NIH R01CA160688 and Susan G. Komen IIR 1222224.
Citation Format: Masayuki Nagahashi, Akimitsu Yamada, Hiroshi Miyazaki, Jeremy C. Allegood, Tomoyoshi Aoyagi, Wei-Ching Huang, Krista P. Terracina, Sheldon Milstien, Sarah Spiegel, Kazuaki Takabe. Determination of sphingosine-1-phosphate levels in tissue interstitial fluid and lymphatic fluid utilizing novel collection techniques. [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 4884. doi:10.1158/1538-7445.AM2014-4884
Abstract 4885: Changes in abundance of oral microbiota associated with oral cancer
Authors: Albertson Donna G. , Kuczynski Justin , Bhattacharya Aditi , Huey Bing , Corby Patricia M. , Queiroz Erica L. S. , Nightingale Kira , Kerr Alexander R. , DeLacure Mark D. , Veeramachaneni Ratna , Olshen Adam , Schmidt Brian L. 
Published: May 2015

Abstract
Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral clinically normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Patients with cancer or dysplasia, however, could be distinguished from healthy normal individuals by increased abundance of Prevotella. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases.
Citation Format: Donna G. Albertson, Justin Kuczynski, Aditi Bhattacharya, Bing Huey, Patricia M. Corby, Erica L. S. Queiroz, Kira Nightingale, Alexander R. Kerr, Mark D. DeLacure, Ratna Veeramachaneni, Adam Olshen, Brian L. Schmidt. Changes in abundance of oral microbiota associated with oral 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 4885. doi:10.1158/1538-7445.AM2014-4885
Abstract 4886: Targeting WNT1-inducible signaling pathway protein 2 (WISP2) alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression
Authors: Akalay Intissar , chouaib salem , thiery jean-paul 
Published: May 2015

Abstract
The molecular basis for the resistance of tumor cells to cell-mediated cytotoxicity remains poorly understood and thus poses a major challenge for cancer immunotherapy. The present study was designed to determine whether the WNT1-inducible signaling pathway protein-2 (WISP2, also referred to as CCN5), a key regulator of tumor cell plasticity, interferes with tumor susceptibility to Cytotoxic T Lymphocytes (CTL)-mediated lysis. We found that targeting WISP2 signaling in human breast adenocarcinoma MCF7 cells impairs CTL-mediated cell killing by a mechanism involving Kruppel-like factor-4 (KLF-4) induction and microRNA-7 (miR-7)downregulation. Inhibition of TGF-β signaling using the A83-01 inhibitor in MCF7-shWISP2 cells resulted in a significant reversal of the Epithelial-to-Mesenchymal Transition (EMT) phenotype, the expression of stem cell marker KLF-4 and a partial recovery of target susceptibility to CTLs. More importantly, we showed that silencing of KLF-4 was accompanied by a reduction in MCF7-shWISP2 resistance to CTLs. Using human breast cancer tissues, we demonstrated the coexpression of KLF-4 with EMT markers and TGF-β pathway. More importantly, we found that KLF-4 expression was accompanied by miR-7 inhibition, which is partly responsible forimpairing CTL-mediated lysis. Thus, our data indicate that WISP2 plays a role in regulating tumor cell susceptibility through EMT by inducing the TGF-β signaling pathway, KLF-4 expression and miR-7 inhibition. These studies indicate for the first time that WISP2 acts as an activator of CTL-induced killing and suggests that the loss of its function promotes evasion of immunosurveillance and the ensuing progression of the tumor.
Citation Format: Intissar Akalay, salem chouaib, jean-paul thiery. Targeting WNT1-inducible signaling pathway protein 2 (WISP2) alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. [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 4886. doi:10.1158/1538-7445.AM2014-4886
Abstract 4904: β-catenin silencing enhances radiation sensitivity through antagonizing effect of AMPK against Ku70/80 in head and neck cancer cells
Authors: Chang Hyo Won , Nam Hae Yun , Kim Mi R. , Lee Hyang J. , Seo Ji Hyun , Lee So Yeon , Kim Seong Who , Kim Sang Yoon 
Published: May 2015

Abstract
The Wnt/β-catenin pathway regulates the cell growth and survival following radiation in various types of cancer cells. Our previous report show that activation of the Wnt/β-catenin signaling pathway is a key radioprotective mechanism in irradiated head and neck cancer (HNC) cells. However, the molecular mechanisms by which β-catenin regulates radiation sensitivity are not clear. Here we attempted to elucidate the mechanism of cell death following radiation by studying how β-catenin silencing controls the radiation sensitivity of radioresistant HNC cells.
Of nine cell lines examined, the most radioresistant cell line (AMC-HN-9) were selected for this experiments. β-catenin silencing using small interfering RNA(siRNA) down-regulated β-catenin expression up to 72 h, which was confirmed by western blot analysis. The sensitivity to radiation was anlayzed by clonogenic analysis and MTT assay. As a result, β-catenin silencing remarkably decreased the survival of irradiated AMC-HN-9 cells and the cell viability also significantly reduced more by the combination treatment with β-catenin siRNA and radiation (0.37±0.034 fold) than when treated with β-catenin siRNA or radiation alone (0.68±0.055 fold and 0.90±0.043 fold, respectively). Interestingly, whereas expression of Ku70/80 was up regulated in AMC-HN-9 cells following irradiation (4Gy), in the cells treated with combination of radiation and β-catenin siRNA, Ku70/80 expression was dramatically decreased. In additionally, when exposed to radiation after β-catenin silencing, the up-regulation of irradiation-induced Ku80 completely was prevented by β-catenin silencing-induced AMPK.
Taken together, these results suggest that suppression of Ku70/80 expression through β-catenin silencing-induced AMPK is associated with its radio-sentitizing effect in AMC-HN-9 cells, thus supporting a novel radiosensitive mechanism of radioresistant HNC cells.
Citation Format: Hyo Won Chang, Hae Yun Nam, Mi Ra Kim, Hyang Ju Lee, Ji Hyun Seo, So Yeon Lee, Seong Who Kim, Sang Yoon Kim. β-catenin silencing enhances radiation sensitivity through antagonizing effect of AMPK against Ku70/80 in head and neck cancer 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 4904. doi:10.1158/1538-7445.AM2014-4904
Abstract 4907: Upregulation of furin is associated with the invasiveness of cumulatively irradiated cancer cells
Authors: Lee Myungjin , Rhu Changhwan , Kim Seong Who , Kim Sang Yoon 
Published: May 2015

Abstract
Furin, a subtilisin/kesin-like proprotein convertase (PC), activates membrane-bound MT1-MMP, which facilitates pro-gelatinase A (MMP2). These activated MT1-MMP and MMP2 are involved in cancer cell invasion and metastasis. In this study, we investigate the contribution of MMP2 activated by furin to cellular invasiveness of cumulatively irradiated cells.
Using previously established AMC-HN3 and AMC-HN8 cell line from laryngeal carcinoma patient, we have generated isogenic model of cumulatively irradiated AMC-HN3R and AMC-HN8R cell line, respectively. AMC-HN3R cells were increased furin expression with upregulation of MT1-MMP/MMP2 and their invasiveness by two fold (p &lt; 0.05) compared to AMC-HN3, while AMC-HN8R cells had no differences compared to AMC-HN8. In case of AMC-HN3R, inhibition of furin activity with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethyl-keton, CMK, showed a significant decrease of MT1-MMP/MMP2 and in vitro cellular invasiveness. Tumors obtained after subcutaneous (s.c.) inoculation of AMC-HN3R cells were larger, developed earlier and increased more furin than the tumor of parent cells, AMC-HN3. Although AMC-HN3R and AMC-HN8R cells identically undergo EMT, inhibition of furin activity decreases activated MMP2 and invasive potential of HN3R cell line unlike HN8R cell line, suggesting that furin is a potentially useful target for therapeutics.
Citation Format: Myungjin Lee, Changhwan Rhu, Seong Who Kim, Sang Yoon Kim. Upregulation of furin is associated with the invasiveness of cumulatively irradiated cancer 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 4907. doi:10.1158/1538-7445.AM2014-4907
Abstract 4909: Novel radiation mitigators and cancer chemoprevention drugs
Authors: Schiestl Robert H. , Rivina Yelena , Davoren Michael 
Published: May 2015

Abstract
The possibility of a radiation disaster from a nuclear detonation or accident has existed for over 50 years and spawned much of the basic research in radiobiology in the 1950-60s. The recent Fukushima accident was yet another reminder that there remains a dire need to develop novel therapies against radiation-induced toxicities. Here we report on the development of two novel radiation countermeasure therapies: Yel001 and Yel002. These small, biologically active, drug-like molecules were uncovered in the DEL high throughput assay reducing radiation-induced cyto- and geno-toxicity in yeast. Radiation-modulating activity was further confirmed in yeast plate-based DEL Assay: addition of either Yel001 or Yel002 to irradiated cultures reduced cell death and genomic instability. Further, Yel compounds increases survival to 75% in vivo following an LD100/30 dose of ionizing radiation (IR) with the first therapeutic injection administered 24 hours post exposure followed by injections at 48,72,96, and 120 hours. Additionally, treatment with Yel001 and Yel002 compounds reduces radiation-induced leukemia from 90% to to 50% and 40% respectively. Of note, treatment with either Yel001 or Yel002 reduced spontaneous leukemia rate from 10% to 0%. Furthermore, Yel002 significantly prolonged the life of Atm deficient mice. Treatment with Yel002 following IR accelerates the recovery of the hematopoietic cells and protects stem cells after sub-lethal exposures. In addition, treatment with Yel002 reduces I131, EMS, MMS, UV, cigarette smoke extract as well as nitrogen mustard induced toxicity as well as genotoxicity showing a broad application spectrum. Proteomics shows that Yel002 induces DNA repair mediated by Atm signaling, homologous recombination, nonhomologous end joining, base excision repair, DNA damage binding proteins and chromosome segregation functions. Toxicity has not been observed in neither in vitro or in vivo administrations, even in a two generation teratogenicity assay. Overall, Yel compounds have much potential as stockpile therapies for radiation-induced lethality and cancer as well as spontaneous cancer: they are highly effective when administered up to 24hours post exposure, they reduce radiation-induced sequelae such as leukemia, and appear to have an acceptable toxicity profile.
Citation Format: Robert H. Schiestl, Yelena Rivina, Michael Davoren. Novel radiation mitigators and cancer chemoprevention drugs. [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 4909. doi:10.1158/1538-7445.AM2014-4909
Abstract 4915: High degree of G2/M arrest induced by Polo-like kinase 1 (PLK1) inhibition is associated with radiosensitization
Authors: Wong Nelson , Khan Mohamed 
Published: May 2015

Abstract
Inhibition of polo-like kinase 1 (PLK1) seems to be a plausible avenue for sensitizing cancer cells to radiation. It has been demonstrated that normal cells tolerate PLK1 depletion well, when compared to cancer cells, suggesting a wide therapeutic index. This has been confirmed with our results from proliferation assays conducted with two primary human cell lines and various cancer cell lines. Recently, it has been shown that head-and-neck squamous cell carcinoma and medulloblastoma cells can be radiosensitized by PLK1 inhibition. Furthermore, PLK1 is involved in repair of DNA double-strand breaks. Together, these results suggest that PLK1 inhibition is a particularly attractive means of radiosensitization.
To further investigate the radiosensitization property of PLK1 inhibition, clonogenic assays were carried out. Various cancer cell lines were treated with specific PLK1 inhibitor BI 2536 and subjected to various doses of ionizing radiation. The cancer cell lines were of breast, colorectal, and pancreatic origin. We found that some, but not all, cancer cells were radiosensitized by pre-treatment with BI 2536. Mutational statuses of p53 and KRAS were examined, but no relationship between the mutational statuses and radiosensitization by BI 2536 treatment was found.
Since PLK1 inhibition causes G2/M arrest, which is the cell cycle phase that is known to be more sensitive to ionizing radiation, we assessed the percentage of cancer cells at G2/M phase when treated with or without BI 2536. Cells were treated with BI 2536 for 24 hrs before they were fixed, stained with propidium iodide, and analyzed with flow cytometry. The degree of G2/M arrest induction was assessed by G2/M induction index, as defined by % of G2/M cells before treatment / % of G2/M cells after treatment. We found that the G2/M induction indices were significantly higher with the cells that can be radiosensitized with PLK1 inhibition, when compared to those of the cells that cannot be radiosensitized. Therefore, we conclude that high G2/M induction index is predictive of radiosensitization with PLK1 inhibition. Future experiments of this project include determining the G2/M induction index threshold required for achieving radiosensitization and indentifying the molecular basis of such association.
Citation Format: Nelson Wong, Mohamed Khan. High degree of G2/M arrest induced by Polo-like kinase 1 (PLK1) inhibition is associated with radiosensitization. [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 4915. doi:10.1158/1538-7445.AM2014-4915
Abstract 4916: Efficiacy of NU7441-encapsulated PLGA nanoparticles in radiation sensitization of prostate cancer cells
Authors: Menon Jyothi U. , Tumati Vasu , Hsieh Jer-Tsong , Nguyen Kytai T. , Saha Debabrata 
Published: May 2015

Abstract
Introduction: Prostate cancer remains the leading cause of cancer-related mortality in men with an estimated 241,740 new cases and 28,170 deaths expected by end of 2012. Conventional cancer treatments such as radiation therapy can be ineffective due to radiation resistance of prostate cancer cells. This resistance arises due to their increased DNA double strand break (DSB) repair ability, especially through Non-Homologous End Joining (NHEJ). In this study, we have developed biodegradable and biocompatible poly lactic-co-glycolic acid (PLGA)-based nanoparticles containing the potent radio-sensitizer NU7441 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one) for radiation sensitization of prostate cancer cells by inhibiting DNA-dependent protein kinase, which regulates NHEJ.
Methods: PLGA nanoparticles encapsulating NU7441 and iron oxide as an imaging and targeting agent were prepared by a standard double emulsion technique and characterized for size and surface charge. R11 peptide was surface conjugated onto the nanoparticles for prostate cancer-specific targeting. Stability studies in de-ionized (DI) water and serum were conducted over 5 days followed by drug release studies in DI water at 37oC. Further, in vitro studies were done to study cytocompatibility with prostate epithelial cells (PZ-HPV7) and cellular uptake by prostate cancer cells (PC3). DSB repair kinetics of prostate cancer cells following nanoparticle uptake was studied using a DSB repair assay.
Results: Our nanoparticles had an average size of 274.13+ 79.96 nm and showed good stability in water and serum for 5 days. The nanoparticles also showed bi-phasic NU7441 release within 21 days at 37oC and &gt;80% PZ-HPV7 cell viability up to 2000 µg/ml nanoparticle concentration. Further, the particles were selectively uptake by PC3 cells in a dose and magnetic field-dependent manner and showed effective radiation sensitization of these cells in vitro.
Conclusions: Our results thus demonstrate that R11-conjugated PLGA-iron oxide nanoparticles containing NU7441 are biocompatible and can be potentially used to radio-sensitize prostate cancer cells in vivo.
Citation Format: Jyothi U. Menon, Vasu Tumati, Jer-Tsong Hsieh, Kytai T. Nguyen, Debabrata Saha. Efficiacy of NU7441-encapsulated PLGA nanoparticles in radiation sensitization of prostate cancer 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 4916. doi:10.1158/1538-7445.AM2014-4916