bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1159: Downregulation of TMPRSS11B in squamous cell carcinoma
Authors: Amano Suburu , Iwaya Takeshi , Nishizuka Satoshi , Kume Kohei , Ito Chie , Akiyama Yuji , Shioi Yoshihiro , Endo Fumitaka , Sasaki Akira 
Published: July 2016

Abstract
[Background] Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers. The molecular mechanism of ESCC development has not been fully elucidated. [Aim] The aim of this study is to identify responsible genes for ESCC development. [Materials and Methods] Firstly, we performed transcriptome sequence (RNA-seq) analysis of surgically resected tumor and corresponding normal tissues form 3 ESCC patients with different tumor locus, histrogical differentiation, and TNM stage.by RNA-seq analysis: (Case 1) upper thoracic esophagus, well differentiated SCC, TNM, Stage I; (Case 2) middle thoracic esophagus, poorly differentiated SCC, T3N0M0, Stage II; and (Case 3) lower thoracic esophagus, moderately differentiated SCC, T3N1M0, Stage III. Next, we validated the expression status of the candidate gene in 64 clinical samples and 10 ESCC cell lines (KYSE150, KYSE270, KYSE410, KYSE450, KYSE510, TE1, TE6, TE8, TE9, and TE10) using quantitative real-time PCR (qRT-PCR). [Results] In RNA-seq analysis, 34 genes showed more than 30-fold decrease in tumor samples compared to normal tissues, and the most downregulated gene was transmembrane protease serine 11B (TMPRSS11B). Amon these 34 genes, other 5 genes of TMPRSS11 family (TMPRSS11A, TMPRSS11BNL, TMPRSS11D, TMPRSS11E, and TMPRSS11F) were included. qRT-PCR analysis revealed that TMPRSS11B expression in ESCC samples were lower than those in normal samples (p &lt; 0.001). Downregulation of TMPRSS11B in tumor samples compared to corresponding normal samples were observed in 51 cases out of 64 (79.7%). Patients with expression levels of TMPRSS11B that were below the median value were assigned to the low expression group (n = 32), whereas those with expression values above the median were assigned to the high expression group (n = 32). Significant difference was not observed between two groups regarding clinicopathological data, including age, gender, TNM stage, and lymphatic/venous invasion. TMPRSS11B expression was not detected in all of ESCC cell lines and noncancerous esophageal epithelial cell line, HET1A. [Conclusion] Our results suggest that downreguration of TMPRSS11B expression occurs in early stage of the ESCC oncogenesis and that TMPRSS11B has tumor suppressive roles in ESCC development.
Citation Format: Suburu Amano, Takeshi Iwaya, Satoshi Nishizuka, Kohei Kume, Chie Ito, Yuji Akiyama, Yoshihiro Shioi, Fumitaka Endo, Akira Sasaki. Downregulation of TMPRSS11B in squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1159.
Abstract 1215: Utilization of podoplanin as a chemotherapeutic target for oral squamous cell carcinoma
Authors: Retzbach Edward P. , Krishnan Harini , Ochoa-Alvarez Jhon A. , Shen Yongquan , Nevel Evan , Kephart David J. , Kalyoussef Evelyne , Baredes Soly , Fatahzadeh Mahnaz , Rameriz Maria I. , Yin Kingsley , Young Mary Ann , Deluca-Rapone Lisa , Shienbaum Alan J. , Jensen Lasse D. , Goldberg Gary S. 
Published: July 2016

Abstract
Oral cancer is diagnosed in over 300 thousand people, and kills over 100 thousand people, around the world each year. Current treatments rely on radiation and surgery procedures that often decrease the quality of life for oral cancer survivors. There is a clear need to improve treatments for these patients. Over 90% of oral cancers are formed by oral squamous cell carcinoma (OSCC). Most OSCC cells express the transmembrane receptor podoplanin (PDPN), which has emerged as a promising target for OSCC treatment. The PDPN receptor promotes tumor cell invasion and metastasis which leads to the vast majority of cancer deaths. Here, we describe efforts to target PDPN intracellularly and extracellularly in order to prevent and treat oral cancer. PDPN contains intracellular serine residues that can be phosphorylated by protein kinases including CDK5 and PKA to decrease cell migration. Additionally, the extracellular portion of PDPN can be targeted with Maackia amurensis seed lectin (MASL) to inhibit tumor cell migration and viability. Previous studies suggest that PDPN induces RhoA GTPase activity to promote cell migration. However, we show here that MASL dynamically binds PDPN to downregulate Cdc42 GTPase activity, but not RhoA or Rac1 GTPase activity. These data suggest that MASL suppresses Cdc42 GTPase activity to disrupt cell polarity and inhibit cell migration. Taken together, these data indicate that PDPN can serve as a functionally relevant target to prevent and combat oral cancer.
Citation Format: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Maria I. Rameriz, Kingsley Yin, Mary Ann Young, Lisa Deluca-Rapone, Alan J. Shienbaum, Lasse D. Jensen, Gary S. Goldberg. Utilization of podoplanin as a chemotherapeutic target for oral squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1215.
Abstract 1239: NVP-HDM201: Biochemical and biophysical profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2
Authors: Stachyra-Valat Thérèse , Baysang Frédéric , D’Alessandro Anne-Cécile , Dirk Erdmann , Furet Pascal , Guagnano Vito , Kallen Joerg , Leder Lukas , Mah Robert , Masuya Keiichi , Stutz Stefan , Vaupel Andrea , Hofmann Francesco , Chène Patrick , Jeay Sébastien , Holzer Philipp 
Published: July 2016

Abstract
An effective strategy to restore p53 activity in cancer cells containing wild type p53 is to inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-HDM201 is a novel PPI inhibitor currently under evaluation in a Phase I clinical trial. It binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction of the two proteins and leading to the activation of the p53 pathway.
NVP-HDM201 belongs to a novel chemical series with a distinct biophysical and biochemical profile. Affinity constant of NVP-HDM201 for Mdm2 is in the picomolar range, with a selectivity ratio greater than a 10000-fold vs. Mdm4. Analysis of its binding mode provides evidence for a distinct set of critical interactions between the small molecule and its target, as compared with our other Mdm2 inhibitor NVP-CGM097, and explains as to why NVP-HDM201 binds equally to human, mouse, rat and dog Mdm2. Characterization of its binding kinetics indicates that the optimized interactions of NVP-HDM201 with Mdm2 protein are responsible for the increased stabilization of the complex resulting in high potency against Mdm2. This feature, together with favorable physicochemical and drug-like properties, supported the selection of NVP-HDM201 for clinical development.
Citation Format: Thérèse Stachyra-Valat, Frédéric Baysang, Anne-Cécile D’Alessandro, Erdmann Dirk, Pascal Furet, Vito Guagnano, Joerg Kallen, Lukas Leder, Robert Mah, Keiichi Masuya, Stefan Stutz, Andrea Vaupel, Francesco Hofmann, Patrick Chène, Sébastien Jeay, Philipp Holzer. NVP-HDM201: Biochemical and biophysical profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1239.
Abstract 1259: MutT homolog 1 (MTH1) is upregulated in glioblastoma multiforme: its inhibition by siRNA or crizotinib results in impaired cell migration and tumor growth in vivo
Authors: Timmer Marco , Kannampuzha Sara Gerdi , Röhn Gabriele , Goldbrunner Roland 
Published: July 2016

Abstract
Introduction:
MutT homolog1 (MTH1) is required for the survival of cancer cells. These are characterized by irregular redox formation resulting in the production of reactive oxygen species which damage the deoxynucleoside triphosphate pool and subsequently the DNA. MTH1 inhibits the incorporation of oxidized bases into the DNA thus avoiding apoptosis of cancer cells. Our aim was to analyze the pathophysiological role of MTH1 in glioma.
Materials and Methods:
MTH1 expression was analyzed using quantitative PCR and Western Blot analysis in human glioma tissue (n = 80). We compared peritumoral tissue with grade II, III, and IV gliomas. Moreover, we compared primary to secondary GBM and initial tumors with recurrent tumors after temozolomide treatment. U87 cell migration was tested after siRNA knock-down of MTH1 and treatment with the MTH1 inhibitor crizotinib by scratch assays. After orthotopic implantation of MTH1-siRNA treated U87 into rats, tumor size was measured after 8 days.
Results:
In RT-PCR and Western blot we found a significantly higher expression of MTH1 in primary and secondary glioblastoma than in lower grade brain tumor. Immunofluorescence staining of histological sections of glioblastoma showed also a higher level of MTH1 than in lower grade tumors. By nucleofection, we transfected siRNA MTH1 into the U-87 glioblastoma cells and a slower migration was investigated applying migration assay. Furthermore, treatment with the drug crizotinib inhibited MTH1 and decreased U-87 cell migration. The xenograft study
showed a slower tumor growth when U87 cells were transfected with MTH1 siRNA compared to normal U87.
Conclusion:
These results show that MTH1 plays an essential role in migration and proliferation of glioma cells resulting in clinically observed malignization of glioma and disease progression in recurrent glioblastoma. Moreover, MTH1 can be targeted by Crizotinib indicating a role for potential future therapies.
Citation Format: Marco Timmer, Sara Gerdi Kannampuzha, Gabriele Röhn, Roland Goldbrunner. MutT homolog 1 (MTH1) is upregulated in glioblastoma multiforme: its inhibition by siRNA or crizotinib results in impaired cell migration and tumor growth in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1259.
Abstract 1284: Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines, and angiogenic factors in preclinical models
Authors: Allavena Paola , Belgiovine Cristina , Liguori Manuela , Bello Ezia , Frapolli Roberta , Galmarini Carlos M. , D’Incalci Maurizio 
Published: July 2016

Abstract
Lurbinectedin, currently undergoing clinical evaluation in ovarian, breast and small-cell lung cancer patients, inhibits active transcription. The drug is structurally related to trabectedin containing the same pentacyclic skeleton of the fused tetrahydroisoquinoline rings, but differing by the presence of a tetrahydro-B-carboline replacing the additional tetrahydroisoquinoline of trabectedin. We investigated whether lurbinectedin has the ability to regulate the inflammatory tumor microenvironment in vitro and in vivo. Human purified monocytes were highly sensitive to lurbinectedin (IC50: 5-10 nM) and, after drug treatment, underwent caspase-8-dependent apoptosis. Furthermore, in vitro, lurbinectedin significantly inhibited the production of selected inflammatory chemokines (CCL2, CXCL8) and VEGF by stimulated monocytes and liposarcoma cell lines. Administration of lurbinectedin to mice bearing a murine fibrosarcoma -resistant to this compound in vitro- resulted in significant anti-tumor activity (T/C value around 50%). The analysis of immune cells of blood spleen and tumor tissues during treatment with lurbinectedin revealed a significant and selective decrease in the subset of monocytes and macrophages, including tumor-associated macrophages (TAM). A gene expression analysis of monocytes treated with lurbinectedin indicated a modulation of the transcriptional program in LPS-stimulated human monocytes. Overall, these results indicate that lurbinectedin affects the inflammatory micro-environment, with a selective apoptotic-inducing effect on mononuclear phagocytes and a specific inhibition of production of inflammatory cytokines.
Citation Format: Paola Allavena, Cristina Belgiovine, Manuela Liguori, Ezia Bello, Roberta Frapolli, Carlos M. Galmarini, Maurizio D’Incalci. Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines, and angiogenic factors in preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1284.
Abstract 1287: The dual IAP antagonist, ASTX660, increases the anti-tumor activity of paclitaxel in preclinical models of triple-negative breast cancer in vivo
Authors: Smyth Tomoko , Nakatsuru Yoko , Fujita Ryoto , Ward George , Bevan Luke , Lewis Jon , Wallis Nicola , Lyons John 
Published: July 2016

Abstract
Background: Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine signaling loops that can reduce paclitaxel-induced apoptosis with resultant cancer cell survival (paclitaxel resistance). One mechanism of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs): Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-κB activation, blocking the activation of effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptotic pathway. Antagonism of IAPs in the setting of paclitaxel treatment may enhance the cancer cell death by switching the chemotherapy-induced inflammatory TNFα signaling from pro-survival to apoptosis. ASTX660 is an orally bioavailable dual antagonist of cIAP and XIAP, currently being investigated in a single-agent Phase 1/2 clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423). Here, we characterize the activity of ASTX660 in triple-negative breast cancer (TNBC) preclinical models as a single agent and in combination with paclitaxel.
Results: We first investigated the viability of 21 TNBC cell lines treated with ASTX660 in vitro and found that 43% were sensitive either to ASTX660 alone (MDA-MB-231 and HCC38) or in the presence of exogenous TNFα (HCC1806, Hs578T, BT549, HCC1395, DU4475, MDA-MB-453 and mouse EMT6). In HCC1806 xenografts in mice, both ASTX660 (daily oral treatment) and paclitaxel (weekly intravenous treatment) as single agents caused moderate tumor growth inhibition but not regression. ASTX660 and paclitaxel combination treatment, however, caused regression and all tumors achieved a partial response by Day 19 of treatment. An increase in circulating acute-phase-proteins in animals was also observed on paclitaxel treatment.
Conclusions: Our study suggests that paclitaxel treatment causes an inflammatory response which could qualitatively change the tumor environment. Inhibition of IAPs in such inflammatory environment induced by paclitaxel may lead to rapid apoptotic cell death. Thus, addition of IAP antagonist may be a promising approach to enhance the TNBC response to paclitaxel therapy.
Citation Format: Tomoko Smyth, Yoko Nakatsuru, Ryoto Fujita, George Ward, Luke Bevan, Jon Lewis, Nicola Wallis, John Lyons. The dual IAP antagonist, ASTX660, increases the anti-tumor activity of paclitaxel in preclinical models of triple-negative breast cancer in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1287.
Abstract 144: Gene expression analysis of HPV negative and HPV positive penile cancer
Authors: Sánchez-Vázquez María , Rohena-Rivera Krizia , Pérez-Ruiz Carlos , Puras-Báez Antonio , Cadilla Carmen , Martínez-Ferrer Magaly 
Published: July 2016

Abstract
Penile cancer is a disease with a high morbidity and mortality among developing countries. Although penile cancer is a relatively uncommon cancer in developed countries, its incidence is nearly four times higher in Puerto Rico when compared with other racial and ethnic groups in the United States. Approximately 40% to 45% of penile cancers are HPV-related. The etiology of penile cancers is not completely understood and additional research is necessary to fully delineate the sequence of molecular events involved in both HPV mediated and non-HPV mediated pathways leading to penile cancer. The objective of this study is to determine the genome-wide expression profiles in HPV mediated and non-HPV mediated penile cancer. Penile cancer fresh tissue was obtained from surgically intervened cases. The global gene expression profile was identified and analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Microarray analysis showed a total of 158 genes differentially expressed between HPV mediated and non-HPV mediated penile cancer. Ingenuity Pathway Analysis (IPA) revealed alterations in the celular movement, cancer, lipid metabolism, carbohydrate metabolism, interleukin, TGF-B, integrin, PI3-kinase and MMP signaling pathways. The microarray results were confirmed by quantitative real-time PCR for some representative genes. Functional and pathway annotation using bioinformatics tools helped to identify specific pathways. Knowledge of the biological pathways and networks of the genes that are significantly expressed or altered are pertinent to understanding the molecular basis of the penile cancer.
Citation Format: María Sánchez-Vázquez, Krizia Rohena-Rivera, Carlos Pérez-Ruiz, Antonio Puras-Báez, Carmen Cadilla, Magaly Martínez-Ferrer. Gene expression analysis of HPV negative and HPV positive penile cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 144.
Abstract 1451: Analysis of expression MHC class I chain-related gene A and B (MICA/B) in normal and tumor tissue
Authors: Ghadially Hormas , Brown Lee , Lewis Arthur , Czapiga Meggan , Valge-Archer Viia , Wilkinson Robert W. 
Published: July 2016

Abstract
MHC class I chain-related gene A and B (MICA and MICB) are highly polymorphic proteins that are induced upon stress, damage or transformation of cells which act as a “kill me” signal through the NKG2D receptor expressed on Natural Killer, CD8+ and γδ T cells.
Experimentally, the MIC/NKG2D axis has been shown to be important for the recognition of tumour cells by cytotoxic cells of the immune system and many tumours have evolved strategies to evade the detection by NKG2D expressing cells, e.g. by shedding MIC from the cell surface.
Expression of MIC has been reported for most tumour types and in normal gastrointestinal tract epithelium but the published data is often difficult to interpret. Additionally, it is not clear how much of the protein is expressed on the cell surface as MIC cell surface expression is known to be regulated tightly on multiple levels.
A validated MICA/B IHC assay was developed using an in-house tool antibody to profile multiple frozen human normal and tumour tissue microarrays (TMA’s) by both standard and confocal microscopy techniques.
Using a stringently characterised novel antibody that detects MICA as well as MICB this study describes the expression patterns in a wide range of tumours and normal tissues. With this method we generated data with unprecedented resolution, which enabled us to analyse the expression of MICA and MICB not only on the cellular but also on the sub-cellular level.
Citation Format: Hormas Ghadially, Lee Brown, Arthur Lewis, Meggan Czapiga, Viia Valge-Archer, Robert W. Wilkinson. Analysis of expression MHC class I chain-related gene A and B (MICA/B) in normal and tumor tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1451.
Abstract 1542: Identification and utilization of molecular pathways correlated with osteosarcoma metastasis to predict targeted therapies
Authors: Klippenstein Laird , Fowles Jared S. , Lear Sierra K. , Gustafson Daniel L. 
Published: July 2016

Abstract
Osteosarcoma (OSA) is the most prevalent primary bone tumor and accounts for approximately 2% of childhood cancers. Approximately 40% of all OSA patients succumb to metastatic disease within 5 years. Canine OSA occurs about 10 times more frequently than human OSA and has been shown to be very similar to pediatric OSA biologically, histologically, molecularly, and in treatment. This suggests that canine OSA is an excellent pre-clinical model to investigate better treatment options for metastatic OSA. We compared in-vitro markers of metastatic potential with gene expression data in eight canine OSA cell lines to identify molecular pathways that will be potential chemotherapeutic targets to treat and prevent metastatic OSA.
The metastatic potential of 8 canine OSA cell lines was characterized utilizing Incucyte Zoom based migration and invasion scratch wound assays. Gene expression analysis was performed using Affymetrix GeneChip Canine Genome 2.0 Arrays. Genes that were statistically correlated with migratory and invasive phenotypes were used to enrich molecular pathways described in several databases utilizing Enrichr software. Altered pathways and associated targeted agents that would inhibit the pathways enriched by the correlated gene sets were identified.
Chemotherapeutics targeting significantly enriched pathways were screened for their ability to inhibit metastatic potential. Dasatinib and Stattic were the only inhibitors screened to date that inhibit migration of the osteosarcoma cell lines at clinically relevant doses. The remaining significantly correlated pathways will be targeted as well as rational combinations of pathways. An orthotopic murine model is currently being tested to further explore the utility of efficacious chemotherapeutics in-vivo. Pathway Inhibition and Anti-Migratory EffectsPathwayP-ValueTargeted AgentIC50 vs MigrationMap Kinase0.0037Selumetinib&gt;25 uM *Focal Adhesion0.0059Dasatinib18 nM - 214 nMErbb2/30.0214Lapatinib&gt;8 uM *TubulinControlPaclitaxel7 nM - 54 nMmTOR0.0054Rapamycin&gt;20 nM *STAT30.0004Stattic2.4 uM - 4.6 uMBMPR2&lt;0.0005Tacrolimus&gt;12.5 nM *ALK&lt;0.0005Crizotinib&gt;900 nM *VEGFR0.0226VandetanibTBDITK&lt;0.0005IbrutinibTBDPDPK10.0011CelecoxibTBD* We were not able to reach an IC50 at clinically relevant doses
Citation Format: Laird Klippenstein, Jared S. Fowles, Sierra K. Lear, Daniel L. Gustafson. Identification and utilization of molecular pathways correlated with osteosarcoma metastasis to predict targeted therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1542.