bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 462: Soluble CD80 restores T-cell activation and overcomes tumor cell programmed death ligand-1-mediated suppression.
Authors: Haile Samuel , Dalal Sonia P. , Clements Virginia , Tamada Koji , Ostrand-Rosenberg Suzanne 
Published: August 2014

Abstract
Many tumor cells escape anti-tumor immunity through their expression of Programmed Death Ligand 1 (PDL1 or B7-H1), which interacts with T cell-expressed PD1 and results in T cell apoptosis. We previously reported that transfection of human tumor cells with a membrane-bound form of the costimulatory molecule CD80 prevented PD1 binding and restored T cell activation. We now report that membrane-bound CD80 similarly reduces PDL1-PD1-mediated suppression by mouse tumor cells, and that a fusion protein consisting of the extracellular domains of CD80 fused to an Fc domain of IgG1 overcomes PDL1-mediated suppression by human tumor cells. T cell activation experiments assessing costimulation indicate that the soluble CD80 fusion protein mediates its effects by binding to PDL1 and inhibiting PDL1-PD1 interactions. Comparison of the CD80 fusion protein to antibodies specific for PD1 or PDL1 demonstrate that soluble CD80 treatment is more effective in restoring T cell activation than treatment with mAb to either PD1 or PDL1. These studies identify soluble CD80 as an alternative and potentially more efficacious therapeutic agent for overcoming PDL1-induced immune suppression and facilitating tumor-specific immunity.
Citation Format: Samuel Haile, Sonia P. Dalal, Virginia Clements, Koji Tamada, Suzanne Ostrand-Rosenberg. Soluble CD80 restores T-cell activation and overcomes tumor cell programmed death ligand-1-mediated suppression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 462. doi:10.1158/1538-7445.AM2013-462
Abstract 4620: Unconventional genetic determinants of resistance to 5-aza-2’-deoxycytidine.
Authors: Ting Angela H. , Matkin Lars 
Published: August 2014

Abstract
5-aza-2’-deoxycytidine (DAC) is approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome. It is also being tested in Phase I and II clinical trials for efficacy against other malignancies, including brain, prostate, breast, and lung cancers. Identifying modifier genes that could confer resistance to DAC treatments is, therefore, essential in realizing the full potential of DAC as a chemotherapeutic agent. DAC is a cytosine analog that is incorporated into newly synthesized DNA, where it can prevent propagation of DNA methylation by irreversibly trapping DNA methyltransferases. The consequent reversal of epigenetic silencing of tumor suppressor genes contributes to tumor cell death in the therapeutic context. Previous studies have identified relatively few determinants of DAC resistance, including the equilibrative nucleoside transporters, deoxycytidine kinase, and cytosine deaminase. While these genes are logical candidates because of their functions in cellular pyrimidine uptake and metabolism, our large-scale, unbiased random insertional mutagenesis screen in human cancer cell lines have identified additional, unexpected loci involved in DAC resistance. Our initial screen produced 9 mutant clones resistant to DAC at concentrations of 0.1μM and 1μM. In particular, several of the insertional mutants targeted components of the DNA damage response pathway, including ubiquitin conjugating enzymes and Fanconi anemia complementation group genes, indicating that the primary mechanism of killing by DAC may not be DNA demethylation. This is consistent with the observation that DNA double-strand breaks are among the consequences of DAC treatments. Ongoing functional studies of the mutant clones also suggest that cancer cells with increased efficiency at repairing genomic DNA damage may survive DNA demethylation in the presence of DAC. These results not only inform us of the mechanism of action of DAC-mediated cytotoxicity, our findings also have important clinical implications as these genetic modifiers are also valuable biomarkers and therapeutic targets for achieving personalized cancer treatments involving DAC.
Citation Format: Angela H. Ting, Lars Matkin. Unconventional genetic determinants of resistance to 5-aza-2’-deoxycytidine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4620. doi:10.1158/1538-7445.AM2013-4620
Abstract 4663: Acquired resistance to gefitinib is associated with cancer stem-like phenotype and EMT in EGFR mutant lung adenocarcinoma.
Authors: Lim Sun Min , Kim Hyun Jung , Ban Young Ho , Ha Sang Jun , Cho Byoung Chul 
Published: August 2014

Abstract
Background: Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung adenocarcinoma to tyrosine kinase inhibitor (TKI) such as gefitinib. During gefitinib treatment, however, the tumor becomes resistant by acquiring specific types of resistance via the somatic changes. Although the underlying mechanisms for acquired resistance include the amplification of c-Met gene and the secondary mutation in EGFR genes, there are still unknown mechanisms that cannot be explained by the two types of genetic changes. Here, we sought to find a novel mechanism to explain TKI-resistance of EGFR-dependent lung adenocarcinoma.
Methods: We developed resistant cells (HCC827-GR) from gefitinib-sensitive HCC827 cells harboring EGFR deletion mutation by chronic exposure to increasing concentrations of gefitinib. Acquired resistance mechanisms of HCC827-GR cells were analyzed.
Results: HCC827-GR showed much less phosphorylation of most receptor kinases including EGFR but higher phosphorylation of downstream signaling molecules, Erk and Akt, than its parental cell. By comparing the gene expression profiles between HCC827 and HCC827-GR, we found that cancer stem cell (CSC) markers, CD44 and ALDH1A1 genes, were highly induced in HCC827-GR compared with those in HCC827. Knockdown of CD44 and ALDH1A1 expression by RNA interference induced inactivation of both Akt and Erk phosphorylation in HCC827-GR. Furthermore, HCC827-GR displayed CSC-like functionality such as colony formation and the phenotype of epithelial-mesenchymal transition (EMT). Higher level of vimentin, ZEB1 and ZFHX4 and lower level of E-cadherin were observed in HCC827-GR together with morphological change. Interestingly, miR200c, a tumor suppressive microRNA, was dramatically decreased in HCC827-GR. Forced expression of miR200c in HCC827-GR abrogated the increased expression of ZEB1 and ALDH1A1, resulting in the restoration of E-cadherin.
Conclusions: These findings imply that cancer stemness induced via CD44 and ALDH1A1 expression and EMT contribute to the acquisition of gefitinib resistance in EGFR-TKI sensitive lung adenocarcinoma. Therefore, CSC markers including CD44 and ALDH1A1 and EMT regulators such as miR200c can be used as therapeutic targets for TKI-resistant EGFR-dependent lung adenocarcinoma.
Citation Format: Sun Min Lim, Hyun Jung Kim, Young Ho Ban, Sang Jun Ha, Byoung Chul Cho. Acquired resistance to gefitinib is associated with cancer stem-like phenotype and EMT in EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2013-4663
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 467: Bcl2A1 - an IFN-gamma dependent master switch for the function of CD11b+Gr-1high myeloid derived suppressor cells.
Authors: Haile Lydia , Echeverz Jose Medina , Zhao Fei , Métais Jean-Yves , Dunbar Cynthia , Korangy Firouzeh , Greten Tim 
Published: August 2014

Abstract
Myeloid derived suppressor cells (MDSC) play a crucial role in suppression of immune responses in cancer and inflammation. Here, we describe differential IFN-γ/STAT1 dependent regulation of the suppressor function of CD11b+Gr-1high granulocytic and CD11b+Gr-1dull/int monocytic MDSC subsets. IFN-γ induced STAT1 phosphorylation in both MDSC subsets, which led to NOS2 expression in CD11b+Gr-1dull/int. monocytic MDSC and enhanced suppression of T cell proliferation. In sharp contrast, the suppressor function of CD11b+Gr-1high granulocytic MDSC was enhanced in the absence of IFN-γ using IFN-γR-/- MDSC or IFN-γ-/- effector cells, which led to upregulation of Bcl2a1 and improved survival of the granulocytic subpopulation during MDSC-T cell interaction. Likewise Bcl2a1 overexpression in CD11b+Gr-1high granulocytic MDSC supported their suppressor activity. Thus, depending on the local IFN-γ concentration, STAT1 regulates the function of MDSC subsets antithetically so that these two cell subpopulations can substitute each other and suppress antigen-specific T cell immunity.
Citation Format: Lydia Haile, Jose Medina Echeverz, Fei Zhao, Jean-Yves Métais, Cynthia Dunbar, Firouzeh Korangy, Tim Greten. Bcl2A1 - an IFN-gamma dependent master switch for the function of CD11b+Gr-1high myeloid derived suppressor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 467. doi:10.1158/1538-7445.AM2013-467
Abstract 4671: Radioguided detection of lymph node metastasis in non-small cell lung cancer.
Authors: Nwogu Chukwumere , Demmy Todd , Yendamuri Sai , Tan Wei , Bogner Paul , Dexter Elisabeth , Picone Anthony , Hennon Mark , Hutson Alan , Reid Mary , Cheney Richard , Adjei Alex 
Published: August 2014

Abstract
Background:
Lymph node staging provides the most important prognostic information in patients with loco-regional non-small cell lung cancer. We hypothesized that gamma radiation detection using an intra-operative hand-held gamma probe following intravenous 18F-fluorodeoxyglucose (FDG) injection would identify lymph nodes containing metastases in a much more sensitive manner than standard pathological practices. We compared the accuracy of detecting thoracic lymph node metastases using positron emission tomography- computed tomography (PET-CT) versus the gamma probe.
Methods:
One hundred patients with resectable lung cancers had pre-operative positron emission tomography-computed tomography (PET-CT) and mediastinoscopy. 10mCi of FDG was injected on the day of surgery. A handheld gamma probe detected increased FDG uptake within thoracic lymph nodes during pulmonary resection procedures. The lymph nodes that demonstrated increased FDG uptake, but were non-malignant by conventional H&E staining underwent further serial sectioning, immunohistochemistry (IHC) and RT-PCR (reverse transcriptase - polymerase chain reaction). Sensitivity and specificity for lymph node metastasis detection by PET-CT and the gamma probe were calculated.
Results:
Three patients had metastatic lymphadenopathy detected at mediastinoscopy, so their procedures were aborted, while the others proceeded to lung resection and complete lymphadenectomy. Fifteen additional patients had lymph node involvement on routine pathologic analysis. IHC and RT-PCR detected micrometastatic lymph node disease in 4 and 29 patients, respectively. Using RT-PCR as the gold standard, the sensitivity and specificity of PET-CT for detection of lymph node metastasis were 11% and 98% respectively, in contrast to 38% and 50% respectively for the gamma probe.
Conclusion:
The intra-operative hand held gamma probe is more sensitive but less specific than PET-CT in detecting lymph node metastasis from lung cancer. Its overall accuracy was low, resulting in limited up-staging of patients. RT-PCR analysis of FDG-avid lymph nodes for epithelial markers increased the clinical utility of this probe in detecting micrometastasis. Such up-staged patients could derive a survival benefit from adjuvant chemotherapy. More specific radioisotopes are being developed to improve the clinical utility of this technique.
Citation Format: Chukwumere Nwogu, Todd Demmy, Sai Yendamuri, Wei Tan, Paul Bogner, Elisabeth Dexter, Anthony Picone, Mark Hennon, Alan Hutson, Mary Reid, Richard Cheney, Alex Adjei. Radioguided detection of lymph node metastasis in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4671. doi:10.1158/1538-7445.AM2013-4671
Abstract 4681: Characterization of pulmonary hypertension in lung cancer.
Authors: Storn Samantha , Pullamsetti Soni Savai , Kojonazarov Baktybek , Schermuly Ralph Theo , Grimminger Friedrich , Rapp Ulf R. , Seeger Werner , Savai Rajkumar 
Published: August 2014

Abstract
Introduction: Approximately 60%-70% of patients with lung cancer have dyspnea at presentation, and 90% experience it just prior to death. Considering case reports describing the formation of pulmonary hypertension (PH) via pulmonary tumor microemboli from gastric and gallbladder cancer, we analyzed the involvement of PH in the development of dyspnea in lung cancer using different mouse models and human lung tumor samples.
Methods: Three murine lung cancer models have been used: C57BL/6N-mice that received an injection of Lewis-lung-carcinoma-cells (LLC1) via tail vein, K-rasLA2 knock-in-mice and SP-C-c-raf-1-BxB-23 transgene mice. They underwent echocardiographic analyses at different time points and hemodynamic measurements to assess the right ventricular systolic pressure (RVSP) and systemic arterial pressure. Histological evaluation was performed to determine the pulmonary vascular morphometry in the tumor-area as well as the total collagen of the right ventricle. Identical histological analyses have been done in human lung tumor samples. In addition, to understand the contribution of immune cells to the development of PH in lung cancer setting, pulmonary vascular walls were analyzed in human lung tumor tissue and quantified for macrophages (CD68+), T-lymphocytes (CD3+) and dendritic cells (CD209+).
Results: For each mouse model, echocardiography reveals an impaired systolic, diastolic and global function of the right ventricle, as well as a dilated right ventricle. Hemodynamics show an increased RVSP. Murine and human lung tumor samples demonstrate vascular remodeling, affecting both wall thickness and the degree of muscularization in the tumor-area. The quantification of total collagen enables to prove a right ventricular fibrosis. Higher incidences of T-lymphocytes and macrophages in pulmonary vascular walls were demonstrated in the tumor-area of human lung section.
Conclusion: This study provides clear evidence for the existence of PH in human as well as animal models affected by lung cancer. Repeated echocardiographic analyses show that the detected PH represents an end-stage phenomenon. The increased content of T-lymphocytes and macrophages in the vascular walls leads us to the hypothesis that these cell types might be involved in the remodeling of small pulmonary vessels in tumors.
Citation Format: Samantha Storn, Soni Savai Pullamsetti, Baktybek Kojonazarov, Ralph Theo Schermuly, Friedrich Grimminger, Ulf R. Rapp, Werner Seeger, Rajkumar Savai. Characterization of pulmonary hypertension in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2013-4681
Abstract 4683: Correlation of transcript levels of members of the urokinase-type plasminogen activator system with clinico-pathological parameters in prostate cancer .
Authors: Al-Janabi Omar , Taubert Helge , Wach Sven , Stöhr Robert , Burger Maximilian , Wieland Wolf Ferdinand , Lohse-Fischer Andrea , Fröhner Michael , Wirth Manfred P. , Wullich Bernd , Magdolen Viktor , Kotzsch Matthias , Fuessel Susanne 
Published: August 2014

Abstract
Background: Members of the urokinase-type plasminogen activator (uPA) system play an important role in tumor progression and angiogenesis in different human malignancies including breast, kidney, colon, stomach and prostate cancer (PCa). Aim of the study was to characterize mRNA expression levels of members of the uPA system in tissue specimens from primary PCa and their potential association with clinico-pathological parameters.
Methods: Transcript levels of members of the uPA system, i.e., uPA, uPA receptor (uPAR) and plasminogen activator inhibitor type 1 (PAI-1) were analyzed in a cohort of 132 corresponding pairs of malignant and adjacent non-malignant prostate tissue samples. Relative gene expression levels were determined by quantitative PCR (qPCR) and normalized to the reference gene TATA-box-binding protein (TBP). Potential correlations between the three markers themselves and the clinico-pathological parameters were assessed by Spearman's Rho test and by Fisher's exact test.
Results: There were no significant differences in expression levels of uPA system genes between the corresponding malignant and non-malignant tissue specimens. Transcript levels of all members of the uPA system displayed a significant correlation with each other in the tumor tissues. At stratifying uPA, uPAR and PAI-1 expression levels by the median a significant correlation between an elevated expression of uPA and PAI-1 was correlated with higher Gleason score (P = 0.001 and P = 0.007). In addition, a significant positive correlation between uPAR transcript levels and tumor stage was detected (P = 0.025).
Conclusion: Our results demonstrate that mRNA expression levels of members of the uPA system correlated with each other and with clinico-pathological parameters. We suggest that transcript levels of uPA system members can be helpful markers for the study of tumor behavior of prostate cancer.
Citation Format: Omar Al-Janabi, Helge Taubert, Sven Wach, Robert Stöhr, Maximilian Burger, Wolf Ferdinand Wieland, Andrea Lohse-Fischer, Michael Fröhner, Manfred P. Wirth, Bernd Wullich, Viktor Magdolen, Matthias Kotzsch, Susanne Fuessel. Correlation of transcript levels of members of the urokinase-type plasminogen activator system with clinico-pathological parameters in prostate cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4683. doi:10.1158/1538-7445.AM2013-4683
Abstract 4685: SH2D4A is frequently downregulated in hepatocellular carcinoma.
Authors: Andreozzi Mariacarla , Quagliata Luca , Kovac Michal , Tornillo Luigi , Makowska Zuzanna , Heim Marcus , Heinimann Karl , Piscuoglio Salvatore , Terracciano Luigi Maria 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The lack of effective therapeutic options combined with an increasing incidence rate in the past 20 years calls for the identification of early stage HCC molecular markers. SH2D4A maps to human chromosome 8p21.3 and encodes for SH(2)A. The chromosomal region containing SH2D4A has been shown to be frequently lost in colorectal, lung and HCC cancers. Using a combination of gene expression, protein level and clinical data, our study aimed to investigate the SH2D4A involvement in HCC pathogenesis. Transcriptome analysis (Affymetrix) performed on 37 HCC samples (matched with their corresponding non-neoplastic liver parenchyma) and 5 normal liver donors revealed that SH2D4A is downregulated in HCC. These results were validated by qPCR in fresh frozen tissues [25 out of 37 samples (67.6%) showed SH2D4A downregulation; p&lt;0.026]. Furthermore, the combination of qPCR data and immunohistochemistry staining performed on corresponding formalin-fixed paraffin embedded (FFPE) needle biopsies demonstrated a direct correlation between the SH2D4A mRNA expression and SH(2)A protein levels. Additional data obtained from the analysis of a tissue microarray (TMA) containing 336 informative specimens confirmed that SH(2)A protein levels are frequently reduced in HCC and additionally in cirrhosis nodules compared to normal liver samples. To conclude, our study revealed that SH2D4A is frequently downregulated in HCC samples thus corroborating its putative role as tumor suppressor gene. In addition, we provide new evidence for SH2D4A involvement in HCC pathogenesis demonstrating for the first time its deregulation also in cirrhotic nodules.
Citation Format: Mariacarla Andreozzi, Luca Quagliata, Michal Kovac, Luigi Tornillo, Zuzanna Makowska, Marcus Heim, Karl Heinimann, Salvatore Piscuoglio, Luigi Maria Terracciano. SH2D4A is frequently downregulated in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2013-4685
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4698: Gene expression profiles of triple negative breast cancer epithelial and stromal cells are predictive of treatment response.
Authors: Jovanovic Bojana , Chen Steven X. , Lehmann Brian D. , Johnson Kimberly N. , Sanchez Violeta , Kuba Maria G. , Sanders Melinda E. , Mayer Ingrid A. , Moses Harold L. , Pietenpol Jennifer A. 
Published: August 2014

Abstract
Lacking human epithelial growth factor receptor 2 (HER2) amplification as well as estrogen and progesterone receptors, TNBC is a heterogeneous collection of biologically diverse cancers that likely contributes to variable clinical outcomes for patients suffering from this disease. Since TNBC lacks well-defined molecular targets, we recently performed gene expression (GE) analyses and identified six distinct molecular TNBC subtypes with unique biologies. To further decipher the contribution of tumor epithelium and its adjacent stroma to the biology of TNBC and clinical response to treatments, we performed GE analysis on biopsy material from 20 TNBC patients enrolled in a phase II clinical trial [VICC-BRE0904; a neoadjuvant study of cisplatin and paclitaxel±RAD001 (mTOR inhibitor)]. We isolated RNA from both tumor epithelial and stromal cells using laser capture microdissection. Our goal is to determine if GE from tumor epithelial and/or stromal cells is predictive of response to treatment. Our preliminary results indicate that there is differential GE in both tumor epithelial as well as stromal cells in pretreatment biopsies of responders versus non-responders. Patients with higher expression of proliferation genes such as MKI67, KIFCI, AURKB, E2F3, and DNA damage response genes TP53BP2, CHEK1, RPA1, BLM were more responsive to treatment compared to non-responders. Upon completion of the phase II clinical trial and correlative molecular analyses, we anticipate identifying biomarkers of drug sensitivity that will provide insight to novel combination therapies for the different subtypes of TNBC.
Citation Format: Bojana Jovanovic, Steven X. Chen, Brian D. Lehmann, Kimberly N. Johnson, Violeta Sanchez, Maria G. Kuba, Melinda E. Sanders, Ingrid A. Mayer, Harold L. Moses, Jennifer A. Pietenpol. Gene expression profiles of triple negative breast cancer epithelial and stromal cells are predictive of treatment response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2013-4698