bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5844: Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, improved radiosensitivity of human hepatocellular carcinoma
Authors: Chen Fang-Hsin , Yu Ching-Fang , Hong Ji-Hong 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Radiotherapy (RT) is one of modalities for HCC therapy in clinics, but the therapeutic effect is unsatisfied due to high radiosensitivity of normal liver tissues that limits the optimal dose. This study is to develop a new theraprutic approach to enhance the efficiency of RT on HCC tumors. Suberoylanilide hydroxamic acid (SAHA), a FDA approved chemotherapeutic drug, is an inhibitor of histone deacetylase (HDACs) and has been reported to enhance radiosensitivity in many cell lines. This study hypothesized that combination of SAHA and RT could improve tumor control on HCC tumors. HCC-834 cell, a primary culture of human HCC, had a dose-dependent response to RT when analyzed by clonogenic assay. SAHA had mild cytotocixity to HCC-834 cell (IC50=1μM). Combination of SAHA and RT reached a synergestic effect to prevent colony formation. In detailed, SAHA treatment did not induce DNA damage on HCC-834 cells when assayed by the expression of γH2AX. RT of 2Gy induced highest γH2AX expression within 10min and quickly returned to baseline after 24hrs. The expression of γH2AX was sustained at 24hrs when treated by SAHA and RT, and gradually recovered after 48hrs. This data indicated that SAHA inhibited the DNA repair process in HCC-834 cell lines after RT. An orthotopic tumor model was developed for further exploring the role of SAHA on HCC tumor radiotherapy. Mice were orally fed with SAHA (100mg/kg) 3hrs and 24hrs before RT of 25Gy. Mice were sacrificed at day10 after RT and maximum tumor area was examined by H&E staining. Either RT (38.81 ± 15.6mm2) or SAHA alone (45.09 ± 4.493mm2) inhibited tumor growth significantly compared with control tumors (99.1 ± 0.732mm2). Combined SAHA with RT had an additive effect on tumor control (28.03±12.25mm2). These results supported our hypothsis and demonstrated that SAHA combined with local RT was effective on inhibiting DNA repair and anti-tumor growth. This study provided a new strategy on HCC tumor therapy that SAHA could act as a radiosensitizer to improve the therapeutic efficiency of RT on HCC tumors.
Citation Format: Fang-Hsin Chen, Ching-Fang Yu, Ji-Hong Hong. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, improved radiosensitivity of human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5844. doi:10.1158/1538-7445.AM2017-5844
Abstract 5866: t-Darpp chemoresistence protein: insights into its structure, oligomerization status, calcium-binding properties and phosphorylation sites
Authors: Magdziarz Patrycja , Feng You , Jiang Dianlu , Parga Elizabeth , Celis Arianna , Denny Erin , Wang Xiaoying , Phillips Martin , Zhou Feimeng , Kane Susan E. , Momand Jamil 
Published: July 2017

Abstract
t-Darpp, one of two protein isoforms encoded by the PPP1R1B gene, is overexpressed in gastric, esophageal, colon, prostate, and breast cancers; and confers resistance to trastuzumab in Her2+ breast cancer cells. To gain insight into the trastuzumab-resistance mechanism of t-Darpp, we studied its structure, oligomerization status, metal-binding properties, and sites of phosphorylation. Circular dichroism spectroscopy analysis showed that recombinant t-Darpp exhibits 12% alpha helix, 29% beta strand, 24% beta turn and 35% random coil character at 25°C. Upon mild heat treatment (50°C for five min) the secondary structure does not appreciably change. Metal ion-binding analyses through inductively coupled plasma-mass spectrometry and graphite furnace-atomic absorption indicated that t-Darpp co-purifies with calcium, but not other metals commonly found in biological systems. The T75 site, critical for t-Darpp activation of the Akt signaling pathway, is a substrate for phosphorylation by cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 5 (CDK5). Gel filtration chromatography, sedimentation equilibrium analysis, native blue gel electrophoresis, and glutaraldehyde-mediated crosslinking experiments showed that the majority of t-Darpp (calculated mass = 19 kDa) exists as a monomer, but forms low levels (&lt; 3%) of hetero-oligomers with its longer isoform Darpp-32. t-Darpp has a relatively large Stokes radius of 4.4 nm, suggesting an elongated structure. In summary, this study indicates that t-Darpp is an elongated, mild-heat-stable, and monomeric calcium-binding protein that is capable of being phosphorylated at T75 by CDK1 and CDK5. Blockage of t-Darpp calcium binding capacity or T75 phosphorylation may therefore help sustain Her2+ breast cancer sensitivity to trastuzumab therapy.
Citation Format: Patrycja Magdziarz, You Feng, Dianlu Jiang, Elizabeth Parga, Arianna Celis, Erin Denny, Xiaoying Wang, Martin Phillips, Feimeng Zhou, Susan E. Kane, Jamil Momand. t-Darpp chemoresistence protein: insights into its structure, oligomerization status, calcium-binding properties and phosphorylation sites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5866. doi:10.1158/1538-7445.AM2017-5866
Abstract 5878: Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway
Authors: Kuo Kuan-Lin , shi Chung-Sheng , Hsieh Ju-Tong , Chen Shiang-Peng , Lin Wei-Chou , Liao Shih-Ming , Liu Shing-Hwa , Huang Kuo-How 
Published: July 2017

Abstract
Trichostatin A (TSA), a potent histone deacetylase (HDAC) inhibitor, has been reported to elicit anti-proliferative response in various tumors. Here, we investigated antitumor effect of TSA alone or in combination with conventional chemotherapeutic agents on urothelial carcinoma (UC) cells. We use one high-grade UC cell line (T24) and another UC cells (NTUUC) obtained by primary culture from the surgical specimen of a women with high-grade and metastatic bladder UC. The cytotoxicity and apoptosis induced by TSA alone , chemotherapeutic agents (cisplatin, gemcitabine and doxorubicin) and combined treatment were assessed by MTT assay and fluorescence-activated cell sorting and flow cytometry. The expression of phosphor c-Raf, phosphor-MEK1/2, and phosphor-ERK1/2 were measured by Western blot. urther elucidation on the role of Raf/MEK/ERK pathoway on the TSA-enhanced cytoxicity were exmained by using ERK1 siRNA knockdown and the specific MEK inhibitor (PD98059). Our results showed TSA markedly enhances the cytotoxicity and apoptosis of three chemotherapeutic agents in UC cells with concurrent suppression of Raf/MEK/ERK signaling pathway. Consistently, inhibition of Down-regulation of ERK by MEK inhibitor or by ERK 1 siRNA knockdown potentiated the chemotherapeutic agnet-induced cytotoxicity of TSA in UC cells. We concluded that TSA potentiates the therapeutic efficacy of cisplatin, gemcitabine and doxorubicin in human UC cells through Raf/MEK/ERK signaling pathway. These findings provide a new treatment strategy against UC.
Note: This abstract was not presented at the meeting.
Citation Format: Kuan-Lin Kuo, Chung-Sheng shi, Ju-Tong Hsieh, Shiang-Peng Chen, Wei-Chou Lin, Shih-Ming Liao, Shing-Hwa Liu, Kuo-How Huang. Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5878. doi:10.1158/1538-7445.AM2017-5878
Abstract 5885: Sialyl Lewis X-P-selectin connection between ovarian tumor-mesothelium in early stage metastasis
Authors: Li Shan-Shan , Ip Carman K. M. , Hassan Ayon A. , Tang Matthew Y. H. , Yung Susan , Chan Tak-Mao , Shum Ho Cheung , Wong Alice S. T. 
Published: July 2017

Abstract
Metastasis is one of the major challenges for the treatment of ovarian cancer. Unlike other solid tumors, ovarian cancer primarily disseminates within the peritoneal cavity. A crucial step in metastasis formation is the adhesion of ovarian cancer cells onto the peritoneal mesothelium under ascitic shear flow. However, the adhesion mechanisms engaged in this tumor-mesothelium interaction remain elusive due to a lack of physiologically relevant model to manipulate and investigate this dynamic process. In this study, using a 3D microfluidic platform, we found that the metastatic population of cancer stem cells (M-CSCs) exhibited slower rolling velocity and higher binding ability to the peritoneal mesothelium than non-metastatic (NM)-CSCs under flow condition. This adhesion cascade was mediated by P-selectin which expressed on the peritoneal mesothelium. The key carbohydrate determinant on M-CSCs was a glycoprotein, but not a glycolipid, with its recognition as sialyl-Lewis X (sLeX) in a sialic acid- and fucose-dependent manner. Moreover, several glycosyltransferase genes including B4GALT4, ST3GAL3, ST3GAL4 and FUT-5 involved the synthesis of sLeX were upregulated in M-CSCs. Knocking down FUT-5 significantly inhibited ovarian tumor cell adhesion on the mesothelium in vitro and reduced the metastatic potential in vivo. Taken together, our findings revealed that a distinct sLeX-P-selectin axis of ovarian tumor-mesothelium interaction in early metastasis and may offer the possibility of new therapeutic targets. (This work is supported by RGC grant 17122014)
Citation Format: Shan-Shan Li, Carman K. M. Ip, Ayon A. Hassan, Matthew Y. H. Tang, Susan Yung, Tak-Mao Chan, Ho Cheung Shum, Alice S. T. Wong. Sialyl Lewis X-P-selectin connection between ovarian tumor-mesothelium in early stage metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5885. doi:10.1158/1538-7445.AM2017-5885
Abstract 5899: Compartment-resolved proteomics reveal NNMT as a master metabolic regulator of cancer associated fibroblasts
Authors: Eckert Mark A. , Coscia Fabian , Pan Shawn , Tienda Samantha M. , Chryplewicz Agnieszka A. , Chiang Chun-Yi , Montag Anthony , Yamada S. Diane , Mann Matthias , Lengyel Ernst R. 
Published: July 2017

Abstract
The poor outcome of ovarian cancer patients is due to late detection and the ability of ovarian cancer cells to metastasize quickly throughout the abdominal cavity. Recent research, including histopathological studies and experiments with mouse models, suggest that ovarian cancer may actually arise in the fallopian tube as serous tubal intraepithelial carcinomas (STIC). Lesions of the ovary would, therefore, represent metastases from the fallopian tube. To better understand the molecular events that occur in both the tumor and stromal compartment during ovarian cancer progression, we performed shotgun proteomics on laser-microdissected tumor and stromal compartments from anatomic sites representing the hypothetical progression series for ovarian cancer (STIC → fallopian tube → ovary → omentum). With an optimized sample preparation technique, we successfully quantified 4-5000 proteins per anatomic site with high reproducibility and with as few as several thousand microdissected cells derived from formalin-fixed and paraffin-embedded (FFPE) biobank specimens. Proteomics of the tumor compartments revealed high inter-patient heterogeneity, with no conserved protein signatures associated with invasion or metastasis. In strong contrast, a highly conserved molecular signature of stromal proteins associated with metastasis to the omentum was identified. In particular, nicotinamide N-methyl transferase (NNMT) was highly upregulated in the stroma of omental and peritoneal metastases. Functionally, NNMT was necessary and sufficient for multiple aspects of the cancer associated fibroblast (CAF) phenotype, including expression of CAF markers and secretion of cytokines and oncogenic extracellular matrix. NNMT expression was necessary for the ability of CAFs to support ovarian cancer cell migration, proliferation, adhesion, and in vivo growth. Mechanistically, high expression of NNMT in CAFs led to a depletion of S-adenosyl methionine (SAM) and a reduction in histone methylation associated with gene expression changes in the tumor stroma. This work supports the use of ultra-low input proteomics for compartment-resolved identification of candidate drivers of disease phenotypes and identifies NNMT as a central, metabolic regulator of CAF differentiation.
Citation Format: Mark A. Eckert, Fabian Coscia, Shawn Pan, Samantha M. Tienda, Agnieszka A. Chryplewicz, Chun-Yi Chiang, Anthony Montag, S. Diane Yamada, Matthias Mann, Ernst R. Lengyel. Compartment-resolved proteomics reveal NNMT as a master metabolic regulator of cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5899. doi:10.1158/1538-7445.AM2017-5899
Abstract 5921: Microenvironmental changes in the progression from adenocarcinoma in situ to early-invasive adenocarcinoma of the lung
Authors: NAITO MASAHITO , Satoh Yukitoshi , Ishii Genichiro 
Published: July 2017

Abstract
Introduction:
Lepidic predominant adenocarcinoma of the lung was classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive lepidic predominant adenocarcinoma (LPA) in current WHO classification, 4th edition. Furthermore, LPA is thought to progress in a stepwise fashion from AIS and MIA. However, those classifications were diagnosed by observation of pathologists based on morphology only. The aim of this study was to investigate the microenvironmental changes in the process of development from AIS, MIA to LPA, and subjective marker of stepwise progression. We have published a part of data in this study in Lung Cancer (100:53-62, 2016), and we believe that this study makes a contribution to elucidate the mechanism of development of LPA of the lung.
Materials and Methods:
Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3 cm (S-LPA, n=113), and LPA larger than 3 cm (L-LPA, n=47) were analyzed. We then immunohistochemically evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related
molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), and growth factor receptors (EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed.
Results:
LPA-S showed significantly frequent vascular and pleural invasion than MIA (p&lt;0.05); however, no significant difference in those factors was found between S-LPA and L-LPA. Laminin-5 expression in the non-invasive component of MIA was significantly higher than that of AIS (p&lt;0.001). During the progression from MIA to S-LPA, the expression level of laminin-5 in the invasive component was significantly elevated (p&lt;0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p&lt;0.05, CD204+ TAMs; p&lt;0.001, CD34+ microvessel; p&lt;0.05). Ezrin expression in the invasive component of L-LPA was significantly increased (p&lt;0.05) compared to S-LPA; however, the number of tumor-
promoting stromal cells were not different between these two groups.
Conclusion:
Our current study indicated that microenvironmental molecular changes occur during the progression from MIA to S-LPA. Thus, it was suggested that this process may play an important role in disease progression from AIS to LPA of the lung.
Citation Format: MASAHITO NAITO, Yukitoshi Satoh, Genichiro Ishii. Microenvironmental changes in the progression from adenocarcinoma in situ to early-invasive adenocarcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5921. doi:10.1158/1538-7445.AM2017-5921
Abstract 606: Targeting multiple immune checkpoints and their ligands using a humanized mouse model of ovarian cancer
Authors: Huang Ruea-Yea , Odunsi Kunle 
Published: July 2017

Abstract
We have recently reported that multiple immune checkpoints are expressed in the TILs (tumor infiltrating T lymphocytes) and TALs (tumor associated T lymphocytes) from a murine ovarian cancer model and that blockade of one checkpoint pathway induces an upregulation of the other unblocked checkpoints. We hypothesized that resistance to single agent blockade (e.g. anti-PD1) is resulted from the compensatory upregulation of the other pathways (e.g. CTLA4 or LAG-3). To test this hypothesis in human ovarian cancer, we first examined the level of several immune checkpoints and their ligands in TILs or TALs from ovarian cancer patients. In addition to the highly expressed PD-1 and CTLA4, other checkpoint molecules such as TIM3, LAG3, VISTA, and TIGIT are also elevated in TALs as compared with control PBMC. The levels of multiple ligands for the immune receptors in the tumor samples were also analyzed. To translate the results from mice to humans, we developed several aggressive human ovarian cancer cell lines from patient derived xenografts to test the combinatorial checkpoint blockade strategies. Using a humanized mouse model of ovarian cancer we observed that adaptive transfer of autologous T cells in combination with checkpoint blockade of PD1 mildly delays ovarian tumor growth. The effect of blocking PD-1 and CTLA-4 pathways on tumor growth and the upregulation of other checkpoints are currently underway.
Citation Format: Ruea-Yea Huang, Kunle Odunsi. Targeting multiple immune checkpoints and their ligands using a humanized mouse model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 606. doi:10.1158/1538-7445.AM2017-606
Abstract 612: Methylation changes in DNA of CD8 T cells following CD137 costimulation
Authors: Aznar M. Angela , Labiano Sara , Diaz-Lagares Angel , Esteller Manel , Sandoval Juan , Melero Ignacio 
Published: July 2017

Abstract
Introduction: CD137 ligation imprints long term changes in the behavior of costimulated T-cells (1). There is not a satisfactory mechanistic explanation yet.
Experimental procedures: to determine the specific DNA methylation changes occurring upon CD137 costimulation, purified human CD8+ T cells from three healthy donors were activated in vitro for 5 days with anti-CD3 monoclonal antibody and either with an anti-CD137 monoclonal antibody or its corresponding isotype (huIgG4). Activated lymphocytes were left 5 days in culture with huIL-7 without further stimulation. Such back-to-resting CD8+ lymphocytes were reestimulated with anti-CD3 for 12, 24 and 36h to validate the expression of the genes differentially methylated upon primary stimulation at mRNA and protein levels.
DNA methylation profiles of both activated and resting cell subsets were characterized with Infinium 450K DNA methylation array (Illumina). To further confirm our observations, identical experimental procedure was performed with a different anti-CD137 agonist antibody (mIgG1 isotype) in a CD8+ T-cell donor.
Differentially methylated genes between anti-CD3+anti-CD137 versus their corresponding control counterparts were validated by pyrosequencing on activated and resting CD8+ from independent group of healthy donors (n=8 for hIgG anti-CD137 and n= 11 for mIgG anti-CD137). Expression changes were confirmed by qRT-PCR and flow cytometry in activated, rested and reestimulated CD8+ lymphocytes.
Results: 853 genes were differentially methylated in hIgG4 anti-CD137-treated CD8+ T cells as compared with their controls, 52 of which were shared with mIgG1 anti-CD137-costimulated CD8+ T lymphocytes. A number of differentially methylated genes are involved in i) T cell migration, ii) T cell activation, survival and homeostasis and iii) regulation of gene expression including key T-cell transcription factors.
Conclusions: CD137 costimulation induces CD8+ T lymphocytes that are poised to respond more effectively to a second antigen exposure. These acquired functions are imprinted in the genomic DNA of the CD8+ T cells by DNA methylation changes upon CD137 co-stimulation, and involve key genes for CD8+ T cells.
References: 1.
Hendriks, J., Y. Xiao, J.W. Rossen, K.F. van der Sluijs, K. Sugamura, N. Ishii, and J. Borst, During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. J Immunol 2005, 175: p. 1665-76.
Citation Format: M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Ignacio Melero. Methylation changes in DNA of CD8 T cells following CD137 costimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 612. doi:10.1158/1538-7445.AM2017-612