bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2725: Establishment of the primary human tumor xenograft (tumorgraft) mouse model of pancreatic ductal adenocarcinoma.
Authors: Garcia Patrick L. , Gamblin Tracy , Council Leona N. , Christein John D. , Heslin Martin J. , Richardson Joseph , Yoon Karina J. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer continues to be plagued by a low overall 5 year survival rate, which has remained at a stagnant 5% over the past 30 years. In addition, pancreatic cancer is the 10th leading diagnosed cancer, yet is the 4th leading cause of cancer related deaths in the US, in both men and women. Recent research efforts have been focused on increasing our understanding of the molecular and genetic aspects of pancreatic cancer, in order to improve outcome for these patients. A major tool of pancreatic cancer research has been the use of established cancer cell lines, although the inherent ability of these cell lines to recapitulate human pancreatic disease is not ideal, due to growth in artificial environment and homogenous nature. Implantation of primary human tumor samples into immune compromised mice have been shown to be more genetically heterogeneous, and allow for more relevant genetic profiling data when compared to established cell lines. To better understand the molecular and genetic events in pancreatic cancer, we established a patient derived primary human tumor xenograft (tumorgraft) model system. Briefly, non-diagnostic tumor tissue was procured from previously consented patients at the University of Alabama at Birmingham Hospital, under IRB approved protocols. The tumors were then examined grossly by a pathologist, and immediately implanted into the flank of immune compromised mice. Here we report, a set of 10 PDAC tumors, with a mean age of patients at diagnosis of 68.3 (± 11.6) years. Primarily, these tumors were stage II (six IIA and four IIB) and with a histological grade reported as five moderately differentiated and five poorly differentiated. Lymph node involvement at the time of surgical resection was also assessed and six patients were positive, while four patients were negative. The tumorgrafts retained the morphological and histological characteristics of the primary tumor, even after serial passage in mice, as determined by a pathologist blinded to tumor identity. Currently, we are using next generation sequencing to generate detailed gene expression, epigenetic, and genotyping profiles of these established PDAC tumors. This work is supported by UAB/UMN SPORE in Pancreatic Cancer-Career Development Award and the Department of Pharmacology/Toxicology, UAB.
Citation Format: Patrick L. Garcia, Tracy Gamblin, Leona N. Council, John D. Christein, Martin J. Heslin, Joseph Richardson, Karina J. Yoon. Establishment of the primary human tumor xenograft (tumorgraft) mouse model of pancreatic ductal 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 2725. doi:10.1158/1538-7445.AM2013-2725
Abstract 273: Molecular markers promoting metastases to the brain via EMT: Genes, proteins, and functional analysis.
Authors: Jeevan Dhruve S. , Sridhara Sudeepta , Braun Alex , Murali Raj , Jhanwar-Uniyal Meena 
Published: August 2014

Abstract
Brain metastasis is the most common cause of mortality and morbidity of many cancers and occurs in more than 40% of patients. The metastatic cascade entails an orderly sequence of steps enabling tumor cells to migrate from the primary tumor and colonize at secondary locations. The underlying mechanisms of metastatic dissemination to the brain remain to be defined. However, In order to achieve this metastatic potential a cancer cell may go through a cellular reprogramming process, namely epithelial-to-mesenchymal transition (EMT), and its counterpart mesenchymal-to-epithelial transition (MET), by acquiring multiple genetic alterations and a stem cell like phenotype. We hypothesized that EMT would play a crucial role in brain metastasis. In order to achieve our goal we studied the expression of markers of EMT, MET, and stem cells in metastatic brain tumor samples. Microarray analysis of metastatic tumors was also done using a plate form of 17,000 genes. Furthermore, functional analysis establishing the metastatic phenotype of cancer cells towards a cerebral environment was also demonstrated using metastatic cell lines. Our results demonstrated that the expressions of EMT markers (Snail, TWIST, pSTAT3, NFkB), as well as the mesenchymal marker Vimentin, were present in metastatic tumor samples. The stem cell marker CD44 was also highly expressed. Gene expression analysis established the high presence of transcriptional factors associated with differentiation and reprogramming. Lastly, Immunofluorescence analysis demonstrated the presence of the mesenchymal marker Vimentin in brain tumor specimens. Tumor cells grown in astrocytic media displayed an increased cell proliferation, as well as enhanced S-phase cell cycle entry using an EDU incorporation technique. Migration of primary tumor cells was significantly enhanced in astrocytic media as evidenced by scratch wound migration. Furthermore, the tumor cells have a greater affinity for astrocytic media as demonstrated by chemotatic migratory tests. Moreover, co-culture analysis of primary tumor cells with astrocytic cells shows amicable mutual growth with Immunofluorescence demonstrating cell-to-cell interaction via E-Cadherin. In conclusion results of this study suggests that reprogramming via EMT/MET plays a crucial step in brain metastasis, and that the cerebral milieu provides a suitable microenvironment for metastatic cells to grow and disseminate.
Citation Format: Dhruve S. Jeevan, Sudeepta Sridhara, Alex Braun, Raj Murali, Meena Jhanwar-Uniyal. Molecular markers promoting metastases to the brain via EMT: Genes, proteins, and functional analysis. [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 273. doi:10.1158/1538-7445.AM2013-273
Abstract 2746: Microsomal prostaglandin E2 synthase-1 may provide a novel specific therapeutic target in neuroblastoma.
Authors: Kock Anna , Rasmuson Agnes , Korotkova Marina , Idborg Helena , Johnsen John Inge , Jakobsson Per-Johan , Kogner Per 
Published: August 2014

Abstract
Background: Neuroblastoma (NB) cells are enriched in the omega-6 fatty acid arachidonic acid, the substrate for the cyclooxygenase (COX) enzymes and prostaglandin biosynthesis. The inducible isoform, COX-2 is overexpressed in NB and NB cells produce prostaglandin E2 (PGE2) that acts as an autocrine and/or paracrine survival and proliferation factor. Downstream of the COX enzymes, specific synthases are responsible for the production of the respective prostaglandins. Microsomal prostaglandin E2 synthase-1 (mPGES-1) specifically converts PGH2 to PGE2 and is thought to primarily couple to COX-2. The aim of this study was to investigate if inhibition of mPGES-1 could represent an alternative therapeutic approach to COX- inhibition in NB.
Methods: Western blot and immunohistochemistry were used for protein detection. Cell viability of seven NB cell-lines treated with the mPGES-1 inhibitor CAY1052 was determined by MTT-assay. Stable mPGES-1 knockdown SK-N-BE2 clones were established using shRNA and the clonogenic capacity was analysed by clonogenic assay. To study the in vivo effect of COX inhibition, four week old homozygous TH-MYCN mice were treated with 10mg/L diclofenac for two weeks. Ex vivo analyses of COX-metabolites in tumors were performed by LC-MS/MS.
Results: Expression of mPGES-1 in human NB tumors and in NB cell lines could be detected. Inhibition of mPGES-1 reduced NB cell growth in vitro and knockdown of mPGES-1 significantly reduced the clonogenic capacity. Expression of COX-1, COX-2 and mPGES-1 in TH-MYCN tumors could be detected and treatment with the dual COX-inhibitor diclofenac significantly reduced tumour weight, compared to untreated animals. Ex vivo analysis of tumor tissues from treated animals revealed a significantly decreased level of COX metabolites compared to controls. The expression of mPGES-1was not affected by the treatment. Furthermore, cells staining positive for cleaved caspase-3 were more prevalent in treated tumors indicating apoptosis Induction.
Conclusion: We found that mPGES-1 is expressed in NB, with a potential role for PGE2 synthesis and tumor growth. mPGES-1 represents an alternative therapeutic target for inhibiting NB growth through specific PGE2 inhibition and the TH-MYCN model is well suited for in vivo studies with this purpose.
Citation Format: Anna Kock, Agnes Rasmuson, Marina Korotkova, Helena Idborg, John Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Microsomal prostaglandin E2 synthase-1 may provide a novel specific therapeutic target in neuroblastoma. [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 2746. doi:10.1158/1538-7445.AM2013-2746
Abstract 2751: Wnt/β-catenin regulates the expression of MGMT through TCF/LEF transcription: new strategy for DNA alkylators in cancer therapy.
Authors: Wickström Malin , Baryawno Ninib , Dyberg Cecilia , Milosevic Jelena , Sveinbjörnsson Baldur , Northcott Paul A. , Taylor Michael , Kool Marcel , Kogner Per , Johnsen John I. 
Published: August 2014

Abstract
Background: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects DNA from the biological effects of alkylating agents. MGMT has been implicated in resistance to alkylating drugs such as temozolomide used in the clinic against brain tumors. Temozolomide has been shown to be ineffective in tumors expressing elevated levels of MGMT. Finding agents that induce MGMT deficiency and increase the susceptibility to alkylating chemotherapeutic agents is highly warranted.
Methods: The correlation between Wnt activity and MGMT expression was investigated in primary medulloblastomas, gliomas and colon cancer using gene expression cohorts. Cell lines from medulloblastomas, gliomas, colon cancer and neuroblastomas were examined for Wnt/β-catenin activity and MGMT expression using immunoblotting and real-time RT-PCR. siRNA against β-catenin, forced overexpression of β-catenin, and MGMT promotor reporter plasmids were used to study β-catenin mediated regulation on MGMT. Cell cytotoxicity and clonogenicity of chemotherapeutic drugs in combination with celecoxib were examined in cell lines using fluorometric microculture cytotoxicity assay and clonogenic assay, respectively. In vivo, nude NMRI mice carrying xenografts were treated with celecoxib in combination with temozolomide.
Results: Wnt signaling activity was shown to be correlated to increased MGMT expression levels both in primary tumors and cell lines. Transfection experiments revealed that β-catenin regulates MGMT expression. The clinically available COX-2 inhibitor celecoxib augmented the cytotoxic effect of temozolomide in cells with elevated MGMT expression through a reduction of Wnt/β-catenin activity and a subsequent reduction in MGMT expression.
Conclusions: This study demonstrates that celecoxib reduces the transcription of the MGMT gene through a prostaglandin E2-Wnt/β-catenin route and thus increases the susceptibility to temozolomide. These finding are the first reported that Wnt/β-catenin pathway regulates the expression of MGMT and thus provides a rational approach for improved efficacy of temozolomide therapy in the treatment of medulloblastoma and other cancers.
Citation Format: Malin Wickström, Ninib Baryawno, Cecilia Dyberg, Jelena Milosevic, Baldur Sveinbjörnsson, Paul A. Northcott, Michael Taylor, Marcel Kool, Per Kogner, John I. Johnsen. Wnt/β-catenin regulates the expression of MGMT through TCF/LEF transcription: new strategy for DNA alkylators in cancer therapy. [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 2751. doi:10.1158/1538-7445.AM2013-2751
Abstract 2770: Anti-leukemic response of a NSAID, tolfenamic acid.
Authors: Sutphin Robert M. , Connelly Sarah F. , Lee Chris M. , Sankpal Umesh T. , Eslin Don , Basha Riyaz 
Published: August 2014

Abstract
Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug is known to inhibit human cancer cells and mouse tumor growth in some cancer models; however its anti-leukemic response is not yet evaluated. Research from our laboratory and others showed that TA targets specificity protein (Sp) transcription factors which mediate the expression of several genes associated with cancer. We also showed that TA inhibits the expression of survivin, a key member of inhibitor of apoptosis family in several human cancer cells. Recent work from several laboratories revealed a strong association of survivin in leukemia. We hypothesize by targeting Sp proteins and survivin, TA can act as an anti-leukemic agent. The anti-proliferative response of TA was determined using four human leukemia cell lines, Jurkat (acute T-cell leukemia), Nalm-6 (pre-B cell leukemia), Molt-4 (acute lymphoblastic leukemia; T lymphoblast), and Reh (acute lymphoblastic leukemia, non-T; non-B) Cells were treated with increasing (25/50/75/100 μM) concentrations of TA and the cell viability was measured at 24, 48, and 72 h post-treatment using CellTiter-Glo kit. Results show a consistent decrease in cell viability in a dose and time-dependent manner. Confirmatory studies to elucidate the mechanism of action were conducted using selected cell lines, Jurkat and Nalm-6. Apoptosis and cell cycle analysis was performed using flow cytometry. The expression of c-PARP, Sp1, survivin, CDC2, CDC4, Cyclin D3 and pRb was determined by Western blot analysis and the caspases were measured by using Caspse-Glo kit(s). Results showed a significant increase in the apoptotic (annexin V positive) cell population following TA treatment, while cell cycle phase distribution analysis showed G0/G1 arrest. TA-induced cell apoptosis is supported by robust activation of caspases (3/7, 8 and 9), and the expression of c-PARP. TA down-regulated the expression of CDC2, CDC4, Cyclin D3 and pRb that mediate the early phases of cell cycle. In summary, TA modulated the expression of critical candidate genes associated with the early phases of cell cycle with validated efficacy in causing G0/G1 arrest. Western blot results reveal that TA significantly decreases Sp1 and survivin expression. Further work is needed to clarify the role of TA as a novel therapeutic agent for leukemia.
Citation Format: Robert M. Sutphin, Sarah F. Connelly, Chris M. Lee, Umesh T. Sankpal, Don Eslin, Riyaz Basha. Anti-leukemic response of a NSAID, tolfenamic acid. [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 2770. doi:10.1158/1538-7445.AM2013-2770
Abstract 2772: Inhibition of EGFR activity reduces AML cell survival via inhibition of downstream Akt and Erk signaling pathways.
Authors: Scheepers Ellen R. , Kampen Kim R. , de Bont Eveline SJM 
Published: August 2014

Abstract
Epidermal growth factor receptor (EGFR) inhibitor erlotinib, has been shown to induce complete remission of acute myeloid leukemia (AML) in two patients with concurrent lung cancer, suggesting a prominent role for EGFR in AML. However, EGFR expression analysis in AML is poorly defined and the role of EGFR in AML is still unclear.
In this study, we determined the EGFR protein expression in different human AML cell lines and studied the impact of EGFR inhibition by canertinib on the AML cell survival, proliferation, apoptosis and their downstream signaling routes. Using flowcytometry, we have shown that total EGFR as well as the phosphorylated residue Tyr1068 is expressed in five out of the eight AML cell lines (range of 4.9-46.6% for total and phosphorylated EGFR). EGFR phosphorylation was found to be induced by EGF stimulation, which could be prevented by canertinib treatment, showing functional activity and specificity of the EGFR phosphorylation site. Canertinib was shown to decrease the AML cell survival sufficiently (at a median IC50 of 6.2 μM, range: 0.9 - 15.2 μM canertinib in n=8 AML cell lines) as measured by WST-1 assays. The lower cell survival was the net result of lower numbers of mitotic phospho-histone H3 positive cells and an increase in the number of Annexin V positive cells. Immunoblot analysis revealed that canertinib treatment (5uM) reduced the phosphorylation of Akt and Erk intracellular proteins downstream of the EGFR signaling pathway in AML cells. Long-term canertinib treatment (5uM) showed that downstream targets were re-activated after 24 hours, which suggest kinomic reprogramming by alternative escape mechanisms compensating for the loss of EGFR activity. These findings suggest encouraging possibilities for targeting EGFR as a therapeutic strategy in AML. Future studies are necessary to determine the exact mechanism through which EGFR activity might contribute to AML progression, relapses as well as to interact with possible escape mechanisms of AML cells.
Citation Format: Ellen R. Scheepers, Kim R. Kampen, Eveline SJM de Bont. Inhibition of EGFR activity reduces AML cell survival via inhibition of downstream Akt and Erk signaling pathways. [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 2772. doi:10.1158/1538-7445.AM2013-2772
Abstract 2800: IL-5 induced migration of HT1376 cells via ERK1/2-mediated MMP-9 expression by inducing activation of NF-κB .
Authors: Lee Eo-jin , Lee Se-Jung , Moon Sung-Kwon 
Published: August 2014

Abstract
Interleukin-5 (IL-5) plays an important role in the growth and differentiation of human B cells and eosinophils. However, little is known about the effect of IL-5 on cancer cells. In this study, we investigated the molecular mechanism involved in the IL-5-induced migration of bladder cancer HT1376 cells. Our results indicated that IL-5 significantly enhanced migration and MMP-9 expression in HT1376 cells. We also found that IL-5 induces transcriptional activation of the binding of NF-kB and AP-1, which are two important nuclear transcription factors that are linked to MMP-9 expression in HT1376 cells. In subsequent experiments, we found activation of ERK1/2 in IL-5-treated HT1376 cells. To examine the involvement of the ERK1/2 signaling pathway on IL-5-induced cell responses, we pretreated HT1376 cells with the ERK1/2 inhibitor U0126 followed by IL-5 treatment. The results showed that U0126 treatment inhibited migration of IL-5-treated HT1376 cells. Moreover, IL-5-stimulated MMP-9 expression was suppressed by the addition of U0126. Inhibition of ERK1/2 function consistently rescued transcriptional activity of NF-kB, without altering AP-1 activation, in IL-5-treated cells. Finally, inhibition of IL-5 specific receptor IL-5R alpha by small interfering RNA (siRNA) suppressed migration, ERK1/2 activation, MMP-9 expression and binding activation of NF-kB in IL-5-treated HT1376 cells. The results of the present study indicate that the IL-5/IL-5R alpha dyad induced cell migration through ERK1/2-mediated expression of MMP-9 by binding activation of NF-kB in bladder cancer cells. In conclusion, these novel findings indicate that binding of IL-5 to IL-5R alpha plays a critical role in MMP-9 expression, which might be involved in the migration of bladder cancer.
Citation Format: Eo-jin Lee, Se-Jung Lee, Sung-Kwon Moon. IL-5 induced migration of HT1376 cells via ERK1/2-mediated MMP-9 expression by inducing activation of NF-κB . [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 2800. doi:10.1158/1538-7445.AM2013-2800
Abstract 2803: Disabeled-2 (Dab-2) modulates platelet-cancer cell interactions through its sulfatide binding domain.
Authors: Andreano Kaitlyn , Fu Xiangping , Capelluto Daniel , Finkielstein Carla 
Published: August 2014

Abstract
Platelets’ role in cancer progression and metastasis has largely been attributed to platelet-mediated enhancement of tumor cell survival, extravasation (exiting form capillaries and entering organs), and angiogenesis. Correlations exist between the ability of some tumor cells to aggregate platelets in vitro and their metastatic potential in vivo that it is manifested as a hypercoagulable state found in most cancer patients. We have identified a tumor suppressor molecule (Dab-2) that it is released upon platelet activation and that modulates the extent of blood clotting. Our results show Dab-2 is released from alpha-granules in the platelet to the membrane surface where specifically binds to the integrin receptor, thus inhibiting platelet aggregation. Binding of Dab-2 to integrins is modulated by sulfatides, a form of glycosphingolipid that accumulate in platelet membrane and effectively compete for Dab-2 levels. Interestingly, we found that the N-terminal region of Dab-2 specifically binds to sulfatides through two conserved sulfatide-binding sites. Upon activation, sulfatides protect Dab-2 from thrombin cleavage, facilitate its internalization and modulate the surface expression of P-selectin, a coagulation protein needed for stabilization of platelet aggregates. P-selectin also mediates both tumor cell adhesion to vascular endothelial cells and the interaction between activated platelets and cancer cells (emboli) during metastasis. Interestingly, our data show that Dab-2/sulfatide recognition influences the stability of platelet aggregates heterotypically with cancer cells through sulfatide binding and, indirectly, by controlling P-selectin levels. Thus, we hypothesize that manipulation of Dab-2 function in response of platelet activation will impact emboli formation offering an alternative route for therapeutic strategies aimed to control metastatic processes.
Citation Format: Kaitlyn Andreano, Xiangping Fu, Daniel Capelluto, Carla Finkielstein. Disabeled-2 (Dab-2) modulates platelet-cancer cell interactions through its sulfatide binding domain. [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 2803. doi:10.1158/1538-7445.AM2013-2803