bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4935: PDZ–domain binding kinase promotes invasion in prostate cancer cells through up–regulation of matrix metalloproteinases–2 and –9.
Authors: Brown-Clay Joshua D. , Shenoy Deepika N. , Banerjee Partha P. 
Published: August 2014

Abstract
Members of the protein kinase superfamily of enzymes modulate many of the facets of the tumor phenotype, such as survival, proliferation, invasion and metastasis. Genetic, epigenetic or regulatory alterations can result in aberrant kinase behavior; the targeted inhibition of which has been a growing focus in anti-cancer drug development. PDZ-domain binding kinase (PBK) is an under-studied, dual-specificity serine/threonine kinase that has been shown to play a key role in cell division and regulation of multiple signaling pathways. It is expressed physiologically in spermatogenic germ and proliferating neural precursor cells, as well as aberrantly in a variety of cancer types. However, the role of PBK in prostate cancer has not been clearly defined. We have found that PBK expression varies greatly across a panel of human prostate cancer cell lines. Interestingly, the level of expression of PBK in prostate cancer cells directly correlates with their invasive ability. Since matrix metalloproteinases (MMP) -2 and -9 are key invasive effectors in a variety of cancers, we investigated their protein levels in relation to that of PBK. Expression of exogenous PBK in low PBK-expressing prostate cancer cell lines (LNCaP and VCaP) significantly upregulated levels of both the propeptide and active forms of MMP-2 and MMP-9; conversely, knockdown of PBK expression in a high PBK-expressing prostate cancer cell line (PC3M) significantly down-regulated both forms of these two MMPs. To determine if a change in PBK levels produces a significant phenotypic effect, we measured the effect of PBK overexpression or knockdown on the prostate cancer cell lines’ invasive ability, as measured in a modified Boyden chamber invasion assay. Overexpression of PBK increased prostate cancer cell invasion approximately ten fold, while PBK knockdown reduced PC3M invasive ability more than three fold. Moreover, immunohistochemical analysis revealed that PBK is present in the majority of human prostate cancer samples tested but not at all in the benign or normal human prostate tissue. These data indicate a novel function of PBK where its presence plays a role in invasion of human prostate cancer cells through up-regulation of MMP-2 and MMP-9. Therefore, the role of PBK in promoting cell invasion, combined with its general lack of expression in normal cells, nominates PBK as a potentially important therapeutic target for prostate cancer.
Citation Format: Joshua D. Brown-Clay, Deepika N. Shenoy, Partha P. Banerjee. PDZ–domain binding kinase promotes invasion in prostate cancer cells through up–regulation of matrix metalloproteinases–2 and –9. [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 4935. doi:10.1158/1538-7445.AM2013-4935
Abstract 4943: Peroxisome Proliferator-Activated Receptor γ inhibits cell nvasion, migration and epithelial-mesenchymal transition through up-regulating Galectin-9 in gastric cancer cells and in zebrafish xenograft model.
Authors: Cho Soo-Jeong , Kook Myeong-Cherl , Choi Il Ju 
Published: August 2014

Abstract
Background: PPARγ (peroxisome proliferator-activated receptor γ) is a member of the nuclear hormone receptor that is known to be anti-neoplastic. Little is known about clinical significance in gastric cancer (GC). We aimed to evaluate the mechanism related to tumor invasion, migration and epithelial-mesenchymal transition (EMT) in GC cells and in an animal model.
Methods: We controlled the expression of PPARγ and galectin-9 using siRNAs and lenti-viral constructs in human GC cells, and determined the effects of PPARγ and galectin-9 on EMT using RT-PCR, and on cell migration using transfilter assay and zebrafish xenograft model. Direct binding and interaction between PPARγ and galectin-9 were evaluated using luciferase and ChiP assays.
Results: Over-expression of PPARγ was accompanied by increased galectin-9 mRNA. Enhanced expression of PPARγ either galectin-9 increased the expression of E-cadherin, decreased the expression of N-cadherin, fibronectin, snail, MMPs-1, and -9, and reduced cell invasion and migration. Silencing either PPARγ or galectin-9 decreased the expression of E-cadherin, increased the expression of N-cadherin, fibronectin, and snail, and also increased cell migration and invasion. ChiP assay showed PPARγ bound to the promoter region of galectin-9. Luciferase assay demonstrated that the galectin-9 promoter activity significantly increased in PPARγ over-expressing cells compared to empty vector-treated cells, but significantly decreased in PPARγ siRNA-treated cells compared to scRNA-treated cells. PPARγ agonist caused dose-dependent cell death in GC cells, and increased the subdiploid fraction of DNA. In the zebrafish xenograft model, the number of zebrafishes in which transplanted AGS cells were migrated to tail vein and the number of migrated cancer cells were much less in PPARγ-overexpressing GC cells than in empty vector transfected cells, respectively.
Conclusions: PPARγ inhibits cell invasion, migration, and EMT through up-regulation of galectin-9 in vitro and in vivo. PPARγ could be a potential therapeutic target of GC.
Citation Format: Soo-Jeong Cho, Myeong-Cherl Kook, Il Ju Choi. Peroxisome Proliferator-Activated Receptor γ inhibits cell nvasion, migration and epithelial-mesenchymal transition through up-regulating Galectin-9 in gastric cancer cells and in zebrafish xenograft model. [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 4943. doi:10.1158/1538-7445.AM2013-4943
Abstract 497: Engagement of activatory Fc γ receptors by immunoregulatory receptor-targeting antibodies mediates antitumor activity.
Authors: Bulliard Yannick , Jolicoeur Rose , Windman Maurice , Rue Sarah , Knee Deborah , Wilson Nick , Dranoff Glenn , Brogdon Jennifer 
Published: August 2014

Abstract
Inhibitory FcγRIIB receptors are required for the therapeutic effects of agonistic antibodies targeting several tumor necrosis factor receptor (TNFR) superfamily members, including CD40, DR5, and Fas. However, it remains unclear how general this requirement is and whether activating FcγRs may be required for antibodies targeting other immunoregulatory receptors. Here we have explored the involvement of FcγRs for the antitumor effects of antibodies targeted to costimulatory TNFRs expressed on T cells. Surprisingly, FcγRIIB was completely dispensable for antibody-mediated anti-tumor effects. In contrast, activating FcγRs were required for maximal in vivo activity. A similar dependence on activating FcγRs was observed for antibodies targeted to the T cell surface antigen CTLA-4. Important changes in the tumor microenvironment and draining lymph nodes correlated with the in vivo efficacy of these antibodies. Our findings uncover a previously unknown requirement for activating FcγRs in the anti-tumor effects of immunomodulatory antibodies and raise important questions about the role of receptor signaling for therapeutic activity. A greater understanding of this activatory FcγR-based mechanism may improve the design and activity of immune-modulatory antibodies in clinical development, and those already approved for the clinic.
Citation Format: Yannick Bulliard, Rose Jolicoeur, Maurice Windman, Sarah Rue, Deborah Knee, Nick Wilson, Glenn Dranoff, Jennifer Brogdon. Engagement of activatory Fc γ receptors by immunoregulatory receptor-targeting antibodies mediates antitumor activity. [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 497. doi:10.1158/1538-7445.AM2013-497
Abstract 4982: Comparison of T cell responses to a melanoma-related antigen in elderly and young melanoma patients.
Authors: Chakraborty Nitya G. , Singh Prashant , Dadras Soheil S. , Mukherji Bijay , Hegde Upendra P. 
Published: August 2014

Abstract
It is widely believed that a hypo-and/or dysfunctional state in T cells in the elderly is a negative factor in immune defense against cancer. Accordingly, cancer patients are often excluded from immune-based clinical trials and therapies. The incidence of melanoma is rapidly rising in the elderly. To our knowledge, a critical assessment of the immune responsiveness by the elderly against a relevant melanoma associated antigen has not been carried out. Using the MART-127-35 (M27) epitope as a melanoma-associated target epitope and M27 specific T cell receptor (TCR)-engineered T cells from the elderly (over 70) and young (below 45) as common elements in the comparison, we examined the T cell responses in both cohorts to the M27 epitope and to the Influenza matrix peptide MP58-66 (Flu58) as a control, ex vivo. We also compared the expressions of a number of genes associated with immune response by real-time reverse transcription polymerase chain reaction (qPCR) in formalin fixed primary melanomas from both cohorts, in situ.
While we detected a compromised CD8+ T cell response to Flu58 in the elderly, T cells from both cohorts proliferated and synthesized Th1 type cytokines in comparable levels when stimulated by the M27 epitope. qPCR analyses of primary melanomas from elderly patients showed lower levels of Fox-P3 expression but revealed comparable levels of expression of IL-2, IFNγ, TNF α, IL-4, IL-10, IDO, and TGFβ. These findings indicate that elderly patients are quite capable of responding to tumor antigens and need not be excluded from immune-based therapies or clinical trials.
Citation Format: Nitya G. Chakraborty, Prashant Singh, Soheil S. Dadras, Bijay Mukherji, Upendra P. Hegde. Comparison of T cell responses to a melanoma-related antigen in elderly and young melanoma patients. [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 4982. doi:10.1158/1538-7445.AM2013-4982
Abstract 4992: A novel role of soluble E-selectin as a chemoatractant to human leukocytes through the PI3kinase signaling pathway in breast cancer.
Authors: Blache Celine A. , Hasan Nafis , Park Jeehna , Suh Stephen , Gorenstein David G. , Rui Hallgeir , Tanaka Takemi 
Published: August 2014

Abstract
Solid tumors are multicellular complexes where the tumor stroma that is comprised of endothelial cells, pericytes, fibroblasts and immune cells, all of which orchestrate to assist in cancer cell growth, angiogenesis and invasion. The tissue infiltration of immune cells is mediated by a multistep adhesion cascade and involves the selectin family of calcium-dependent cell surface glycoproteins Among this family, E-selectin (CD62E, ELAM-1 or LECAM-2) is exclusively expressed on the surface of endothelial cells in a highly inducible manner in response to inflammatory cytokines, and consequently an elevated E-selectin expression has been reported in many types of diseases including cancer. Endothelial E-selectin (eE-sel) assists in the initial adhesion of circulatory leukocytes to the surface of vascular endothelium by interacting with its ligands (sLeX, sLeA and CD44). The external domain of E-selectin can be cleaved off and shed into the circulation as soluble E-selectin (sE-sel). sE-sel is present in the serum of cancer patients and is associated with occurrence of metastases and poor survival in breast and colorectal cancers. However, the biological relevance of sE-sel is not clearly understood. In this study, we aim to identify the biological role of sE-sel in breast cancer growth. We have demonstrated that sE-sel enhances the adhesion and tissue migration of leukocytes into breast tumor both in vitro through the activation of PI3 kinase and its downstream signaling cascade. We have also demonstrated that 7 times more peripheral blood mononuclear cells (PBMC) migrate into breast tumor when pre-incubated with sE-sel as compared to untreated condition. Therefore, we conclude that sE-sel serves as a chemoattractant that enhances the tissue migration of leukocytes, which lead to the development of solid tumor stroma that enhances the growth of breast tumor and invasion.
Citation Format: Celine A. Blache, Nafis Hasan, Jeehna Park, Stephen Suh, David G. Gorenstein, Hallgeir Rui, Takemi Tanaka. A novel role of soluble E-selectin as a chemoatractant to human leukocytes through the PI3kinase signaling pathway in breast 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 4992. doi:10.1158/1538-7445.AM2013-4992
Abstract 50: Anchored multiplex PCR for detection of gene rearrangements and mutations using next-generation sequencing.
Authors: Zheng Zongli , Zhelyazkova Boryana , Panditi Divya , Robinson Hayley , Engelman Jeffrey A. , Iafrate John A. , Le Long 
Published: August 2014

Abstract
We describe a rapid targeted RNA-seq library construction method for the detection of gene fusions in cancer using next generation sequencing. The method involves ligation of half-functional sequencing adaptors to double strand cDNA, followed by two successive PCR reactions using hemi-nested gene-specific 3’ primers with the 5’ adaptor primer, and generates libraries ready for bi-directional sequencing. RNA extracted from formalin-fixed paraffin-embedded biopsies can be used directly without the need to deplete ribosomal RNA, non-target mRNA or genomic DNA. Importantly, the assay can be performed without the need to know the 5’ partner in a gene fusion event. The method can also be applied to genomic DNA for detection of gene mutations, insertions, deletions and copy number changes. The method is very flexible and can allow multiplexing of over 500 targets. We have designed a lung cancer translocation panel which includes 18 amplicons for detections of gene rearrangements involving ALK, ROS1 and RET. For targeted genomic DNA-seq, we have designed a small 96-amplicon panel including tumor hotspots and entire coding sequences of key tumor suppressor genes TP53 and PTEN, and a 623-amplicon panel for 370 exons of 18 tumor suppressor genes. Unlike conventional PCR-based method, this method generates libraries with random sequencing start sites and allows for direct sequencing without having to spiking in controls (e.g. PhiX) on those platforms where high starting site complexity is required, such as the Illumina Miseq sequencer. The assays generally achieve high on-target specificity (&gt;90%), and are very cost-effective. The targeted RNA-seq assay has detected various gene rearrangements in known FISH-positive cases with previously unknown 5’ partners using our archived samples. The small 96-amplicon genomic DNA assay showed 100% of targeted bases having &gt;100-fold coverage and 99.9% having &gt;500-fold coverage with minimal optimization. In our first attempt of targeting 370 exons (626 amplicons, target size 52.3 kilobases), this assay achieved 97% of targeted bases having &gt;100-fold coverage and 93% having &gt;500-fold using ¼ of a Miseq sequencing run.
Citation Format: Zongli Zheng, Boryana Zhelyazkova, Divya Panditi, Hayley Robinson, Jeffrey A. Engelman, John A. Iafrate, Long Le. Anchored multiplex PCR for detection of gene rearrangements and mutations using next-generation sequencing. [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 50. doi:10.1158/1538-7445.AM2013-50
Abstract 5009: Stem cells and their signals during skin tumor regression.
Authors: Zito Giovanni , Saotome Ichiko , Greco Valentina 
Published: August 2014

Abstract
Basic mechanisms of tissue development and regeneration are often hijacked during Cancer. A subset of skin squamous cell carcinoma is known to be able to spontaneously self-regress. These tumors are commonly referred as Keratoacanthoma and thought to arise from the skin hair follicle. Because skin hair follicles undergo continuous growth and regression, we hypothesized that the molecular mechanisms that regulate hair follicle regression drive Keratoacanthoma self-regression. In order to test this hypothesis we ask 1) what is the cellular origin of Keratoacanthoma, 2) and what signaling mechanisms are responsible for Keratoacanthoma self-regression.
First, in order to understand the cellular origin of Keratoacanthoma, we utilize a genetic lineage tracing approach in combination with a DMBA-based chemical carcinogenesis protocol that recapitulates human Keratoacanthoma growth and self-regression in mice. Given that the location and identity of hair follicle stem cells has been identified, we utilize a spatially restricted Tamoxifen inducible CreER mouse line that specifically label hair follicle stem cells and their descendants (K19CreER;GFPr). By these means, we found that GFP labeled cells are observed within Keratoacanthoma tumors, thus suggesting that hair follicle stem cells contribute to the development of the self-regressing Keratoacanthoma tumors. Second, in order to identify the molecular mechanisms that drive Keratoacanthoma self-regression, we use a parallel approach of both human and mouse transcriptional analysis of Keratoacanthoma during either growth or regression. By focusing on signaling pathways that regulate hair follicle regression, we found that Wnt signaling is switched off during Keratoacanthoma self regression in both human and mouse Keratoacanthomas by immunofluorescence and real time PCR approaches. We are currently testing 1) whether Wnt is sufficient and/or required for Keratoacanthoma regression behavior and 2) what is upstream of Wnt down-regulation during the regression phase by genetic and sequencing approaches.
The identification of the cells and signals that regulate Keratoacanthoma tumor growth and regression will provide key clues on the relevant cell populations and signaling that will likely be proper targets in other tumors beyond Keratoacanthomas, and allow for the design of treatment strategies that exploit stem cell regression pathways to switch off stem cell populations in cancerous tissues.
Acknowledgements: New York Stem Cell Foundation (NYSCF) Postdoctoral Fellowship Grant (GZ) and ACS grant #121966-RSG-12-059-01-DDC (VG).
Citation Format: Giovanni Zito, Ichiko Saotome, Valentina Greco. Stem cells and their signals during skin tumor regression. [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 5009. doi:10.1158/1538-7445.AM2013-5009
Abstract 5065: Orally active nontoxic dual MMP2 and CAIX inhibitors as anticancer therapy.
Authors: Breuer Eli 
Published: August 2014

Abstract
Carbonic anhydrases IX and XII, (CAIX and CAXII) are critical to maintain a low pH in the tumor cell's microenvironment, and MMP-2 is critical for breaching the basement membrane that opens the way to the dissemination of metastases. The expression of carbonic anhydrase IX (CAIX), a marker for hypoxic tumors, is correlated with poor prognosis. In this presentation, we wish to report that carbamoylphosphonates (CPOs) have been identified as orally bioavailable dual inhibitors of matrix metalloproteinase-2 (MMP-2) on the one hand, and carbonic anhydrases (CAs) on the other hand, especially the IX and XII isoforms, well known as cancer promoting factors. We have also demonstrated that the ionized CPO acids are unable to cross the cell membrane and thus are limited to interact with enzymes present in the extracellular domains of as are both CA isozymes CAIX and CAXII and MMP-2. Finally, exposing cancer cells to CPOs in hypoxic conditions resulted in the dose dependent release of lactate dehydrogenase, confirming the direct interaction of the CPOs with the cancer related isozymes CAIX and XII and thereby promoting cellular damage. Thus, CPOs can be regarded as novel orally active nontoxic drug candidates for CAIX expressing tumor targeted chemotherapy acting by two synergistic mechanisms, namely, inhibiting CAs and MMPs simultaneously.
Citation Format: Eli Breuer. Orally active nontoxic dual MMP2 and CAIX inhibitors as anticancer 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 5065. doi:10.1158/1538-7445.AM2013-5065
Abstract 5069: Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic.
Authors: Mehner Christine , Batra Jyotica , Robinson Jessica , Radisky Derek C. , Radisky Evette S. 
Published: August 2014

Abstract
Matrix metalloproteinases (MMPs), a family of extracellular matrix degrading proteins, have been found to be upregulated in many human cancers and have been shown to contribute to cancer progression. There have been many aborted attempts to target MMPs therapeutically using small molecule inhibitors; the limited selectivity of most MMP inhibitors may be a major factor contributing to their poor effectiveness. As an alternative to small molecule MMP inhibitors, we are developing new methodology to create selective protein inhibitors of MMPs, based on the scaffold of the natural inhibitor TIMP-1, that may be used as protein therapeutics. Because TIMP-1 has a very short plasma half-life, we have developed methods for PEGylation that extend the plasma half-life to about 24h while preserving MMP inhibitory activity, rendering it more suitable for in vivo applications. We have also generated mutations in TIMP-1 that confer selective binding toward particular MMPs. The targets thus far pursued include MMP-9, MMP-3, and MMP-10, which represent therapeutic targets of interest in breast cancer and lung cancer. In the future, the methods developed here can be used to identify TIMP-1 variants selective toward additional MMPs, which may be of utility in the research and treatment of many human cancers.
Citation Format: Christine Mehner, Jyotica Batra, Jessica Robinson, Derek C. Radisky, Evette S. Radisky. Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic. [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 5069. doi:10.1158/1538-7445.AM2013-5069