bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3977: Evaluation of miR10b and miR9 expression in breast cancer and correlations with distant metastases development
Authors: Barbano Raffaela , Pasculli Barbara , Copetti Massimiliano , Fontana Andrea , Coco Michelina , Vitulano Lorenzo , Poeta Maria Luana , Picardo Francesca , Marangi Gianfranco , Murgo Roberto , Ciuffreda Luigi , Valori Vanna Maria , Valori Vanna Maria , Morritti Maria , Maiello Evaristo , Fazio Vito Michele , Parrella Paola 
Published: August 2015

Abstract
We have recently demonstrated that the evaluation of miR10b expression relative to its normal counterparts (Relative Expression Ratio, RER) is able to predict patients risk to develop distant metastases. To confirm these results and evaluate whether other microRNAs could be predictive of outcome in breast cancer we evaluated the expression of miR10b and miR9 in paired tumors and apparently normal breast tissues 2 cm distant from tumour (NBT) on an extended cohort (n = 127) with a longer follow up (median 42 months). As control normal breast tissues from 10 healthy subjects (HBT) treated by reductive mammoplasty were analyzed. An increased expression was seen for the miR9 and miR10b in NBT samples as compared with HBT (P&lt;0.01). Whereas the expression of each of the two miRNAs was significantly lower in tumour samples as compared to the NBT specimens with RER value of 0.15 for miR10b (P = 0.001) and 0.59 for miR9 (P = 0.05). However only higher miR10b RERs were associated with distant metastases development in multivariable analysis (HR = 1.12; P = 0.04). Our results confirm the role of miR10b as predictive biomarkers of metastases development in breast cancer. In addition our data suggest a deregulation of miRNAs expression in the normal tissue surrounding tumor as compared to normal breast of healthy individuals.
Citation Format: Raffaela Barbano, Barbara Pasculli, Massimiliano Copetti, Andrea Fontana, Michelina Coco, Lorenzo Vitulano, Maria Luana Poeta, Francesca Picardo, Gianfranco Marangi, Roberto Murgo, Luigi Ciuffreda, Vanna Maria Valori, Vanna Maria Valori, Maria Morritti, Evaristo Maiello, Vito Michele Fazio, Paola Parrella. Evaluation of miR10b and miR9 expression in breast cancer and correlations with distant metastases development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3977. doi:10.1158/1538-7445.AM2015-3977
Abstract 4038: Role of the Rho-GTPase CDC42 in glioma migration
Authors: Okura Hidehiro , Golbourn Brian J. , Luck Amanda J. , Smith Christian A. , Rutka James T. 
Published: August 2015

Abstract
Introduction: Malignant astrocytoma is a highly proliferative and invasive neoplasm that infiltrates diffusely into regions of normal brain rendering total surgical extirpation impossible and effective local radiation therapy difficult. Conventional chemotherapy frequently fails because most agents administered systemically will not cross the blood-brain barrier. Despite recent reports which have shown a 2-month survival advantage when adjuvant temozolomide chemotherapy is used for glioblastoma multiforme, death ensues in most cases within 2 years of diagnosis. For truly significant advances to be made in the treatment of patients with malignant astrocytoma, we must develop a greater understanding of the basic biology of these neoplasms. PURPOSE: The aim of this study is to examine a key pathway involving the Rho-GTPase family of proteins that regulates glioma cell migration from the tumor mass into normal brain tissue. One of the Rho-GTPase family proteins, CDC42 is the major regulator of cell polarity. It plays a crucial role in controlling the direction of cell migration by determining the cell membrane localization of lamellipodia, and by moving the microtubule-organizing center and Golgi apparatus in front of the nucleus and towards the leading edge of the cell. However, there have been few reports on the role of CDC42 in human astrocytomas. METHOD: In order to examine the role of CDC42 in glioblastoma, we generated stable doxycycline (DOX) inducible cell lines expressing wild type (WT) -, constitutively active (CA) -, and dominant negative (DN) -CDC42. Cell viability, migration, and invasion assays were performed using the cell lines. We also used orthotopic xenograft mouse models and evaluated the survival by Kaplan-Meier analysis. RESULTS: Administration of DOX induced the expression of CA-CDC42 and demonstrated significantly increased migration and invasion properties compared to WT and DN-CDC42. Furthermore, CA-CDC42 bearing mice with DOX treatment had significantly decreased survival compared to WT and DN with DOX. CONCLUSION: Our results demonstrated that CA-CDC42 enhances the astrocytoma invasion and migration. Furthermore, CA-CDC42 increased the size of implanted tumor in the murine brain leading to early mortality. We concluded that CA-CDC42 plays an important role for astrocytoma malignancy.
Citation Format: Hidehiro Okura, Brian J. Golbourn, Amanda J. Luck, Christian A. Smith, James T. Rutka. Role of the Rho-GTPase CDC42 in glioma migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4038. doi:10.1158/1538-7445.AM2015-4038
Abstract 4048: HPV16 immunity induced by immune responses to mutations in E6 and E7 proteins
Authors: Agarwal Maria , Saint-Fleur Ashley , Fu Jie , Levitsky Hyam , Trimble Cornelia L. 
Published: August 2015

Abstract
Human papillomavirus (HPV) causes 30% of cancers attributable to infectious pathogens. HPV16 causes most cervical, anal, vaginal, vulvar, and oropharyngeal cancers. Although preventive vaccines targeting HPV16 and 18 are available, rates of vaccination are uneven. The incidence of HPV-associated cancers for which no screening algorithms have been validated continues to increase.
Development of squamous cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN) 2/3 is associated with integration of HPV genome into the host genome, and expression of the HPV E6 and E7- gene products, which inactivate p53 and pRb respectively. Since E6 and E7 are constitutively expressed in cervical carcinomas and CIN, they present attractive immunotherapeutic targets. Development of immunotherapies has been limited, in part, by modest immunogenicity of vaccines tested to date. The purpose of this study is to augment the immunogenicity of the E6 and E7 antigens through mutational screening.
A subset of CIN2/3 do undergo complete regression. Our lab has carried out a series of prospective clinical studies, including immunotherapeutic interventions, in subjects with CIN2/3. Peripheral blood T cell responses to E6 and E7 are marginal, and do not distinguish regressors in either vaccinated or unvaccinated subjects. However, in vaccinated subjects, the lesion microenvironment is comprised of new tertiary lymphoid structures, evidence of T cell proliferation elicited by cognate antigen, and clonally expanded TCRs. Tissue T cells in vaccinated subjects access dysplastic epithelium, in contrast to T cells in persistent lesions, which were confined to the stromal compartment. These findings suggest that T cells that could mediate regression can be elicited by vaccination. However, strategies to enhance immunogenicity would likely increase therapeutic effect. Here we present an approach designed to determine the effect of mutations in E6 and E7 on antigenicity. Mutations can enhance immune responses to antigens by several mechanisms, including altering antigen processing, trafficking, glycolsylation, and affinity to major histocompatibility complexes. Using error prone PCR, we generated libraries containing random mutations in the coding sequence of E6 and E7. Clones from each library are currently being screened in vitro to identify immunogenic mutants, which could be potentially used for multi-epitope vaccines.
Citation Format: Maria Agarwal, Ashley Saint-Fleur, Jie Fu, Hyam Levitsky, Cornelia L. Trimble. HPV16 immunity induced by immune responses to mutations in E6 and E7 proteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4048. doi:10.1158/1538-7445.AM2015-4048
Abstract 4062: Role of CD137 signaling in immune evasion of Hodgkin and Reed-Sternberg cells
Authors: Rajendran Sakthi , Schwarz Herbert 
Published: August 2015

Abstract
Hodgkin lymphoma (HL), a lymphoid malignancy, is a frequently occurring cancer among adolescents and young adults. HL is marked by the presence of malignant Hodgkin and Reed-Sternberg (HRS) cells, which constitute only a small fraction of the tumor mass. HRS cells are present in a complex stroma of inflammatory leukocytes, but are often able to evade the host immune system. These cells express various receptors to recruit leukocytes and hijack them for supporting the tumor growth. Our group has reported the overexpression of CD137, a member of the tumor necrosis factor receptor (TNFR) superfamily, on the HRS cells of HL tumor samples. CD137 is a co-stimulatory molecule expressed by T cells, only upon activation. We speculated that the expression of CD137 on the HRS cells may be associated with its malignancy, as HRS cells are clonally derived from B cells which are not expressing CD137. Our study aims to analyse the functional role of CD137 expression behind the survival, progression, and cytokine release of the malignant HRS cells. We found that the induction of CD137 signaling in HRS cell lines enhanced the secretion of cytokines such as IL-6, TNF-α and IL-13. In order to investigate the effect of these cytokines on the immune microenvironment, we cultured peripheral blood mononuclear cells (PBMCs) in the supernatants derived from CD137-induced HRS cells. PBMCs, when cultured in the above mentioned conditioned supernatants, secreted lesser levels of IFN-γ (a Th1 cytokine essential for T cell and NK cell cytotoxicity), implying a suppressed state of immune cells. Further, neutralisation of IL-13 (a Th2 cytokine) in the conditioned supernatants reversed the reduction of IFN-γ observed in PBMCs. This shows that IL-13 secreted by the HRS cells upon CD137 signaling is responsible for the inhibition of IFN-γ secretion by PBMCs. To summarize, CD137 signaling in HRS cells leads to the secretion of cytokines, which drive the polarization of helper T cells towards Th2 type, thus reducing Th1 immune responses against cancers. Taken together, our findings reveal the role of CD137 signaling as a novel mechanism of immune escape in HRS cells. Hence, targeting CD137 can be a potential therapeutic option for HL patients.
Citation Format: Sakthi Rajendran, Herbert Schwarz. Role of CD137 signaling in immune evasion of Hodgkin and Reed-Sternberg cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2015-4062
Abstract 4070: Prolonged silencing of diacylglycerol acyltransferase-1 induces a dedifferentiated phenotype in human liver cells
Authors: Chang Soyoung , Sung Pil Soo , Lee Jungsul , Park Junseong , Shin Eui-Cheol , Choi Chulhee 
Published: August 2015

Abstract
Diacylglycerol acyltransferase-1 (DGAT1), a key enzyme in triglyceride (TG) biogenesis, is highly associated with metabolic abnormalities, such as obesity and type 2 diabetes. However, the effects of DGAT1 sliencing in the human liver have not been elucidated. To investigate the effects of DGAT1 silencing in human liver cells, we compared the cellular behaviors of DGAT1-deficient Huh-7.5 cell lines with those of control Huh-7.5 cells. DGAT1-deficient cells acquired dedifferentiated and stem cell-like characteristics, such as formation of aggregates in the presence of high levels of growth factors, high proliferation rates, and loss of albumin secretion. In relation to aggregate formation, the expression level of various adhesion molecules was significantly altered in DGAT1-deficient cells. Microarray data analysis and immunostaining of patient tissue samples clearly showed decreased expression levels of DGAT1 and integrin β1 in patients who have nodular cirrhosis without fatty degeneration.
Note: This abstract was not presented at the meeting.
Citation Format: Soyoung Chang, Pil Soo Sung, Jungsul Lee, Junseong Park, Eui-Cheol Shin, Chulhee Choi. Prolonged silencing of diacylglycerol acyltransferase-1 induces a dedifferentiated phenotype in human liver cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4070. doi:10.1158/1538-7445.AM2015-4070
Abstract 4083: Deletion of the BMP receptor BMPR1a results in EMT and impairs mammary gland tumor formation and metastasis
Authors: Hover Laura D. , Pickup Michael W. , Gorska Agnieszka E. , Chytil Anna , Guo Yan , Novitskiy Sergey V. , Moses Harold L. , Owens Philip 
Published: August 2015

Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMP ligands have recently been shown to be overexpressed in human breast cancers. Normal and cancerous breast display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyVmT oncogene with mice lacking BMPR1a in mammary epithelial cells and found this deletion resulted in delayed tumor onset and extended survival significantly (p-value = &lt;0.001). We examined the histopathology of BMPR1a knockout (cKO) tumors and found a striking loss of epithelial characteristics combined with stromal desmoplasia. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicated that epithelial-to-mesenchymal (EMT)-like transitions were occurring in cKO tumors. We performed microarray analysis on these tumors and found changes that supported EMT-like changes with increased Snail mRNA expression. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and upon in vivo implantation. Additionally, cKO tumor cells had reduced migration yet not invasion in vitro. We next analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions and found high BMPR1a gene expression correlated with worse survival regardless of molecular breast cancer subtype. In conclusion, we found that loss of the BMPR1a impairs tumor formation and progression and does not exhibit tumor suppressive functions in mouse and human breast cancer.
Citation Format: Laura D. Hover, Michael W. Pickup, Agnieszka E. Gorska, Anna Chytil, Yan Guo, Sergey V. Novitskiy, Harold L. Moses, Philip Owens. Deletion of the BMP receptor BMPR1a results in EMT and impairs mammary gland tumor formation and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4083. doi:10.1158/1538-7445.AM2015-4083
Abstract 4089: CADM1 is a TWIST1 regulated suppressor of melanoma invasion
Authors: Hartsough Edward J. , Weiss Michele B. , Kugel Curtis H. , Rosenbaum Sheera R. , Aplin Andrew E. 
Published: August 2015

Abstract
Melanoma is the deadliest form of skin cancer; however, with early detection prior to metastatic dissemination, patients generally have a good prognosis. Recently, our lab has implicated the transcription factor TWIST1 in the progression of melanoma towards metastasis. In melanoma cells, we found that RAS-RAF-MEK-ERK (ERK1/2 pathway) signaling increases TWIST1 expression, which promotes invasive properties in the dermal microenvironment at least in part by enhancing levels of the matrix metalloproteinase, MMP1. Other TWIST1 regulated targets are poorly described. In this study, we compared expression profiling data from cells expressing shRNA against TWIST1 or cells overexpressing TWIST1 in order to determine TWIST1 regulated genes. KEGG and GO analysis revealed that TWIST1 is responsible for regulating a number of genes involved in cellular adhesion. We found that TWIST1 levels inversely correlate with levels of cell adhesion molecule 1 (CADM1) (NECL-2, IGSF4, TSLC1, SynCAM). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrate that TWIST1 physically interacts with CADM1 promoter and this is associated with reduced CADM1 levels. Additionally, CADM1 expression is inversely associated ERK1/2 signaling and TWIST1 expression. Modulation of cellular CADM1 levels does not seem to affect proliferations rates however, overexpression of CADM1 augments cell-cell interaction, and cell aggregation. Furthermore, exogenous CADM1 inhibited serum directed migration and invasion through matrigel coated boyden chambers, while knockdown of CADM1 was associated with an enhancement in the migratory and invasion properties. Taken together, these data provide evidence that CADM1 is negatively regulated by TWIST1, and may act as a suppressor of melanoma invasion.
Citation Format: Edward J. Hartsough, Michele B. Weiss, Curtis H. Kugel, Sheera R. Rosenbaum, Andrew E. Aplin. CADM1 is a TWIST1 regulated suppressor of melanoma invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2015-4089
Abstract 41: The Wnt3a targetome in triple-negative breast cancer cell lines
Authors: Maubant Sylvie , Tesson Bruno , Maire Virginie , Ye Mengliang , Rigaill Guillem , Gentien David , Cruzalegui Francisco , Tucker Gordon C. , Roman-Roman Sergio , Dubois Thierry 
Published: August 2015

Abstract
The canonical Wnt/beta-catenin pathway has been shown to be activated in triple-negative breast cancer (TNBC). The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change &gt; 1.3) of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGF-beta, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change &gt;1.3) which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors.
Citation Format: Sylvie Maubant, Bruno Tesson, Virginie Maire, Mengliang Ye, Guillem Rigaill, David Gentien, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. The Wnt3a targetome in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2015-41
Abstract 410: SPARC expression enhances cellular aggregation and resistance to gemcitabine in pancreatic cancer cells
Authors: Salvatierra Edgardo , Rivas Elvia , Guttlein Leandro , Robitschek Emily , Llera Andrea , Podhajcer Osvaldo 
Published: August 2015

Abstract
Pancreatic cancer (PaCa) is a very aggressive disease with a high mortality rate, characterized by a survival time of only few months after diagnosis. Pancreatic cancers also demonstrate great resistance to chemotherapeutic regimes, associated with an extensive desmoplastic reaction. The matricelular protein SPARC is involved in the interaction between the cell and the extracellular matrix, and its expression has been associated with worse prognosis in general, and in patients treated with gemcitabine. To evaluate its role in pancreatic cancer and chemotherapeutic resistance, we overexpressed SPARC in the SPARC-negative pancreatic cancer cells lines Miapaca2, Sw1990, and Panc1. The in vitro growth of two stable clones obtained from the different cell lines was compared with eGFP-transduced controls. No significant differences were observed in the 2D in vitro growth or the clonogenic capacity between pancreatic cancer cells expressing or not expressing SPARC. However, cell growth in 3D spheroid culture was markedly different. Indeed, SPARC-expressing cells exhibited more compact structures, with 45% reduction in spheroid size compared to control eGFP-expressing cells. This could partially be explained by the fact that the SPARC-expressing cells themselves exhibited more than 50% reduction in their size compared to the eGFP cells. While SPARC expression in pancreatic cancer cells did not affect Gemcitabine EC50 in 2D culture, SPARC-positive Panc1 and SW1990 cells exhibited six to ten times increased EC50 in 3D spheroids. Because the cell-cell interactions could potentially affect drug efficacy, and because increased resistance to gemcitabine has been associated with epithelial-mesenchymal transition (EMT), we analyzed the expression of EMT-associated genes (SNAI1 and OCLN), and genes also involved in cellular junctions (CDH1 and OCLN). SPARC-positive pancreatic cancer cells down regulated the expression of SNAI1 and CDH2, while CDH1 and OCLN were up-regulated Taken together, these data indicate that SPARC expression in PaCa cell lines diminishes cells size and modulates gemcitabine resistance in 3D models of cell culture, possibly through the modulation of epithelial genes related to cell-cell connections and EMT.
Citation Format: Edgardo Salvatierra, Elvia Rivas, Leandro Guttlein, Emily Robitschek, Andrea Llera, Osvaldo Podhajcer. SPARC expression enhances cellular aggregation and resistance to gemcitabine in pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2015-410