bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4241: Glioma spheroids obtained via ultrasonic aspiration are viable and express stem cell markers: a new tissue resource for glioma research
Authors: Jensen Stine S. , Aaberg-Jessen Charlotte , Jabbari Javad , Andersen Claus , Schrøder Henrik D. , Kristensen Bjarne W. 
Published: August 2012

Abstract
Ultrasonic aspirators allow safe, rapid and accurate removal of brain tumors. However, the tissue fragments removed are used surprisingly little in research. The aim of this study was to investigate whether such tissue fragments could be cultured as organotypic multicellular spheroids and whether these spheroids could be used in cancer stem cell research. Biopsy-derived spheroids have earlier been shown to represent an important alternative to commercially available cell lines, but access to biopsy tissue is often limited. Tissue fragments obtained by ultrasonic aspiration from 10 glioblastomas and tumor biopsy tissue from seven of these tumors were collected and cultured in serum-containing and serum-free medium. After culturing, the fragments formed spheroids, which were prepared for histological staining. For comparison, the corresponding fixed non-cultured patient biopsies were also included in the study. Hematoxylin eosin staining showed that viable glioma spheroids were obtained from both ultrasonic and biopsy tissue using both serum-containing and serum-free medium. Independent of the type of tissue used for the spheroids, the immunohistochemical expression of GFAP decreased, whereas the expression of VWF and the Ki-67 proliferation index increased in spheroids cultured in serum-free versus serum-containing medium. Independent of the type of medium, both ultrasonic and biopsy tissue expressed significantly higher levels of the investigated stem cell markers CD133, Nestin and Bmi-1 compared to the non-cultured patient biopsies. In conclusion, we found that is was easy to obtain viable glioma spheroids from ultrasonic tissue fragments. Although differences in expression of the different markers were found, the overall expression was preserved, thereby suggesting ultrasonic tissue fragments as a new tissue resource for glioma research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4241. doi:1538-7445.AM2012-4241
Abstract 4245: Establishment of patients’ primary ovarian cancer xenograft models for test of anticancer agents
Authors: Liu Changnian , Li Yan , Yue Tianfu , Li Wenwei , Zhou Wen , Liu Yong , He Fang , Zhou Rui , Bai Chang 
Published: August 2012

Abstract
BACKGROUND Human xenograft tumor models established by transplantation of human tumor cell lines into immunodifficient mice have been routinely used for preclinical test of anticancer agents. But tumor cell lines have a relatively low transplantability, which resulted in a limited number of tumor models available for test of novel anticancer agents. Recently, we have developed a large number of patients’ primary ovarian tumor xenograft models by transplanting human fresh ovarian tumor tissues into nude mice, which have been employed for preclinical test of clinically used drugs and novel anticancer agents for their chemosensitivity screening. METHODS The fresh ovarian tumor samples were collected from local hospitals. The tumor fragments of 2-3 mm were subcutaneously implanted in the flanks of nude mice by trocar needle. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue (passage 1). The clinically used drugs included cisplatin, carboplatin, paclitaxel, and docetaxel. The histology and gene sequence of the established primary tumor models were analyzed and compared with patients’ original tumors. RESULTS A total of 76 patients’ ovarian tumor samples were implanted into nude mice; and 35 primary tumor models have been established with a tumor taking rates of 47% for the first passage. The tumor taking rates were higher in the later passages ranged from approximately 70-100%. The therapeutic efficacy of the test anticancer drugs was consistent with their clinical findings. The patients’ primary ovarian tumor xenografts from all 5 passages retained a similarity in architecture, histopathological morphology, and genomic mutation status to their patients’ original tumors. CONCLUSIONS The patient primary tumor model system can provide a larger number of models for selection of right models for preclinical testing novel agents based on their anticancer mechanism. The primary tumor models retain a similarity in histology and genomic mutation status to their patients’ original tumors. They may predict more relevant clinical response rate and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs development programs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4245. doi:1538-7445.AM2012-4245
Abstract 4247: Comparison of two-dimensional verses three-dimensional breast cancer models in drug discovery
Authors: Lovitt Carrie J. , Avery Vicky M. 
Published: August 2012

Abstract
Two-dimensional (2D) monolayer cancer cell culture is generally used in most drug discovery screening programmes to identify novel anti-cancer compounds. However, three-dimensional (3D) cell culture more closely represents the in vivo tumor environment thus providing a more accurate measure of compound activity. Development of an automated, reproducible and miniaturised 3D culture model for drug discovery in breast cancer would be highly advantageous. Thus we have developed and optimised a miniaturised in vitro 3D culture model in which breast cancer cells interact with reconstituted basement membrane from MatrigelTM. To determine the effectiveness of our 3D breast cancer model for use in future drug discovery, chemotherapeutic drugs commonly used in breast cancer therapy were tested and differences in drug activity were compared to 2D cell culture models. Once validated, this 3D culture model will be used to evaluate and further characterise novel compounds. The results presented describe the development and reproducibility of our 3D culture model and its 2D culture model counterpart. This includes the linear relationship between fluorescence intensity and cell number for measurement of metabolic activity as an indicator of cell viability when using the indicator dye Resazurin; determination of an adequate signal window and the reproducible average mean sizes of spheroids present under assay conditions. We report that there is significantly more drug resistance in our 3D cell culture model compared to our 2D culture model. This is particularly evident in the presence of taxanes and anthracyclines. Results from this study also show that the degree of drug resistance in 3D is breast cancer cell line dependent for each of the chemotherapeutic drugs studied and not necessarily correlated to the profile observed in 2D. Image based analysis demonstrated a distinct correlation of 3D cell culture morphology to drug dose, where disassociation of spheroids indicates drug effectiveness and intact spheroids indicates ineffectiveness of drug activity. Further research is underway to determine the mechanism for the drug resistance in 3D culture, which may be important in providing information on resistance mechanisms and potential drug targets. Miniaturisation of 3D culture for breast cancer cell lines allows a higher throughput of novel compound testing in a more cost effective, biologically relevant model. Our work highlights the importance of using 3D cell culture in the early stages of drug discovery in evaluating compound activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4247. doi:1538-7445.AM2012-4247
Abstract 4248: A high-fat diet induces an inflammatory tumor microenvironment in MNU-induced estrogen receptor positive mammary tumors
Authors: Zhao Shuangping , Frasor Jonna 
Published: August 2012

Abstract
The link between obesity and breast cancer has received much attention because it is associated with an increased risk of breast cancer, an increased incidence of recurrence, higher death rates, and reduced sensitivity to anti-hormonal therapy in post-menopausal women. In addition, obesity is associated with a chronic, low grade inflammatory status. Surprisingly, obesity can have different effects in pre-menopausal women where patient outcome is actually better in obese than lean women. This study was conducted to create an animal model to examine the effects of high-fat (HF) diet on estrogen-dependent mammary tumors in cycling rats. Sprague-Dawley rats were injected with N-Methyl-N-Nitrosourea (MNU) at 6 weeks of age to induce mammary tumors. The next day they received HF diet (45% kcal from fat) or normal fat (NF) diet (10% fat) (n=6-7) and animals were kept on these diets for an average of 15 weeks. Ninety-six percent of rats developed mammary tumors and all the tumors were ER positive. The tumor volume, tumor weight and tumor growth rate were not different between the HF or NF diet groups. Also, the HF diet did not influence the body weight, liver weight and adipose mass weight. However, the expression of pro-inflammatory cytokines, such as TNFa and IL-1b, was significantly up-regulated in tumors of the HF diet group compared to control. Macrophage infiltration was also increased in the tumors of the HF diet group. There was also a tendency of increased NFkB DNA binding activity in the HF diet group. Moreover, macrophage infiltration was significantly correlated with the amount of proinflammatory cytokine gene expression in the HF but not the NF diet group. In agreement with clinical data, cycling rats on the HF diet responded better to tamoxifen than did rats on the NF diet, with a greater reduction in tumor size over 20 days of treatment. Taken together, these results indicate that a HF diet induces a pro-inflammatory tumor microenvironment without causing obesity in cycling rats and that these tumors may be more responsive to endocrine therapy. Our findings also provide a model for future studies into the mechanism by which high fat diet may affect tumor growth and response to therapy in premenopausal women.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4248. doi:1538-7445.AM2012-4248
Abstract 4368: Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses
Authors: Das Suvendu , Sarrou Eliana , Cassella Melanie , Feirt Nikki , Skobe Mihaela 
Published: August 2012

Abstract
The lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively, by the flow of lymph. Here, we demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node. In vitro, tumor migration to lymphatic endothelium (LECs) was inhibited by blocking CCR8 or CCL1. Recombinant CCL1 promoted migration of CCR8+ tumor cells. Pro-inflammatory mediators TNF-α, IL-1α and LPS increased CCL1 production by LECs as well as tumor cell migration to LECs. Blocking studies showed that CCL1 is a key molecule mediating tumor cell chemotaxis to inflamed lymphatic endothelium. In mouse and human tissues CCL1 protein was detected in lymph node lymphatic sinuses, but not in the peripheral lymphatics. In addition, CCR8 was strongly expressed by human malignant melanoma. In a mouse model, blocking CCR8 function decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1/CCR8 in metastasis and lymph node LECs as a critical check-point for entry of metastases into the lymph nodes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4368. doi:1538-7445.AM2012-4368
Abstract 4375: Sunitinib alone and in combination with SN-38 is active against anaplastic thyroid cancer
Authors: Bocci Guido , Desidero Teresa Di , Fioravanti Anna , Orlandi Paola , Canu Bastianina , Danesi Romano 
Published: August 2012

Abstract
Background: Anaplastic thyroid cancer (ATC) is the most aggressive thyroid gland malignancy. Recent experimental evidences suggest a rationale for the use of multitarget tyrosine kinase inhibitors (TKIs). Sunitinib showed evidences of activity in a phase I trial in different tumors, including thyroid cancers. TKIs are usually more effective in combination with standard chemotherapy. Among chemotherapeutic drugs, preclinical studies using irinotecan seem to be very promising in different types of thyroid carcinomas. The aim of this study is to determine the activity of sunitinib alone and in combination with irinotecan on endothelial and ATC cells. METHODS: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells (HMVEC-d) and ATC (8305C, FB3) cell lines exposed to sunitinib (SU) and SN-38, the active metabolite of irinotecan, for 72h. The synergism was determined with the method by Chou and quantified by the combination index (CI), where CI &lt; 1, CI = 1, and CI &gt; 1 indicates synergism, additive effect, and antagonism, respectively. Cell-based phospho-VEGFR-2 assay was performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Cyclin D1 and CDK2 gene expression were performed with real-time PCR and cyclin D1 intracellular concentrations were measured by ELISA. 8305C xenografts in nude mice were treated with sunitinib (50 mg/kg/day) and tumour volumes were measured. RESULTS: A strong antiproliferative and pro-apoptotic activities were determined by SU on both endothelial and cancer cells, synergistically enhanced by SN38. Phospho-VEGFR-2 levels significantly decreased after SU treatments in activated endothelial cells; ERK1/2 and Akt phosphorylation was significantly inhibited by SU in endothelial and cancer cells, although at lower concentrations in the endothelial ones. Moreover, SU treatment greatly inhibited the expression of the cyclin D1 and CDK2 genes in both endothelial and cancer cells, decreasing the cyclin D1 protein intracellular concentration. In vivo administration of sunitinib was effective and determined a significant tumor regression. CONCLUSIONS: SU demonstrated a highly significant antiproliferative and proapoptotic activity, for activated endothelial and ATC cells. Moreover, the simultaneous combination of sunitinib and irinotecan determined a high synergism on endothelial and ATC cells, suggesting a possible translation of this schedule into the clinics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4375. doi:1538-7445.AM2012-4375
Abstract 4405: Immune modulation and Treg suppression with metronomic cyclophosphamide enhances the anti-tumor effect of a therapeutic peptide vaccine in a murine model
Authors: Weir Genevieve , Stanford Marianne , Karkada Mohan , Berinstein Neil , Mansour Marc 
Published: August 2012

Abstract
In order to be optimally effective therapeutic cancer vaccines must be combined with immune modulatory approaches, particularly in advanced cancer where several different pathways of cancer induced immune suppression may be active. We have developed a potent cancer vaccine enhancement formulation named DepoVaxTM (DPX) that is particularly well suited for the delivery of peptide antigens. DPX is a novel vaccine platform comprised of liposomes in oil that is formulated with a TLR adjuvant, universal T-helper peptide and specific tumor peptide antigens. We have shown that DPX generates better immune responses than Montanide based emulsion formulations. A major obstacle to any cancer vaccine, however, is tumor induced immune suppression. Regulatory T cell (Treg) mediated immune suppression is an important mechanism of tumor immune evasion in many types of cancer including ovarian cancer. We sought to determine if combining a DPX-based peptide vaccine approach with immune modulation in the form of Treg suppression could enhance the anti-tumor effect of the vaccine. Metronomic cyclophosphamide (mCPA) treatment has been reported to selectively sustain reduced regulatory T cell numbers and activity. Using a murine tumor model (C3) we tested the benefit of combining mCPA and DPX vaccination for controlling well established subcutaneous solid tumors in vivo. We found that neither mCPA or DPX treatments alone were sufficient to eradicate advanced C3 tumors. However, combining mCPA with DPX vaccination provided effective tumor control. We further characterized the immune response by isolating and phenotyping tumor infiltrating lymphocytes and testing their immunogenicity by IFN-γ ELISPOT assay. Our results indicate that the DPX vaccine can increase the levels of antigen-specific CD8+ T cells and mCPA treatment reduces the CD4+FoxP3+ T regulatory cells. We conclude that immune responses generated by the DPX vaccine were more effective at controlling advanced tumors together with reduced Treg-mediated immune suppression. We have designed and initiated a phase I/II clinical trial to test a DPX vaccine targeting Survivin (DPX-Survivac), in combination with mCPA in ovarian cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4405. doi:1538-7445.AM2012-4405
Abstract 4406: Clinical efficacious combined chemo/immunotherapy differently activates AKT pathway and functionality of gp100 and Melan-A specific T cell clones
Authors: Palermo Belinda , Donna Cosmo Di , Franzese Ornella , Bello Duilia Del , Gualtieri Novella , Imberti Luisa , Nuzzo Carmen , Proietti Enrico , Catricalà Caterina , Ferraresi Virginia , Nisticò Paola 
Published: August 2012

Abstract
A phase II randomized clinical study is ongoing in our Institution to prove the clinical efficacy of dacarbazine (DTIC) one day before peptide-vaccination (Melan-A and NY-ESO-1) in the prevention of melanoma relapse in clinically disease-free HLA-A2 patients. In a previous pilot study, this combination therapy (using Melan-A and gp100 peptides) increased the number of tumor-reactive long-lasting effector-memory CD8+ lymphocytes. To identify the mechanisms enhancing the immune response, induced by DTIC combined with peptide-vaccination, we analyzed the endogenous and treatment-induced antigen specific CD8 T-cell response at the clonal level. We analyzed the sequence of the TCR α-chain of these clones and the molecular results were correlated with the expression of CD27/CD28 co-stimulatory molecule, AKT activation and anti-tumor lytic activity. The combination of chemo/immunotherapy elicited in Melan-A-specific, but not in gp100 clones, a renewal of high-avidity/tumor-reactive T-cell clones, with a broadening TCR diversity in long-surviving patients, suggesting that the selection of immune-resistant tumor variants may be circumvented by this combination, and thus prevent tumor recurrence in melanoma. In gp100 clones, AKT activation (pSer473-AKT) canonically correlates with CD28 and/or CD27 expression, independent of the treatment while in Melan-A clones, lacking CD27 and CD28 expression, non-canonical AKT activation was only observed after the combination therapy. The identification of the extracellular stimuli and signaling pathway responsible for DTIC-mediated activation of the AKT signaling are currently under investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4406. doi:1538-7445.AM2012-4406
Abstract 4409: A modular polymer platform for the delivery of cytokines is effective in the treatment of head and neck squamous cell carcinoma (HNSCC)
Authors: Lin Yuan , Suwarnasarn Arnold , Luo Jie , Elashoff David , Dubinett Steven , Wu Ben , John Maie St 
Published: August 2012

Abstract
Educational objective: At the conclusion of this presentation, the participants should be able to discuss the benefits of a modular polymer platform, which will improve the outcome for patients with advanced HNSCC. Objective: To evaluate the therapeutic efficacy of an immunomodulator secreting polymer platform in the treatment of HNSCC. Study Design: in vivo animal study. Setting: Academic research laboratory. Subjects and Methods: C3H/HeJ mice were injected with SCCVII/SF cells. After tumors reached 1 cm in size, animals then underwent surgery and were randomized to receive implantation of (1) no polymer; (2) plain polymer; (3) plain polymer with dendritic cells (DC) secreting the chemokine CCL21; (4) plain polymer with DC alone; and 5) plain polymer + daily CCL21 injection. Tumor size was measured until the mice were euthanized. At necropsy, the tumors were excised and weighed. Results: We were able to demonstrate that DC are viable and functionally secrete CCL21 up to 14 days in the polymer. DC-CCL21 secreting polymer effectively reduced tumor growth mice by over 16-fold (P &lt; 0.01) as compared to control, plain polymer, and plain polymer + intratumoral CCL21 injection groups. Flow cytometry analysis revealed that there was a significant increase in CD4+ T cells, as well as a significant decrease in CD4+/CD25+ regulatory T cells in the tumor site, underlying the significant tumor regression observed. Conclusion: The major limitation for the clinical use of cytokines is the lack of an effective protocol for the sustained delivery of cytokines to the tumor milieu. We demonstrate the efficacy of a novel polymer platform in delivering DC-CCL21 to SCCA in a murine model. Our results indicate that this polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4409. doi:1538-7445.AM2012-4409