bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2644: In vivo and in vitro stem cell models suggest a role for LGR5 in regulating intestinal epithelial lineage specification.
Authors: Williams Courtney M. , Harper Jessica L. , Huang Hui , Boland Pat , Zhang Qing , Yancopoulos George D. , Li Zhe , Thurston O. Gavin 
Published: August 2014

Abstract
The stem cell marker Leucine Rich Repeat Containing G-protein Coupled Receptor 5 (LGR5) is frequently upregulated in human colon cancer. Numerous observations implicate LGR5 in stem cell maintenance during intestinal development, tissue homeostasis and cancer, however the precise role of LGR5 in these processes is still unclear. To explore the role of LGR5, we generated mouse embryonic stem cells (ESCs) in which one or both alleles of Lgr5 were deleted and replaced with either β-galactosidase or green fluorescent protein (gfp) reporter genes, or the human LGR5 gene. These cell lines were used in three complimentary systems to differentiate and/or isolate cell lineages. The first system was an in vivo model in which subcutaneous xenografts of murine ESCs grew and formed tumors (teratomas) containing cellular structures from all three germ cell layers. Immunostaining showed that a subset of E-cadherin-positive epithelial cells also expressed Lgr5 reporter genes. Teratomas derived from Lgr5 null ESCs showed an increase in E-cadherin-positive epithelial structures, and gene expression profiling of Lgr5 null teratomas showed an upregulation of epithelial genes including Cdh1, Epcam, Cldn7, Krt5, and Krt14 compared with control teratomas. In contrast, ESCs constitutively overexpressing a secreted form of LGR5 ectodomain formed teratomas with fewer epithelial structures and reduced expression of epithelial genes compared to control teratomas. The second system used in vitro differentiation of ESCs towards an intestinal epithelial lineage, followed by 3D culturing, to derive intestinal organoids. Lgr5+/+ (WT), Lgr5lacZ/+ (Het), or Lgr5lacZ/gfp (Null) ESCs are being examined for their ability to adopt an intestinal fate and form organoids in vitro. A third system used ex vivo culture of murine intestinal crypts isolated from humanized LGR5 heterozygous mice to form intestinal organoids. In summary, the morphological and gene expression changes observed in teratomas implicate a role of LGR5 in regulating epithelial tissue homeostasis. The ability to grow and manipulate organoid cultures ex vivo/in vitro will allow us to use various soluble reagents and detailed microscopy to further assess the role of the Lgr5 pathway in intestinal cell lineage specification as well as tumorigenesis.
Citation Format: Courtney M. Williams, Jessica L. Harper, Hui Huang, Pat Boland, Qing Zhang, George D. Yancopoulos, Zhe Li, O. Gavin Thurston. In vivo and in vitro stem cell models suggest a role for LGR5 in regulating intestinal epithelial lineage specification. [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 2644. doi:10.1158/1538-7445.AM2013-2644
Abstract 2645: Role of embryonic signaling pathways in lung cancer.
Authors: Singh Samer , Robbins David , Capobianco Anthony J. , Nguyen Dao M. 
Published: August 2014

Abstract
Background: Embryonic signaling pathways that play an important role during embryo development, later on support the maintenance of adult stem cells and are also found activated in various cancers. The activated embryonic signaling mainly Hedgehog (HH), WNT and NOTCH have been shown to be activated in a number of cancers and demonstrated to promote growth, provide survival advantage and resistance to various drugs. The role of these embryonic signaling pathways in the development of lung cancer is not well defined. Identification of particular pathways active in cancer and elucidation of their mechanism of action in cancer development could provide the basis of devising a successful therapeutic intervention.
Objective: Define the role of embryonic signaling pathways in cancer cells.
Methodology: The presence and functional interaction of various embryonic signaling pathways in lung cancer was evaluated using human non-small cell lung carcinoma cell lines (e.g. HOP62, A549, H23, H522) as model system. The signaling pathways were inhibited using specific small molecule inhibitors and shRNAs mediated knockdown of the pathway components. The lentiviruses expressing shRNA were made and used to deliver the shRNA in NSCLC cells. The effect on the target gene expression (quantitative real time RT-PCR and western blotting), cell proliferation (ATP quantitation), cell migration (scratch/wound assay) and anchorage independent growth (soft agar assay), was evaluated. Currently, the activation of pathways in cancer cells of primary lung cancer samples is being evaluated by immunohistochemistry (IHC) and RNA in situ hybridization (ISH).
Preliminary Results and Conclusions: Attenuation of individual embryonic signaling pathways using specific small molecule inhibitors and shRNAs, indicated crosstalk and hierarchy of these pathways in controlling various processes in tested cancer cells. Our results suggest the predominance of HH signaling in non-small cell lung carcinoma. We are in the process of expanding our observation to more cell lines and human cancer samples. Our work will establish the role of embryonic signaling pathways in lung cancer and would further help in establishing a framework for future therapeutic intervention.
Citation Format: Samer Singh, David Robbins, Anthony J. Capobianco, Dao M. Nguyen. Role of embryonic signaling pathways in lung 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 2645. doi:10.1158/1538-7445.AM2013-2645
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2647: In vitro niche created by cancer stem-like cells derived from mouse induced pluripotent stem cell.
Authors: Mizutani Akifumi , Matsuda Shuichi , Yan Tin , Sota Tatsuyuki , Kasai Tomonari , Kudoh Takayuki , Murakami Hiroshi , Seno Masaharu 
Published: August 2014

Abstract
Cancer stem cell (CSC) is a cell within tumor, which is considered to possess the capacity of self-renewal and differentiation for providing heterogeneous lineages of cancer cells in the tumor. Previously, we converted mouse iPS (miPS) cells into CSCs by treatment with conditioned medium prepared from Lewis Lung Carcinoma culture (miPS-LLCcm)1. RT-PCR and FACS analysis revealed that miPS-LLCcm could give rise to endothelial cells. When miPS-LLCcm were cultured on MatrigelTM, they exhibited the tubular structure containing CD31 positive cells. In contrast, undifferentiated cells enriched population, which were resistant to puromycin (puro) as parental miPS cell2, failed to form tubes. After puro was removed to allow the differentiate cells to survive, the tube formation was observed again, indicating that the differentiated cells were likely to contribute to tube formation. To confirm the stability of this tube formation capacity, we repeated further two cycles of puro selection and releasing differentiation. As the result, the tube formation ability of the differentiated cells decreased. In parallel, we added the conditioned medium of miPS-LLCcm culture into sphere-forming assay, observed the increase of size and number of spheroids. This effect was partly depended on Notch signaling pathway. These results raise the possibility that the differentiated cells from miPS-LLCcm including endothelial cells or their progenitor cells should be required for the maintenance of miPS-LLCcm to differentiate towards vascular endothelial linage. Collectively, we concluded that the differentiated cells from miPS-LLCcm create a niche in vitro for the self-renewal of CSC in the aspect of not only proliferation but also differentiation lineage.
1. Chen, L., et al. PLoS ONE 7, e33544 (2012).
2. Okita, K., et al. Nature 448, 313-317 (2007).
Citation Format: Akifumi Mizutani, Shuichi Matsuda, Tin Yan, Tatsuyuki Sota, Tomonari Kasai, Takayuki Kudoh, Hiroshi Murakami, Masaharu Seno. In vitro niche created by cancer stem-like cells derived from mouse induced pluripotent stem cell. [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 2647. doi:10.1158/1538-7445.AM2013-2647
Abstract 265: Mechanisms of Met-dependent tumorigenesis in models of triple negative breast cancer.
Authors: Sung Vanessa Y.C. , Knight Jennifer F. , Park Morag 
Published: August 2014

Abstract
Human breast cancer is a heterogeneous disease encompassing multiple subtypes. The basal-like and claudin-low subtypes, collectively known as triple negative (TN) breast cancer, are predominantly negative for the expression of therapeutic targets (Her2 and estrogen receptors) and have poor prognosis. In human breast cancer, elevated levels of MET are correlated with TN subtypes and poor outcome, but the reasons for this are relatively unknown. The Met receptor tyrosine kinase (RTK) is a cell surface protein that is activated in response to the Hepatocyte Growth Factor (HGF). Upon stimulation, Met signaling pathways initiate a program of cell survival, migration, and invasive growth. To investigate the role of Met in tumourigenesis, we generated transgenic mice with mammary specific expression of an oncogenic variant of Met (MMTV-Metmut). These mice develop tumours with features of TN breast cancer.
Tumour-initiating cells (TICs) have emerged as a key concept in prevailing models of tumour development. In breast and other solid tumours, where the bulk of the tumour mass consists of differentiated non-tumourigenic cells, TICs constitute a cell fraction of less differentiated tumourigenic cells, and have been shown to be highly resistant to radiation and chemotherapy. TICs are thus a key therapeutic target, yet little is known about TICs in TN breast cancer. Using tumoursphere assays, we have established the presence of TICs in tumours derived from MMTV-Metmut transgenic mice. MMTV-Metmut TICs have constitutively active Met. Interestingly, treatment with a small molecule inhibitor targeting Met can diminish both tumoursphere formation and proliferation. Thus, in TN breast cancers, elevated levels of Met signaling may promote TIC tumourigenicity. Here, mechanisms of Met-dependent TIC propagation and tumourigenicity will be addressed and supporting data presented.
The molecular events that lead to human basal-like and claudin-low breast cancers are poorly understood. Validating a role for Met in TICs could identify key pathways involved in the pathogenesis of TN breast cancer, providing information for new therapeutic targets.
Citation Format: Vanessa Y.C. Sung, Jennifer F. Knight, Morag Park. Mechanisms of Met-dependent tumorigenesis in models of triple negative 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 265. doi:10.1158/1538-7445.AM2013-265
Abstract 2661: C11 Acetate and 18F FDG PET/CT imaging of MDR2-/- mouse model of hepatocellular carcinoma.
Authors: Skill Nicholas J. , Territo Paul R. , Riley Amanda A. , McCarthy Brian P. , Maluccio Mary A. 
Published: August 2014

Abstract
Our previous research reveals a link between the enzyme autotaxin (ATX) and its product lysophosphatidic acid (LPA) in hepatocellular carcinoma (HCC). We have shown a shift in ATX levels and LPA variant biosynthesis associated with HCC in patients that was corrected by liver transplantation. Moreover we have demonstrated a reduction in hepatic tumor burden in the MDR2-/- mouse model of HCC by treatment with commercial ATX inhibitors. The purpose of this study was to establish the relevance of FDG PET versus 11C acetate imaging to monitor response to ATX inhibition in the in-vivo MDR2 /- mouse model of HCC whereby we would be able to test the impact of novel inhibitors on both the initiation and progression of HCC. Methods: Dynamic high-resolution Positron Emission Tomography (PET) images of 12 month MDR-/- mice and FVB controls were acquired using 18F-FDG or 11C-Acetate (N=3 per group). At the end of the PET imaging session whole body CT images were acquired. Image segmentation for discrete volumes of interests (VOI) was manually constructed from parametric images for the liver for 18F-FDG images while for 11C-Acetate VOIs were submitted to kinetic modeling, using a 3-compartment, 4-parameter model. Results. MDR2-/- mice had significant hepatic tumors at 12 month (7.9±1.8mm) whereas no tumors were observed in FVB controls. MDR2-/- mice had significantly higher hepatic 11C-Acetate uptake and metabolic rates when compared to FVB controls (0.6±0.04 vs 0.49±0.02ml/g/min P=0.038). In contrast there was no significant difference in 18F-FDG metabolism or uptake in the livers of MDR2-/- mice when compared to wild type FVB controls (1.1±0.23 v 1.32±0.2 and 3.61±0.97 vs. 4.3±0.6SUV respectively p=ns). Conclusion: The biology of HCC formation in MDR2-/- is better suited to 11C acetate PET/CT imaging than 18F FDG. 11C acetate is the most effective imaging method available to test response to treatment in an in-vivo model of HCC.
Citation Format: Nicholas J. Skill, Paul R. Territo, Amanda A. Riley, Brian P. McCarthy, Mary A. Maluccio. C11 Acetate and 18F FDG PET/CT imaging of MDR2-/- mouse model of hepatocellular carcinoma. [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 2661. doi:10.1158/1538-7445.AM2013-2661
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2666: Radiation increases permeability and retention of PEG-conjugates in solid tumors.
Authors: Fong Jerry , Ferraro Daniel J. , Hunn Jeremy , Roberts Stefan , Berezin Mikhail Y. , Rogers Buck E. , Hallahan Dennis E. 
Published: August 2014

Abstract
Poly-ethylene glycol (PEG), a hydrophobic polymer used to improve the circulation and biocompatibility of biomolecules, accumulates in solid tumors in a size-dependent manner that has been attributed to the enhanced permeability and retention (EPR) effect. Irradiation of cancer disrupts cancer microvasculature, resulting in enhanced EPR effect. In the present study, we found that radiation increases the retention of PEG in solid tumors. The accumulation of PEG in solid tumors was observed with in vivo imaging. Nude mice were prepared with heterotopic unilateral murine and human glioma (GL261, U87) and lung carcinoma (LLC, A549) tumors. A near-infrared (NIR) dye conjugated to PEG was then administered by IV to the mice which were imaged by NIR for seven days. There was increased retention of PEG-dye in tumors that had been irradiated. To further elucidate the mechanism of this increased retention, a similar in vivo imaging experiment was conducted in bilateral heterotopic tumor models (GL261, U87, LLC, A549) for seven days. The irradiated tumors demonstrated increased accumulation of PEG-dye, suggesting that the response to irradiation influenced the accumulation of PEG-dye. To observe the distribution of PEG-dye in the solid tumors, after the in vivo imaging was complete, the tumors were harvested and then sectioned for microscopy and histological staining. PEG-dye was observed in both the necrotic and non-necrotic regions of the tumor. The cancer microvasculature environment differs depending on where the tumor is located; to determine if the increased uptake was limited to only the hind limb, in vivo imaging was conducted in nude mice bearing orthotopic brain (GL261) and lung (LLC) tumors. PEG-dye was also observed to accumulate in these irradiated tumor models. Radiation induced EPR led to cancer specific delivery of PEG conjugates. Collectively, our data suggest that irradiation increases the retention of PEG-dye in solid tumors. This effect appears in more than one tumor type suggesting that the mechanism may arise from an increase in EPR following irradiation of cancer. If so, the concurrent administration of radiation therapy with polymer-conjugated therapeutic complexes may improve targeted drug delivery to cancer.
Citation Format: Jerry Fong, Daniel J. Ferraro, Jeremy Hunn, Stefan Roberts, Mikhail Y. Berezin, Buck E. Rogers, Dennis E. Hallahan. Radiation increases permeability and retention of PEG-conjugates in solid tumors. [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 2666. doi:10.1158/1538-7445.AM2013-2666
Abstract 2669: Predicting glioblastoma recurrence using novel analysis of perfusion MRI.
Authors: Macyszyn Luke , Akbari Hamed , Da Xiao , Verma Ragini , Wolf Ronald , Bilello Michel , Melhem Elias , O'Rourke Donald , Davatzikos Christos 
Published: August 2014

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in humans. Patients diagnosed with GBM have a poor prognosis, with less than 25% of patients surviving more than two years. Despite intensive, multimodality treatment with extensive surgical resection, radiotherapy, and chemotherapy, recurrence of GBM is inevitable. Thus far GBM research has focused mainly on classification of tumor subtypes, segmentation of enhancing and non-enhancing tumor tissue on MRI, and distinguishing treatment-related effects from recurrence. The purpose of this research is to utilize MR perfusion imaging along with advanced image analysis methods to predict specific areas of future recurrence in GBM.
Forty patients with glioblastoma (WHO Grade IV), who subsequently experience recurrence, were utilized for this study. T1, T1CE, T2, FLAIR, and perfusion images were co-registered and regions of interest (ROIs) were drawn for each subject on imaging obtained prior to surgery in white matter, gray matter, CSF, edema, enhancing tumor, non-enhancing tumor and necrosis. Principal component analysis (PCA) was then employed to extract the uncorrelated variables that reflect the temporal dynamics of perfusion. Leave-one-out cross-validation was used when building the PCA model from a training set and testing it on new patients. The results demonstrate marked separation between edematous peritumoral regions and peritumoral regions that later recurred. Hence, this study indicates that imaging biomarkers predictive of tumor recurrence can be constructed using advanced imaging and analysis methods, potentially leading to the creation of a novel, and important, clinical tool.
Citation Format: Luke Macyszyn, Hamed Akbari, Xiao Da, Ragini Verma, Ronald Wolf, Michel Bilello, Elias Melhem, Donald O'Rourke, Christos Davatzikos. Predicting glioblastoma recurrence using novel analysis of perfusion MRI. [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 2669. doi:10.1158/1538-7445.AM2013-2669
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2672: Early evaluation of response to Vemurafenib treatment with FDG PET/CT in patients with metastatic melanoma.
Authors: Aloj Luigi , Caracò Corradina , Di Gennaro Francesca , Grimaldi Antonio M. , Simeone Ester , Curvietto Marcello , Caracò Corrado , Mozzillo Nicola , Torri Valter , Ascierto Paolo A. , Lastoria Secondo 
Published: August 2014

Abstract
Targeted therapy against the V600 mutated form of BRAF is a proven effective therapy for melanoma. Reduction of FDG accumulation on PET/CT studies occurs very rapidly in responding patients. This exploratory study aims to correlate early changes in FDG uptake patterns with treatment outcome in patients undergoing Vemurafenib treatment. Patients treated at our institution were evaluated with PET-CT at baseline and at day 7, 14 and 28 from the start of therapy. Maximal Standardized Uptake Value (SUVmax) and Total Lesion Glycolysis (TLG, mean SUV x lesion volume) were recorded and compared for single lesions in the 4 studies. Patients were then monitored for clinical, laboratory and imaging signs of progression and results correlated to the early PET/CT findings. Fifteen patients have been studied. A total of 87 lesions are available for comparative evaluation. A greater than 30% reduction in SUVmax compared to baseline was seen in 69 lesions at day 7, 76 at day 14 and 75 at day 28. Nineteen lesions showed a greater than 20% increase in FDG uptake between day 14 and 28. Similar results were found when comparing TLG values. Quantitative and visual analysis of PET/CT studies identified 5 patients showing signs of metabolic progression between day 14 and 28 likely indicating early signs of treatment resistance. Three of these patients showed signs of disease progression by other means within 4 months from the beginning of treatment while 2 are still in treatment with 3 months follow-up. Of the 10 patients not showing metabolic signs of progression at day 28, four have progressed between 2 and 9 months from the beginning of treatment, while the remaining 6 are still in treatment and progression free with 2 to 12 months of follow-up. In conclusion, our preliminary results suggest that PET/CT may be a powerful surrogate marker of treatment response to vemurafenib. Sequential monitoring of targeted therapy with PET/CT may be useful in early identification of treatment resistance, aid in tailoring alternative strategies and deserves further investigation.
Citation Format: Luigi Aloj, Corradina Caracò, Francesca Di Gennaro, Antonio M. Grimaldi, Ester Simeone, Marcello Curvietto, Corrado Caracò, Nicola Mozzillo, Valter Torri, Paolo A. Ascierto, Secondo Lastoria. Early evaluation of response to Vemurafenib treatment with FDG PET/CT in patients with metastatic melanoma. [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 2672. doi:10.1158/1538-7445.AM2013-2672