bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4225: Dynamic control of tumor vasculature with direct observation using intravital microscopy
Authors: Gabriel Emmanuel M. , Fisher Daniel , Kim Minhyung , Powers Colin , Visioni Anthony , Muhitch Jason , Skitzki Joseph 
Published: July 2016

Abstract
Introduction
Intravital microscopy (IVM) provides in vivo real-time imaging of tumor-associated vasculature. Our group was the first to use IVM successfully in human subjects to image melanoma associated vessels. In this preclinical study, we hypothesized that intravenous (IV) nicardipine increases observable blood flow to tumor through vasodilatation and therefore may facilitate drug delivery.
Methods
Standard window chambers for IVM were implanted into female BALB/c mice. The murine colon cancer cell line CT26HA was inoculated in the skin within the chamber. Fluorescein isothiocyanate dextran (FITC-dex) was injected IV to enhance vessel observation prior to nicardipine (8 μg/mouse). Observations were performed at 100x magnification using a modified Olympus microscope for 10 minutes. Naïve mice were used for control observations. Mice bearing CT26HA were observed on post-inoculation day 5, 12 and 20. Vessel architecture and vessel diameter in response to nicardipine were compared.
Results
In non-CT26HA bearing mice, nicardipine resulted in a greater than 10% increase in skin vessel diameters directly measured using IVM (pre-nicardipine diameter 82.4 ± 3.6 μm versus post-nicardipine diameter 93.0 ± 3.9 μm. In CT26HA bearing mice, abnormal vessels were observed as early as day 7 even in the absence of a solid tumor mass. Vessel abnormalities included haphazard areas of increased vessel density, aberrant vessel branching patterns, nonfunctional vessels, and altered flow rates. Following nicardipine injection, the diameter of larger tumor-associated vessels did not increase and remained constant (pre: 111.2 ± 2.7 μm vs post: 109.1 ± 3.3 μm). Paradoxically, for smaller vessels (&lt; 20 μm), tumor-associated vessels vasoconstricted following nicardipine injection and returned to baseline diameter after approximately five minutes. Blood flow in these small vessels decreased or stopped during this observation.
Conclusions
Observation of dynamic vessel changes from vasoactive agents is feasible using IVM. For tumor-associated vessels, nicardipine was not shown to increase vessel diameter and counterintuitively decreased diameters of smaller vessels. Implication on drug delivery from vasoactive agents will lead to further pre-clinical study of applications for human IVM.
Citation Format: Emmanuel M. Gabriel, Daniel Fisher, Minhyung Kim, Colin Powers, Anthony Visioni, Jason Muhitch, Joseph Skitzki. Dynamic control of tumor vasculature with direct observation using intravital microscopy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4225.
Abstract 4237: Decreased hypoxia in a HER2+ breast cancer model following trastuzumab therapy
Authors: Sorace Anna G. , Quarles C. Chad , Sanchez Violeta , Yankeelov Thomas E. 
Published: July 2016

Abstract
Introduction: Hypoxic tumors demonstrate treatment resistance with an increased risk of metastasis. Therefore, alleviating hypoxia has potential to improve efficiency of combination therapies. The primary goal of this study is to quantify alterations in hypoxia in response to trastuzumab in a murine model of HER2+ breast cancer through imaging and histology.
Experimental Design: Mice were implanted subcutaneously with BT474 breast cancer cells (107) and randomly assigned into treated (10 mg/kg trastuzumab) or control (saline) groups. After tumors reached ∼250 mm3, animals (n = 32) were utilized to identify longitudinal changes in functional vascular through an intravenous injection of Hoechst 33342 nuclear stain (immediately prior to sacrifice) and hypoxia through pimonidazole intravenous injection (one hour prior to sacrifice). Tumors were extracted for immunofluorescence between days 0 through 7. Tumor sections were flash frozen and stained with anti-pimonidazole and propidium iodide (nuclear counterstain). Additionally, a set of tumors (n = 36) were sacrificed for immunohistochemistry (days 0 through 7), formalin fixed and stained for CA-IX. All stained sections were scanned in high resolution (20×) and quantitatively analyzed with Leica SCN400 software. Another cohort of animals (n = 10) were imaged with 18F-FMISO (fluoromisonidazole) PET between days 0 through 7 and quantified via mean tracer concentration (%ID/g).
Results: Immunohistochemistry revealed significantly increased hypoxia in the control group compared to treated on days 3 (p = 0.03) and 7 (p = 0.002), as measured through CA-IX staining. Additionally, on day 4, functional vascular delivery was increased while hypoxia (pimonidazole) decreased in treated tumors compared to control. 18F-FMISO PET imaging corroborated histology findings with significantly decreased hypoxia in treated tumors compared to control tumors on day 7 (-47%; p&lt;0.0001).
Conclusion: Trastuzumab has been shown to decrease hypoxia, as measured through gold-standard immunofluorescence. Additionally, this trastuzumab-induced improvement in tumor hypoxia can be measured via clinically relevant, noninvasive imaging (18F-FMISO PET). Temporarily improving the tumor's functional vasculature and decreasing hypoxia during trastuzumab treatment has potential to enhance the effectiveness of combination therapies. Identifying windows of improved vascular and cellular normalization with noninvasive medical imaging provide opportunity to decrease resistance to standard-of-care treatments and optimize therapeutic timing and regimens.
Citation Format: Anna G. Sorace, C. Chad Quarles, Violeta Sanchez, Thomas E. Yankeelov. Decreased hypoxia in a HER2+ breast cancer model following trastuzumab therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4237.
Abstract 4238: Multispectral optoacoustic tomography detects orthotopic pancreatic tumors in vivo using a nano-contrast agent
Authors: Chuong Phillip , Zeiderman Matthew , Grizzle William E. , McNally Lacey R. 
Published: July 2016

Abstract
There have been very modest developments in pancreatic cancer detection and treatment with mortality essentially remaining unchanged in the last four decades. The major challenge for both early detection and treatment of pancreatic tumors lies in overcoming various biological barriers, especially poor perfusion, insufficient contrast agents/drugs uptake by the tumor, and limitations of traditional imaging modalities. The combination of accurate real-time imaging with tumor-specific nano-contrast agents could mitigate these impediments. We constructed highly stable nano-contrast agents by encapsulating GNRs having aspect ratio 3:1 in PAA (1.5 ± 0.5 nm), and MS (6.25 ± 0.25 nm) shell, respectively and targeted to insulin growth factor 1 receptor (IGF1-R) positive pancreatic tumor cells via Syndecan-1 ligand. IGF1-R specific binding of Syndecan-MS GNRs and Syndecan-PAA-GNR was determined using in an IGF1-R negative cell line (MiaPaca-2) or a blocking antibody to IGF1-R in S2VP10L pancreatic cancer cells determined via flow cytometry. In vivo, mice bearing orthotopic pancreatic tumors were iv injected with 100 nM of Syndecan-MS GNRs and accumulation was determined four hours post injection via Multispectral Optoacoustic Tomography. Biodistribution was determined using a Region of Interest method. The cellular uptake of Syndecan-MS-GNRs significantly enhanced in the S2VP10L cells (503.4 counts) compared to MiaPaca-2 cells (64.1 counts), blocking agent (323.7counts) and untargeted MS GNRs (average 47 counts) revealing that Syndecan-MS-GNRs enhanced both tumor specificity and OA signals by binding with IGF1-R in S2VP10L cells. In vivo, Syndecan-MS-GNRs significantly accumulated in S2VP10L orthotopic pancreatic tumors (233.1 MSOT a.u.) with minimal accumulation in kidney(29.7 MSOT a.u.) and liver (31.4 MSOT a.u.). The Syndecan-MS-GNRs did not accumulate within the orthotopic MiaPaca-2 (IGF1-R negative) mouse model with the biodistribution of pancreas tumor (12.4 MSOT a.u.), kidney (114.3 MSOT a.u.), and liver (35.2 MSOT a.u.).
Citation Format: Phillip Chuong, Matthew Zeiderman, William E. Grizzle, Lacey R. McNally. Multispectral optoacoustic tomography detects orthotopic pancreatic tumors in vivo using a nano-contrast agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4238.
Abstract 4242: Rhodamine esters as fluorescent tumor painting agents for glioblastoma
Authors: Lin Yu-Hsi , Millward Steven , Gammon Seth , Satani Nikunj , Hammoudi Naima , Gray Joshua Philip , Kelderhouse Lindsay E. , Ornelas Argentina , Schroeder Haley , Muller Florian L. 
Published: July 2016

Abstract
GBM remains one of the most difficult cancers to treat. Despite surgery, radiation and chemotherapy, tumors invariably recur. There is a strong correlation between extend of resection and subsequent time to recurrence and ultimate patient survival. A key challenge for the neurosurgeon is to minimize removal normal brain tissue whilst being as aggressive as possible with regards of removal of tumor tissue. Defining tumor boundary during surgery remains challenging. Fluorescent dyes such as 5- Aminolevulinic acid, have been studied as aids for tumor delineation but have failed to gain widespread acceptance in clinical practice. It has long been known that a substantial number of cancers, including Glioblastoma, exhibit a hyperpolarization of the plasma and mitochondrial membrane potential. This hyperpolarization is manifest by increased retention of lipophilic cationic dyes (Nernstian probes), such as the SPECT-CT probes 99Tc-Sestamibi and 99Tc-Tetrofosmin in both glioma cells in culture and primary tumors. We synthesized a series of ester derivatives of Rhodamine B with high fluorescence quantum yield in the red spectrum and a very favorable biological safety profile. Utilizing a series of intracranial xenografted glioblastoma pre-clinical mouse models, we show that a single I.V. injection of 1 mg/kg fluoroethylrhodamine ester (RhoFe) results in dramatic selective fluorescence in tumor but not surrounding normal brain tissue. This was observed even in tumors with minimal breakdown of the blood brain barrier, as determined by T1-contrast enhancing agents. RhoFe-tumor-selective fluorescence can remain visible up to 72 hours after injection. Similar results were obtained with Tetramethylrhodamine ester (TMRE) and rhodamine 123 (Rho123), but unlike RhoFe, TMRE proved highly toxic, while Rho123 fluorescence was both weaker and in the green spectrum, accompanied by higher endogenous auto-fluorescence. While well tolerated in vivo, RhoFe shows strong photoxicity in cell culture, suggesting potential as a photodynamic therapy agent. Taken together, these data suggest that RhoFe may be a promising tumor painting agent, with potential utility in fluorescence guided surgery as well as photodynamic therapy.
Citation Format: Yu-Hsi Lin, Steven Millward, Seth Gammon, Nikunj Satani, Naima Hammoudi, Joshua Philip Gray, Lindsay E. Kelderhouse, Argentina Ornelas, Haley Schroeder, Florian L. Muller. Rhodamine esters as fluorescent tumor painting agents for glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4242.
Abstract 4244: Optical imaging of ovarian cancer metastasis in mouse models of obesity
Authors: Leevy W. Matthew , Liu Yueying , Metzinger Matthew , Lewellen Kyle , Stack. M. Sharon 
Published: July 2016

Abstract
Epithelial ovarian cancer (EOC) is a deadly gynecologic malignancy, owing to its propensity for intraperitoneal (IP) metastasis. Indeed, almost 75% of women with EOC are diagnosed during the later stages of the disease in which metastasis is already underway. Pathogenesis of EOC is marked by diffuse and widely disseminated metastatic sites within the IP compartment, often with peritoneal ascites. Mouse models of EOC have been developed to facilitate the pre-clinical research of this deadly disease, however the quantification of metastatic tumor burden in these animals has remained challenging due to the broad distribution of lesions in the IP space. Here we describe a combined In Vivo/Post-Mortem method to monitor and measure EOC metastasis in mouse models of obesity. RFP-labeled ovarian cancer cells were injected IP in obese and control cohorts of mice, followed by weekly in vivo imaging until time of sacrifice. Subsequent post-mortem imaging was conducted after surgical exposure of the peritoneal cavity to reveal organs that were then imaged in situ. Ex vivo imaging was performed last on dissected organs from each animal. Imaging signal was enhanced via multispectral imaging methods to remove tissue auto-fluorescence. Semi-quantitative methods to measure tumor burden are demonstrated in their application to the study of metastasis in both obese and control animals. Ultimately these results demonstrated that obesity dramatically increased ovarian cancer metastatic success, and likely contributes to the reduced EOC survival rates noted in clinical reports of obese patients.
Citation Format: W. Matthew Leevy, Yueying Liu, Matthew Metzinger, Kyle Lewellen, M. Sharon Stack. Optical imaging of ovarian cancer metastasis in mouse models of obesity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4244.
Abstract 4255: EpCAM positive lung cells are involved in organoid formation
Authors: Semba Takashi , Sato Ryo , Suzuki Makoto , Saya Hideyuki , Arima Yoshimi 
Published: July 2016

Abstract
A combination of fluorescence activated cell sorting (FACS) and 3D culture techniques enable us to isolate specific lung cells and to form organoids, which recapitulate organ architectures in vitro. To clarify the cells of origin in the formation of lung organoids and to apply for oncogene-mediated transformation, we conducted spheroid culture and 3D culture experiments using mice lung cells.
We isolated the CD31-/CD45- cells from the lungs of wild-type (wt) or Ink4a/Arf-knockout (Ink4a/Arf-/-) C57BL/6 mice. The single cells were then cultured in serum-free medium in a low-attachment dish for 7 days to form spheres. The spheres were dissociated into single cells again, and were then infected with retroviruses expressing KRASG12V, EML4-ALK, EZR-ROS1 (Arai et al., PLoS ONE 2013), or KIF5B-RET (Saito et al., Carcinogenesis 2014) genes, which were identified as oncogenes in human lung adenocarcinomas. Those oncogene-expressing sphere-derived cells from wt and Ink4a/Arf-/- lung cells neither expressed EpCAM (the epithelial marker) nor TTF-1 (the lung lineage marker). We found that those cells formed undifferentiated invasive lethal tumors in lung lobes when the cells were inoculated into the lungs of mice via the trachea, after bleomycin treatment.
We then isolated the EpCAM+/CD45-/CD31- lung cells from wt or the Ink4a/Arf-/- C57BL/6 mice and these cells were subjected to a 3D culture. Those cells were suspended in a serum-free medium with keratinocyte growth factor, and the 1×104 cells were seeded on a 24 well 0.4μm insert pre-coated with growth factor-reduced Matrigel. After 2 weeks, the cells formed morphologically distinct phenotypes of colonies, such as cystic colonies, dense sphere colonies, and branched colonies. A histopathological study revealed that the EpCAM-positive colonies were composed of TTF-1-positive cells, and included differentiated lung cell markers, SP-C, Aquaporin 5, and CC-10. Interestingly, the EpCAM-/CD45-/CD31- cells from the lungs of the Ink4a/Arf-/- mice did not form organoids under 3D culture conditions.
Our data indicates that the EpCAM-positive normal mice lung cells, but not the EpCAM-negative cells, formed lung organoids including TTF-1-positive cells in a 3D culture. Inoculation of EpCAM+/CD45-/CD31- lung cells expressed oncogenes into the lungs of mice might allow us to develop a well-differentiated lung adenocarcinoma model.
Citation Format: Takashi Semba, Ryo Sato, Makoto Suzuki, Hideyuki Saya, Yoshimi Arima. EpCAM positive lung cells are involved in organoid formation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4255.
Abstract 4259: Long term cell culture models to identify biomarkers of response
Authors: Warrior Usha , Crane Jonathan , Bernards Karen , Nelson Brian , Snead Katie , Angione Alison , Sherman Amber , DeVault Shawn , Hnilo Jim , Shah. jameel 
Published: July 2016

Abstract
In order to test the efficacy of many cancer therapeutics, culturing cells in the presence of compounds for longer than the conventional 72-hr cell growth assay may be necessary. It is shown that the inhibition of many epigenetic targets results in a significantly delayed drug response not revealed by conventional shorter term cell growth assays. OncoPanel™ from Eurofins Pharma Discovery Services is a collection of 300 cell lines with broad cancer type and subtype representation and extensive genomic characterization. We have developed a 10-day assay to test inhibitors of epigenetic targets. Using the EZH2-selective inhibitor, GSK343, we have demonstrated the advantages of cell line profiling under long-term assay conditions when drug response reflects a protracted mechanism of action. We also tested Olaparib, a PARP inhibitor, in this system and showed substancial increased sensitivity against several cell lines versus the 72 hr assay. The significant biomarkers identified from the genomic analysis of the data from both GSK343 and Olaparib substantiate the relevance of long term cell profiling.
Citation Format: Usha Warrior, Jonathan Crane, Karen Bernards, Brian Nelson, Katie Snead, Alison Angione, Amber Sherman, Shawn DeVault, Jim Hnilo, jameel Shah. Long term cell culture models to identify biomarkers of response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4259.
Abstract 4261: Novel tumor microenvironment (TME) restored 3D cell culture model and humanized patient-derived xenograft model for cancer research and drug evaluation
Authors: Zhang Jing , Yang Dabing , Wang Huilin , Song Qiong , Li Hui , Shaw JP , Deng Tianjing 
Published: July 2016

Abstract
New anticancer drug development is an expensive and time consuming process, which typically can take more than 10 years and cost over a billion dollars. Although a majority of late discovery drug candidates demonstrate potency in preclinical models, most will ultimately fail to achieve efficacy in clinical trials. While recent strides have been made to improve preclinical models, the continued widespread use of traditional models creates translational challenges during clinical development. An intrinsic challenge for drug developers is to close the gap between preclinical modeling and translational efficiency for patients. Accurately modeling core attributes of the human tumor microenvironment (TME) in preclinical models is key for identifying novel targets, lowering toxicity and improving translational success. Even for advanced patient-derived xenograft (PDX) in vivo models, the cytokines generated by murine stromal cells fail to replicate many important paracrine networks, which can mislead preclinical pharmacology outcome data. To address this gap, we have begun to establish and characterize nearly 1,000 novel patient tumor samples, spanning over a dozen cancer indications, into robust human TME-restored 3D cell culture models and humanized patient derived xenograft models. Our goal is to improve overall patient-derived tumor model initiation success rates and subsequent translational pharmacology.
Citation Format: Jing Zhang, Dabing Yang, Huilin Wang, Qiong Song, Hui Li, JP Shaw, Tianjing Deng. Novel tumor microenvironment (TME) restored 3D cell culture model and humanized patient-derived xenograft model for cancer research and drug evaluation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4261.
Abstract 4262: Combined 3D quantitative imaging and 3D cell culture for cancer drug discovery
Authors: Vidal Guillaume , Lobjois Valérie , Souguir Zied , Pannetier Pauline , Demange Elise , Lagarde Jean-Michel 
Published: July 2016

Abstract
Monitoring drug activity in multicellular tumor spheroid in vitro models is an important challenge as these 3D models have demonstrated their major relevance in pharmacological screening and anticancer drugs evaluation (1). Optical microscopy coupled to the selective plane illumination microscopy (SPIM)3D microscopy, and, and automatic automated images processing and quantitative analysis are promising approaches to process optimizes the evaluation of drug response in a 3D cell culture models with, in a high/mediumhigh throughput screening waycapabilities.
BIOMIMESYS® used as a 3D cell model is based on hyaluronic to provide an in vivo like environment to the cells.
The In this study the effects of the topoisomerase I inhibitor Topotecan were investigated on colon adenocarcinoma HCT-116 3D cell culture. Spheroids were prepared and grown in BIOMIMESYS® used as a 3D cell model isa matrix based on hyaluronic acid tothat provides an in vivo like environment to the cells.
was monitored and coupled with mMorphometric parameters and with nuclei fluorescence markers were used to monitor analysis for drug activity. Data provideand to characterization characterize of both cytostatic and cytotoxic effects of this drug withon the basis of both quantitative 3D and imaging of the mechanisms.
These data highlight the relevance of combining a biomimetic microenvironment for 3D cell culture recreating the the in vivo features of a tumor cell population biology, together with and high resolution content microscopy-based quantification for drug screening.
This biomimetic model provides an innovative platform for the in-depth analysis of tumor development and for the discovery or the characterization of novel therapeutic targets.
Ref:
1) Breslin S, O’Driscoll L. Drug Discov Today.18: 240-249 (2013)
Citation Format: Guillaume Vidal, Valérie Lobjois, Zied Souguir, Pauline Pannetier, Elise Demange, Jean-Michel Lagarde. Combined 3D quantitative imaging and 3D cell culture for cancer drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4262.