bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4289: Noninvasive monitoring of blood-brain barrier permeability for antibodies by apoptosis imaging: optimization of treatment strategies for maximal brain delivery
Authors: Weber Thomas G. , Mathejczyk Julia , Galbán Stefanie , Rehemtulla Alnawaz , Scheuer Werner 
Published: May 2015

Abstract
Purposes: Large molecules like antibodies cannot penetrate the intact blood-brain barrier (BBB) in adequate amounts to deploy efficacy. Brain shuttle antibodies for enhanced BBB crossing are considered to overcome this obstacle. Thus, we established a non-invasive technology that accelerates quantification of brain tumor delivery and pharmacodynamics of antibodies.
Experimental Procedures: The technology implies intracranial implantation of a split-luciferase apoptosis reporter cell line (Caspase-3/7 GloSensor) in SHO mice. An agonistic Death Receptor 5 antibody (anti-DR5) was used as model substance. To quantify BBB crossing of systemically applied anti-DR5, we compared apoptosis inductions after i.c. and i.v. application at different dosages.
Results: Assuming a 100 % drug delivery after i.c. application, the amount of antibody delivery after i.v. application was calculated relative to its apoptosis induction. We found that less than 1 % of the unmodified anti-DR5 passed the BBB dose-dependently. These data were confirmed by 3-dimensional fluorescence microscopy of explanted brain tissue. Significant anti-tumor efficacy was detected when anti-DR5 is given in adequately high dosages. We further demonstrate in different brain tumor models that unspecific IgG antibody penetration into brain tumors is presumably enhanced by a slightly impaired BBB.
Conclusions: Our technology facilitates the quantification of BBB penetration by measuring apoptosis non-invasively without using radiolabeling approaches. This orthotopic model accelerates the assessment of i.v. dosage optimization and brain shuttle systems for maximal anti-tumor efficacy in brain tumors.
Citation Format: Thomas G. Weber, Julia Mathejczyk, Stefanie Galbán, Alnawaz Rehemtulla, Werner Scheuer. Noninvasive monitoring of blood-brain barrier permeability for antibodies by apoptosis imaging: optimization of treatment strategies for maximal brain delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4289. doi:10.1158/1538-7445.AM2014-4289
Abstract 429: HERP2 as a novel molecular marker and therapeutic target in glioblastoma
Authors: Velpula Kiran Kumar , Asuthkar Swapna , Lee William , Tsung Andrew J. 
Published: May 2015

Abstract
Glioblastoma (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system despite a multi-modality approach. The poor prognosis in GBM patients is due to therapeutic resistance which calls for identifying novel molecular therapeutic targets. Recently, HES-related repressor protein 2 (HEPR2), a mediator of notch signaling has been identified as a molecular target implicated in chemoresistance. This current study aims at both the epigenetic and transcription factor regulation as the potential mechanisms resulting in the expression of HES-related repressor protein 2 (HERP2) in GBM patient specimens and cell lines. Using immunohistochemistry and immunoblot analysis, we observed that the HERP2 protein is highly expressed in human GBM tissues and glioma cells (4910, U251 and 5310) and is significantly correlated with O6-alkylguanine DNA alkyltransferase (MGMT) levels. We also observed that the expression of HERP2 was dependent on the methylation status of a HERP2 promoter-associated CpG island region as evidenced by prominent PCR products using methylation-specific PCR (MSP) analysis. Interestingly, treatment of GBM cells with demethylating agent, 5-aza-2’-deoxycytidine resulted in hypomethylation, whereas sodium butyrate-treated cells remained specific for methylated CpG islands. Additionally, we also demonstrated a positive regulatory loop between HERP2 and NOTCH1 using rescue experiments. Further, we show the anti-tumorigenic role of siHERP2 to be mediated by the negative regulation of NOTCH1 protein. Our studies indicate that targeting HERP2 in cancer patients undergoing chemotherapy will have favorable therapeutic implications.
Citation Format: Kiran Kumar Velpula, Swapna Asuthkar, William Lee, Andrew J. Tsung. HERP2 as a novel molecular marker and therapeutic target in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2014-429
Abstract 4295: A 3D culture model for screening of cancer therapeutics
Authors: Patel Kalpana , O'Clair Belinda , O'Callaghan Tim , Appledorn Daniel M. , Trezise Derek 
Published: May 2015

Abstract
3D cell culture models are currently of great interest to the bioscience community. This is most notable in the cancer biology area, where a growing body of evidence suggests that more relevant and translational observations can be made by testing compounds in a physiological relevant 3D model compared to a 2D model. In this study, we take a kinetic, live-cell imaging approach to measure the growth or shrinkage of non-adherent tumor spheroids using Ultra Low Attachment (ULA) 96-well and 384-well microtiter plates (Corning®). These round-bottomed, hydrogel coated plates facilitate the formation of spheroids by promoting self-adherence as opposed to adherence to the plate surface. In a single cell type, monoculture model, A549 lung epithelial carcinoma cells developed into single spheroid structures in each well of 96 and 384-well plates within 48-96 hours in culture. In both plate types, the resulting spheroid size, ranging from 330 µm - 600 µm, was proportional to the number of cells (1K - 5K cells per well). Post formation, spheroids remained untreated or were subjected to three test agents, staurosporine, oxaliplatin or cycloheximide. The increase or decrease in spheroid size was monitored over 3 - 10 days using the IncuCyte™ ZOOM Live Content Imaging system. Using the red fluorescent channel, spheroid growth was analyzed using fluorescent area and intensity metrics. Whereas staurosporine and oxaliplatin significantly decreased spheroid size at high concentrations, cycloheximide treatment resulted in a cytostatic response, effectively inhibiting spheroid growth in a concentration dependent manner, while not reducing total spheroid area at any tested concentration. Interestingly, in side-by-side comparisons of kinetic 2D and 3D assays, we observed a significant, 10-fold (one log) shift in the pharmacology of cycloheximide. In a 3D co-culture breast cancer model, this study also illustrates the effect of Lapatinib on SK-BR-3 cells grown in the presence of mammary derived stromal cells (fibroblasts). Together, this study describes a kinetic, live-cell approach to measuring spheroid size over time, illustrates a differential response of cycloheximide in a 3D system compared to identically treated cells grown in a 2D monolayer, and details a complex co-culture method for elucidating the effect of Lapatinib in a physiologically relevant 3D model of breast cancer.
Citation Format: Kalpana Patel, Belinda O'Clair, Tim O'Callaghan, Daniel M. Appledorn, Derek Trezise. A 3D culture model for screening of cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4295. doi:10.1158/1538-7445.AM2014-4295
Abstract 4297: Quantifying three-dimensional cellular morphology and its heterogeneity in epithelial cancers by single-cell optical tomography
Authors: Nandakumar Vivek , Helland Stephanie , Han Jessica H. , Davis Geriann , Ashcroft Brian A. , Tran Thai H. , Li Ting , Anderson Karen S. , Pannala Rahul , Mikhael Joseph R. , Fleischer David E. , Johnson Roger H. , Bussey Kimberly J. , Meldrum Deirdre R. 
Published: May 2015

Abstract
The three-dimensional (3D) structure of the cell and its nucleus is intricately associated with cellular function. Aberrations and heterogeneity in cellular and nuclear morphology serve as diagnostically important cues to identify malignant transformation. However, current cytopathology practice is predominantly based on a qualitative, 2D assessment of cellular morphology that may bias the diagnosis. We utilized the Cell-CT® platform to perform single-cell, optical tomography imaging and generate 3D cell images with isotropic, sub-micron spatial resolution. We developed custom image analysis tools to accurately quantify 3D cell and nuclear morphology. We used these measures to characterize the morphological heterogeneity within and among epithelial cell populations, and to identify morphological descriptors that are reliably predictive of cell state. We assessed the efficacy of our approach relative to conventional 2D assessment (at 40x magnification) to detect malignant transformation in immortalized and primary normal-cancer cell line pairs from human esophagus and breast epithelia. We observed the 3D method of assessment to provide a consistently superior performance (sensitivity and specificity) in predicting malignant transformation. Further, some widely used diagnostic parameters, such as nuclear size or nucleus-to-cytoplasm ratio, did not always exhibit the highest predictive power in 3D space. The availability of 3D morphological information also provided novel insights on intra-population morphological heterogeneity in both normal and cancer cell populations. Our results emphasize the need to incorporate 3D morphological information into standard pathological practice.
Citation Format: Vivek Nandakumar, Stephanie Helland, Jessica H. Han, Geriann Davis, Brian A. Ashcroft, Thai H. Tran, Ting Li, Karen S. Anderson, Rahul Pannala, Joseph R. Mikhael, David E. Fleischer, Roger H. Johnson, Kimberly J. Bussey, Deirdre R. Meldrum. Quantifying three-dimensional cellular morphology and its heterogeneity in epithelial cancers by single-cell optical tomography. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4297. doi:10.1158/1538-7445.AM2014-4297
Abstract 4302: The development study of hypoxia responsive chemiluminescent probe for tumor hypoxia imaging
Authors: Okuda Kensuke , Ban Toru , Hirayama Tasuku , Nagasawa Hideko 
Published: May 2015

Abstract
Introduction: The tumor microenvironment is recognized as a major factor that influences not only the response to conventional anticancer therapies but also the potential for malignant progression and metastasis. Therefore, it is considered that tumor hypoxia imaging is critical for cancer diagnosis and therapy. As optical modalities offer the advantages of non-invasive, easy-to-handle, and cost-effective imaging, much effort has been done to develop synthetic fluorescent imaging probes for tumor hypoxia. In particular, we focus our attention on chemiluminescence imaging which can avoid interference from tissue autofluorescence and scattering light. We therefore show the development of hypoxia responsive chemiluminescent probe, which has the advantage of lower detection limits and improved signal-to-noise ratio compared to existing fluorescent probes.
Results and discussion: In our molecular design, luminescence is derived from 1,2-dioxetane cleavage triggered by hypoxia-selective enzymatic reduction of electron-deficient aromatics. At the start, nitrobenzyl moiety was chosen as a bioreductively cleavable protective group linked to 1,2-dioxetane moiety through phenyl ether linker to construct synthetic probe NB-Adm. The compound was synthesized from 2-adamantanone in 19% (overall yield, 6 steps). Then NB-Adm was attempted to be reduced by nitroreductase, however, no luminescence was observed. HPLC analysis of the reaction mixture indicated that our expected reduction did not occur, probably because bulky adamantane moiety prevented the enzymatic reaction owing to steric hindrance. Therefore, a self-immolative linker was employed to keep away 1,2-dioxetane moiety from enzyme recognition moiety. In this time, quinone moiety was chosen as a protective group which was expected to be better substrate than nitrophenyl one in terms of their redox potential. This newly designed compound, TMQ-Adm was synthesized from 2-adamantanone in 16% (overall yield, 6 steps). By the use of TMQ-Adm, we successfully observed luminescent emission from the reaction with nitroreductase. This implied that our bioredctively activatable probe can be applicable for chemiluminescence imaging for tumor hypoxia. Now we are investigating to develop chemiluminescent probe to realize in vivo imaging of tumor hypoxia by improving luminescent quantum yield under physiological condition.
Citation Format: Kensuke Okuda, Toru Ban, Tasuku Hirayama, Hideko Nagasawa. The development study of hypoxia responsive chemiluminescent probe for tumor hypoxia imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4302. doi:10.1158/1538-7445.AM2014-4302
Abstract 4309: Whole slide image analysis quantification in a mouse lung metastasis model
Authors: Sandusky George E. , Surface Ronne , Tonsing-Carter Eva , Silver jayne , Sinn Tony , Pollok Karen 
Published: May 2015

Abstract
Digital whole slide imaging is the technique of digitizing a microscope slide at the highest resolution to produce a “digital virtual microscope slide”. This digital image can be viewed in three or four fields, from low to high power fields, which can be commonly used to evaluate the tissue. Many of these systems have a whole slide software image analysis system.
The goal of this study was to determine if the Aperio positive pixel algorithm (image analysis) could effectively quantitate metastatic mouse lung tumors in a lung section using a H&E stain.
Lung sections from a mouse lung metastasis model with 8 mice in each group were evaluated: control, 50mg/kg, and 75mg/kg carboplatin. H&E and Ki67 immunostain slides were scanned using the Aperio whole slide scanning system (Scanscope CS). A single field of view from each slide representing a whole lung lobe with multiple lung metastases was selected for image analysis. The standard positive pixel algorithm was altered to read the H&E slides. Various histology slides were used to validate the altered algorithm. The immunostain (Ki67) was generated using the standard positive pixel algorithm analysis.
The Aperio automated positive pixel count for a Ki67 immunostain was consistent with the H&E image analysis. The values went down with a dose dependent treatment (control vs. 50mg/kg, and 75mg/kg Carboplatin) and were (H&E) 37%, 28%, 22%, and (Ki67) 9%, 5%, 3%, respectively.
The analysis had decreasing values for both the H&E and Ki67 analysis on a dose dependent drug treatment. The metastases decreased in both treatment groups compared to controls with both the H&E and Ki67 analyses. The Aperio Image Analysis positive pixel algorithm allows large areas of the lung tissue section to be examined and NOT just a single 25x or 40x field like many common image analyses.
Citation Format: George E. Sandusky, Ronne Surface, Eva Tonsing-Carter, jayne Silver, Tony Sinn, Karen Pollok. Whole slide image analysis quantification in a mouse lung metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2014-4309
Abstract 431: CYP26C1 gene is highly methylated and correlated with chemoradiation therapy in esophageal squamous cell carcinoma
Authors: Watanabe Yoshiyuki , Oikawa Ritsuko , Yoshida Yoshihito , Yamamoto Hiroyuki , Itoh Fumio 
Published: May 2015

Abstract
Background: Systemic chemo- and chemoradiation- therapy is widely accepted in esophageal squamous cell carcinoma (ESCC) patients. However resistance to these therapies remaining pretty high and multicentric occurrence of ESCC often can see after treatment. Multiple studies have shown that promoter methylation of tumor suppressor genes underlie esophageal carcinogenesis. But, we still do not know that epigenetic changes after chemoradiation therapy (CRT) in ESCC. Our aim is to identify how change DNA methylation in tumor site (T) but also adjacent normal site (ADJ) before/after CRT. Methods: Tumor and adjacent normal biopsy specimens were obtained before/after treatment from 34 patients (124 samples) enrolled in a uniform CRT protocol. Genomewide DNA methylation analysis was performed using 12 non-treated test samples (T and matched ADJ: 6 each) by methylated CpG island amplification and microarray (MCAM) method (4x44K, Agilent custom array), and selected candidate genes that were highly methylated in T than ADJ. We next analyzed one of the candidate genes CYP26C1 (cytochrome P450, family 26, subfamily C, polypeptide 1) DNA methylation using 112 validation samples by quantitative bisulfate pyrosequencing. Results: CYP26C1 was selected by unsupervised hierarchical clustering after MCAM in test samples. CYP26C1 DNA methylation was significantly high in T than ADJ in both test and validation samples (p&lt;0.04, T: 60.7±7.6, ADJ: 44.5±11.5). However some ADJ also showed high methylation in validation samples. Moreover, CYP26C1 methylation in both T and ADJ were significantly depressed after CRT (T: p&lt;0.01 (45.1±18.3 to 31.6±14.9), ADJ: p&lt;0.0001 (43.8±10.3 to 30.5±13.8)). Conclusions: CYP26C1 has a CpG island in promoter area and was highly methylated in T of ESCC patients. And, some ADJ showed high CYP26C1 methylation, suggesting possibility of multicentric occurs of ESCC. Moreover, CYP26C1 methylation depress after CRT both T and ADJ, suggesting potential clinical application of CRT sensitive biomarker.
Citation Format: Yoshiyuki Watanabe, Ritsuko Oikawa, Yoshihito Yoshida, Hiroyuki Yamamoto, Fumio Itoh. CYP26C1 gene is highly methylated and correlated with chemoradiation therapy in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2014-431
Abstract 4311: Fluorescence-guided surgery of pancreatic cancer using activatable cell penetrating peptides (ACPPs) in orthotopic mouse models
Authors: Metildi Cristina A. , Kaushal Sharmeela , Felsen Csilla N. , Nguyen Quyen T. , Hoffman Robert M. , Tsien Roger Y. , Bouvet Michael 
Published: May 2015

Abstract
Surgical resection with complete removal of tumor remains one of the most effective modalities in the treatment of cancer. The aim of this study was to evaluate the efficacy of using activatable cell penetrating peptides (ACPPs) conjugated to Cy5 fluorophores to accurately label primary pancreatic tumor for fluorescence-guided surgery (FGS) in orthotopic mouse models. Orthotopic mouse models of human pancreatic cancer using surgical implantation of tumor fragments of the MiaPaca-2-GFP pancreatic cancer cell line were established. Two weeks after tumor implantation, the tumors were resected with bright light surgery (BLS) or FGS. FGS was performed with a florescence-dissecting microscope (MVX10, Olympus) 2 hours after periorbital injection of ACPPs. Completeness of resection was assessed from postoperative images obtained with the Maestro CRI Small Imaging System. Postoperatively, we performed whole body imaging of the mice to assess for recurrence. At eight weeks, mice were sacrificed to evaluate pancreatic tumor burden, as well as local and distant recurrence. Cy-5-conjugated ACPPs, cleavable by MMP-2 and MMP-9 permitted clear visualization of tumor margins for fluorescence-guided resection. With FGS, no residual tumor was detected in the postoperative surgical site in all 16 mice. One mouse out of 16 undergoing BLS had evidence of residual tumor postoperatively. At 8 weeks, mice in the BLS group demonstrated larger primary tumors compared to mice in the FGS group (1.72 g ± SE 0.58 vs 0.25 g ± SE 0.14, p=0.026). Mean disease-free survival (DFS) was significantly lengthened from 5.33 weeks in the BLS group to 7.38 weeks in the FGS group (p=0.02). Furthermore, recurrence rates were lower in the FGS group (38% vs 73%, p=0.049). This translated into a lower local and distant recurrence rate for FGS (31% vs 67% and 25% vs 60%, respectively). ACPPs can provide an alternative method to accurately and effectively label cancer cells for improved resection of tumors that do not express specific tumor antigens and result in better outcomes post-resection.
Citation Format: Cristina A. Metildi, Sharmeela Kaushal, Csilla N. Felsen, Quyen T. Nguyen, Robert M. Hoffman, Roger Y. Tsien, Michael Bouvet. Fluorescence-guided surgery of pancreatic cancer using activatable cell penetrating peptides (ACPPs) in orthotopic mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2014-4311
Abstract 4321: Effect of pretreatment, dose and route of administration of BPM31510 (Coenyzme Q10 containing proprietary formulation) alone or in combination with gemcitabine improves survival in pancreatic cancer
Authors: Narain Niven , Mauro Lucia , Lens Assuan , Akmaev Viatcheslav , Sarangarajan Rangaprasad , Jimenez Joaquin 
Published: May 2015

Abstract
In-vitro studies have demonstrated the ability of BPM31510, a Coenzyme Q10 (CoQ10) containing proprietary formulation to effectuate a metabolic switch from glycolysis to mitochondrial OXPHOS resulting in the activation of apoptotic pathways specifically in cancer cells. The effectiveness of BPM31510 in combination with standard of care chemotherapy agents in in-vitro and in-vivo models has been previously established. The current study was to determine the effect of dose, route of administration and combination with gemcitabine on survival in an animal model of pancreatic cancer. BPM31510 administered in three divided doses (50mg/kg vs 75mg/kg body weight daily, intravenous) was associated with dose dependent increase in survival and was significantly better when combined with gemcitabine. Continuous infusion of BPM31510 significantly improved survival rates compared to three divided doses (50mg/kg or 75mg/kg body weight) of BPM31510, with best outcomes at 200mg/kg body weight dose. Sixty day pretreatment with BPM31510 alone followed by combination with gemcitabine was also associated with improved survival outcomes with either gemcitabine or BPM31510 alone. The data suggests that dose and route of administration of BPM31510 alone or in combination with standard of care chemotherapy agents influences and improves survival in animal model of pancreatic cancer.
Citation Format: Niven Narain, Lucia Mauro, Assuan Lens, Viatcheslav Akmaev, Rangaprasad Sarangarajan, Joaquin Jimenez. Effect of pretreatment, dose and route of administration of BPM31510 (Coenyzme Q10 containing proprietary formulation) alone or in combination with gemcitabine improves survival in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4321. doi:10.1158/1538-7445.AM2014-4321