bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1553: Down-expression of ATM gene and protein associated with canine breast tumors.
Authors: Raposo Talita Mariana Morata , Bueno Renata C. , de Carvalho Márcio , Fonseca-Alves Carlos E. , Tinucci-Costa Mirela , De Nardi Andrigo B. , Rogatto Silvia R. , Laufer-Amorim Renée 
Published: August 2014

Abstract
Background: Ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair that plays an important role in the maintenance of genome integrity. ATM transcript and protein down-regulation have been reported in sporadic breast carcinomas and the absence of ATM protein expression was also significantly associated with distant metastasis in women, but the mechanisms involved in the ATM deregulation are not well established.
Aim: Due to the fact that mammary tumor biological behavior is similar between canine and humans, we evaluate ATM gene and protein expression in canine breast cancer and compared with normal mammary gland from dogs.
Patients and methods: Fresh samples of non-metastatic (n=23) and metastatic mammary carcinomas (n=11) and normal breasts (n=10) were evaluated for ATM gene expression by RT-qPCR and from the same animals, another sample of tumor was collected, formalin-fixed and paraffin-embedded to assess ATM protein expression by immunohistochemistry. Evaluation of ATM protein expression was performed by the distribution of positively-immunostained tumor cells in scores: 1 (&lt;25% cells positive), 2 (26% to 50% cells positive) and 3 (&gt;51% cells positive).
Results: Down expression of ATM was detected in tumors samples (non-metastatic and metastatic mammary carcinomas) when compared to normal breast samples (P= 0,0414). Additionally, scores 1 and 2 of ATM protein expression were exclusively observed in metastatic tumors presenting score 1: 18% (2 out of 11), score 2: 55% (6 out to 11) and non metastatic tumors presenting the same score 1 and 2: 17% (4 out to 23) while all normal breast tissues showed score 3 (P=0,0087).
Conclusions: Down expression of ATM transcript was confirmed by ATM protein expression. Low levels of ATM suggest an involvement of DNA damage repair transcript and protein in tumorigenesis process of canine mammary tumors, as in women, corroborating for the use of dogs as a natural comparative model to study mammary gland tumors in humans.
Citation Format: Talita Mariana Morata Raposo, Renata C. Bueno, Márcio de Carvalho, Carlos E. Fonseca-Alves, Mirela Tinucci-Costa, Andrigo B. De Nardi, Silvia R. Rogatto, Renée Laufer-Amorim. Down-expression of ATM gene and protein associated with canine breast 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 1553. doi:10.1158/1538-7445.AM2013-1553
Abstract 1554: Inducible B-Raf and c-Src models as tools for drug development.
Authors: Ehlert Jan E. , Mutschler Bettina , Mueller Melanie , Lingnau Andreas , Hoffmann Steffen , Weber Holger , Kubbutat Michael H. G. 
Published: August 2014

Abstract
C-Src and B-Raf are critical kinases in signal transduction often involved in the onset of cancer and therefore representing promising targets for drug development. In order to assess the kinase-specific inhibitory effect in cellular and in-vivo models, we have generated cell lines exogenously expressing either c-Src or the commonly found mutant B-RafV600E in a regulatable manner, either by Doxicyclin-suppression or Hydroxy-Tamoxifen activation, respectively. Despite moderate kinase expression levels we observe significantly increased kinase activity in the activated state which can be monitored by substrate specific phospho-ELISAs as well as by analysis of phenotypic responses such as soft agar growth. Moreover, these cellular models are applicable for in-vivo analyses, showing strong in vivo growth in the activated state while no tumor growth occurs in the unactivated state. The applicability of these models in drug development is exemplified using c-Src inhibitor Dasatinib and B-Raf inhibitor Sorafenib.
Citation Format: Jan E. Ehlert, Bettina Mutschler, Melanie Mueller, Andreas Lingnau, Steffen Hoffmann, Holger Weber, Michael H. G. Kubbutat. Inducible B-Raf and c-Src models as tools for drug development. [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 1554. doi:10.1158/1538-7445.AM2013-1554
Abstract 1558: Imaging of metastatic B16F10 melanoma in mice using tumor-homing stem cells.
Authors: Shrestha Tej B. , Balivada Sivasai , Basel Matthew , Pyle Marla , Bossmann Stefan H. , Troyer Deryl L. 
Published: August 2014

Abstract
Tumors, like wounds, recruit cells from surrounding tissues and bone marrow. Some of these cells provide support and nutrition, while others participate in an inflammatory response. Bone marrow mesenchymal stem cells (MSCs) exhibit this tropism toward wounds and other areas of pathology. Consequently, stem cell technology for diagnostic and therapeutic purposes is an emerging field in cancer biology. Like bone marrow MSCs, mouse neural progenitor cells (NPCs) tend to migrate toward cancer sites. We found that these cells migrate toward B16F10 lung melanomas, making them very good candidates for delivery of chemotherapeutic drugs, genes of interest, and imaging contrast agents. Among imaging techniques, bioluminescent imaging is non-invasive. Gaussia luciferase (Gluc) is particularly useful, as it is non-toxic and has stronger luminescence than other known luciferases. In the presence of its substrate coelenterazine (coel), Gluc luminescence peaks near 470 nm. In this study, we engineered NPCs to secrete Gluc. These Gluc-engineered cells were injected systemically to C57BL/6 mice bearing metastatic B16F10 lung melanoma and mice were given coel intravenously. Imaging of the mice on the Caliper IVIS Lumina II showed bioluminescence in disseminated areas. The distribution of bioluminescence suggested that the engineered NPCs migrated to the tumor sites and secreted Gluc. In confirmation, necropsy revealed black metastatic tumors in the locations emitting bioluminescence. Although IV injection of metastatic B16F10 lung melanoma cells usually generates lung tumors, we found dissemination of melanoma in other parts of the body. The Gluc-expressing NPCs could find the tumors as early as 2 days post tumor-cell injection, long before tumors were palpable. Thus, this system offers promise for improving cancer diagnosis. For improved imaging, this bioluminescence system can be coupled with other fluorescent dyes for red shifted output. Finally, the same sensitivity and tumor tropism suggests that the NPCs could be useful delivery cells for tumor-targeted therapeutics.
Citation Format: Tej B. Shrestha, Sivasai Balivada, Matthew Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Imaging of metastatic B16F10 melanoma in mice using tumor-homing stem cells. [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 1558. doi:10.1158/1538-7445.AM2013-1558
Abstract 1563: Mouse models for cancer research available from The Jackson Laboratory Repository.
Authors: Beckwith Jason , Lutz Cathleen M. , Mills Kevin D. , Rockwood Stephen F. , Sasner Michael , Donahue Leah Rae 
Published: August 2014

Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, rederivation, distribution and cryopreservation of mouse models. Hundreds of new strains are added annually to one of the largest collections of characterized mouse strains available to the international biomedical research community.
This poster features a detailed description of recently added mouse lines having cancer research applications across multiple therapeutic areas. A wide range of models are ideally suited for studies related to cellular cancers, solid tumors, and conditional/inducible cancer-associated gene expression. To highlight transplantation/engraftment and "humanized" mice research, several mouse lines with improved engraftment and specialized human cell colonization are also described. Such animals complement our NSG (NOD scid IL2rγc-/-) and NRG (NOD Rag1-/- IL2rγc-/-) mice as ideal tools for engraftment with a wide range of malignant or non-malignant human or mouse tissues, as well as a diverse spectrum of cell lines. In addition, newly available Cre-lox, Tet-On/Tet-Off, and fluorescent tool strains are illustrated.
An essential infrastructural component to The Jackson Laboratory Repository is a robust quality control program that surveys allele identity and genetic background, and excludes unwanted alleles. In addition, The Jackson Laboratory's Rare and Orphan Disease Center is a new initiative that focuses on partnering with scientists, foundations, and other experts to enable the development, standardization, optimization, and rapid distribution of preclinical models for drug discovery.
The Jackson Laboratory Repository maintains a searchable online resource to find mice (JAXMice database: www.jaxmice.jax.org/query). Anyone wishing to donate their mouse strains for cryopreservation/distribution may submit them using our online submission form (www.jax.org/donate-a-mouse). The Jackson Laboratory Repository is supported through our NCI designated Cancer Center and other NIH mechanisms, The Howard Hughes Medical Institute, The Ellison Medical Foundation and several private charitable foundations.
Please stop by for a detailed list of recently added mouse lines with cancer research applications across multiple therapeutic areas. Please also visit our cancer-related strains website at: http://jaxmice.jax.org/cancer/index.html
Citation Format: Jason Beckwith, Cathleen M. Lutz, Kevin D. Mills, Stephen F. Rockwood, Michael Sasner, Leah Rae Donahue. Mouse models for cancer research available from The Jackson Laboratory Repository. [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 1563. doi:10.1158/1538-7445.AM2013-1563
Abstract 1588: Canonical Wnt signaling mediates resistance of colorectal cancer cells to radiation therapy.
Authors: Emons Georg , Möller Janneke , Spitzner Melanie , Kendziorra Emil , Gaedcke Jochen , Rave-Fränk Margret , Pukrop Tobias , Ghadimi Michael , Ried Thomas , Grade Marian 
Published: August 2014

Abstract
Background: The clinical response of locally advanced rectal cancers to preoperative chemoradiotherapy is very heterogeneous. We previously identified TCF4, the key downstream effector of the Wnt/β-catenin signaling pathway, as over-expressed in tumors that were resistant to chemoradiotherapy. The aim of this study was to explore the potential functional relevance of Wnt/ß-catenin signaling for mediating treatment resistance.
Methods: Using RNA interference, TCF4 and β-catenin were inhibited in the colorectal cancer cell lines SW837 and SW480. Subsequently, these cell lines were irradiated with varying doses of X-rays. In addition, normal retinal epithelial cells (RPE) were stimulated with Wnt-3a for 28 hours, and also irradiated. Wnt/β-catenin activity was assessed using the TOPFLASH/FOPFLASH reporter assay, and induction of Axin2 was confirmed by Western blotting.
Results: Protein levels of both TCF4 and β-catenin were considerably reduced following RNAi, accompanied by a decreased TOP/FOP reporter activity. Importantly, silencing of both proteins led to a pronounced radiosensitization in SW837 and SW480 cells. Exogenous stimulation of canonical Wnt signaling in RPE cells using Wnt-3a resulted in an increased Axin2 expression and an increased TOP/FOP reporter activity. Importantly, however, this activation of canonical Wnt signaling was associated with significant increase in resistance to radiation therapy.
Conclusion: TCF4 was found to be over-expressed in resistant rectal carcinomas, and its RNAi-mediated silencing caused a significant radiosensitization. To determine whether this effect was dependent on canonical Wnt signaling, we inhibited ß-catenin, another key factor of this pathway and binding partner of TCF4, and observed a similar sensitization to radiation therapy. Follow-up experiments show that external stimulation of canonical Wnt signaling confers radiation resistance in normal cells. These data suggest that targeting canonical Wnt signaling may represent a potential therapeutic strategy for sensitizing tumor cells to radiation. In vivo studies are ongoing to validate these results.
Citation Format: Georg Emons, Janneke Möller, Melanie Spitzner, Emil Kendziorra, Jochen Gaedcke, Margret Rave-Fränk, Tobias Pukrop, Michael Ghadimi, Thomas Ried, Marian Grade. Canonical Wnt signaling mediates resistance of colorectal cancer cells to radiation therapy. [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 1588. doi:10.1158/1538-7445.AM2013-1588
Abstract 1593: Cellular effects of the mitochondrially-directed antioxidant Tempol.
Authors: Kesarwala Aparna H. , DeGraff William , Gamson Janet , Choudhuri Rajani , Cook John A. , Krishna Murali C. , Mitchell James B. 
Published: August 2014

Abstract
The mitochondrial respiratory chain is a major source of reactive oxygen species, making it a high-yield target for antioxidants and potential radioprotection. The lipophilic cation triphenylphosphonium (TPP) has been used to target antioxidants to the mitochondrial membrane. Its lipophilicity permits it free passage through biological membranes while its positive charge traps it in the mitochondrial membrane, which is characterized by a large membrane potential. Among the agents localized to mitochondria via TPP have been stable nitroxide radicals, superoxide dismutase mimetics which also demonstrate the ability to scavenge free radicals. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, or Tempol (TP), is a nitroxide which is radioprotective both in vitro and in vivo when present during ionizing radiation. As with most chemical radioprotectors, relatively high concentrations of Tempol are required for protection. We questioned whether mito-Tempol (MTP), Tempol directed to mitochondria via TPP, would provide protection against radiation or hydrogen peroxide (HP) cytotoxicity as measured by the clonogenic assay in Chinese hamster V79 cells. MTP (10-500 μM) present 10 min prior to, during, and 4 hr after 12 Gy provided no radioprotection. MTP exhibited no cytotoxicity alone. In contrast, both TP and MTP (500 μM), when present immediately before and during a 1 hr exposure to HP, provided significant protection against HP cytotoxicity. We next evaluated the effects of continuous exposure to TP or MTP (100 μM) on the growth rate of several human tumor cell lines (MCF7, HT29, 786-0). TP had little effect on growth of these cell lines while MTP completely inhibited cell growth. The effects of the TPP-carbon linker alone will be presented; in short-term studies it did not exhibit cytotoxicity to V79 cells. These preliminary data with mitochondrial targeting of Tempol demonstrate that MTP exhibited antioxidant properties similar to TP with regard to protection against HP; at concentrations up to 500 μM, however, MTP did not protect against radiation. The latter finding is consistent with the requirement that chemical radioprotectors be present in sufficient concentration in the nucleus to afford radioprotection. Additional studies will be presented addressing the mechanism of MTP-mediated growth inhibition in human tumor cell lines.
Citation Format: Aparna H. Kesarwala, William DeGraff, Janet Gamson, Rajani Choudhuri, John A. Cook, Murali C. Krishna, James B. Mitchell. Cellular effects of the mitochondrially-directed antioxidant Tempol. [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 1593. doi:10.1158/1538-7445.AM2013-1593
Abstract 1603: Synthesis and in vitro evaluation of lipophilic cation conjugated photosensitizers for targeting mitochondria.
Authors: Rajaputra Pallavi , Nkepang Gregory , Watley Ryan , You Youngjae 
Published: August 2014

Abstract
Mitochondria-specific photosensitizers were designed by taking advantage of the preferential localization of delocalized lipophilic cations (DLCs) in mitochondria. Three conjugates, CMP-Rh, CMP-tPP, and CMP-(tPP)2, were successfully synthesized by linking the hydroxy core modified porphyrins (CMP-OH and CMP-(OH)2) to either rhodamine B (Rh B) or one or two triphenyl phosphine (tPP) cations respectively via a saturated hydrocarbon linker. Their ability for delivering photosensitizers to mitochondria was evaluated using dual staining fluorescence microscopy and staining pattern was compared with a mitochondrial specific probe. Fluorescence imaging study suggested that CMP-Rh specifically localized in mitochondria. On the other hand, CMP-tPP and CMP-(tPP)2 showed less significant mitochondrial localization. The conjugation of CMP to Rh and tPP did greatly improve intracellular uptake and in vitro photodynamic activity compared to CMP-OH. In addition, to evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro biological activities were studied in comparison to those of CMP-OH. All conjugates were capable of generating singlet oxygen at rates comparable to CMP-OH. This improved photodynamic activity might be primarily due to an enhanced cellular uptake. Our study suggests that Rh B cationic group is better at least for CMP than tPP as a mitochondrial targeting vector.
Citation Format: Pallavi Rajaputra, Gregory Nkepang, Ryan Watley, Youngjae You. Synthesis and in vitro evaluation of lipophilic cation conjugated photosensitizers for targeting mitochondria. [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 1603. doi:10.1158/1538-7445.AM2013-1603
Abstract 1690: Differential autophagy activation in KRAS and EGFR mutant lung adenocarcinomas.
Authors: Rodriguez Maria L. , Pulido Ines , Soucheray Margaret , Crespo Daniel , Al-shahrour Fatima , Shimamura Takeshi , Ortega Angel , Carretero Julian 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer deaths in western countries, and adenocarcinomas (LADs) are the most frequent histological subtype. The aberrant activation of the kinases promotes plethora of tumorigenic processes, mainly through PI3K and MAPK oncogenic pathways leading to oncogene addiction. The activation of PI3K pathway deregulates mTOR, a master kinase for cell growth and autophagy. Autophagy can be pro- or anti- tumorigenic, however its roles in protecting tumors exposed to metabolic stress under chemotherapy are considered as a survival mechanism for the tumors leading to acquired resistance. Consequently, the inhibition of autophagy is an attractive therapy to prevent the emergence of acquired resistance. Activating mutations in EGFR and KRAS are mutually exclusive and are the most frequent oncogene activation in LAD. There are considerable differences in the control of signalling pathways including PI3K-mTOR axis. Therefore, it is hypothesized that the susceptibility to autophagy differs depending on EGFR or KRAS mutational status. To test the hypothesis, we applied nutrient-starvation conditions, the most well-known inducer of autophagy, to a panel of LAD cell lines bearing known EGFR or KRAS mutations. As a positive control, cells were treated with rapamycin, which also induced autophagy inhibiting MTOR activity. Autophagy activation was analyzed by: i) Western blot of LC3-II and p62/SQSTM1 protein levels, that measures autophagy flux and autophagic protein degradation, respectively; and ii) autophagolysosome detection and lysosomal activity by fluorescent microscopy. Our data suggest that KRAS-mutant LAD cell lines are able to activate autophagy, whereas EGFR-mutant are not, under starvation stress. Furthermore, we found a potential interaction between mutant EGFR and Beclin 1 (BECN1, a protein required for the initiation of the autophagosome) at the cell membrane proximity, using co-immunolocalization by confocal microscopy and immunoprecipitation followed by Western blot. Together, these data provide a compelling rationale to investigate anti-autophagy therapy in mutant KRAS LADs and warrant further investigation in the regulation of autophagy via a novel link between Beclin1 and mutant EGFR.
Citation Format: Maria L. Rodriguez, Ines Pulido, Margaret Soucheray, Daniel Crespo, Fatima Al-shahrour, Takeshi Shimamura, Angel Ortega, Julian Carretero. Differential autophagy activation in KRAS and EGFR mutant lung adenocarcinomas. [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 1690. doi:10.1158/1538-7445.AM2013-1690