bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4419: Pilot toxicology study of the B-cell lymphoma drug candidate SH7139 demonstrates lack of toxicity in beagles.
Authors: Balhorn Rod , Hok Saphon , Balhorn Monique 
Published: August 2014

Abstract
A group of small molecule drug candidates for non-Hodgkin's lymphoma, called Selective High Affinity Ligands (SHALs), have been developed to target the cell surface antigen HLA-DR10 that is known to be over expressed on many B-cell derived malignancies. These compounds are created by chemically linking together two or three small molecule “recognition elements” that have been identified to bind to neighboring unique sites on the surface of the target protein. One of these compounds, SH7139, has been shown previously to be effective in treating human B cell lymphoma in a mouse xenograft model at extremely low doses (5μg/kg). Earlier experiments conducted in mice have also shown the compound to exhibit no signs of toxicity at 2000 times (10mg/kg) this dose. In an effort to obtain preliminary toxicology and safety data on SH7139 and assess the reversibility or persistence of any potential toxic effects prior to its being evaluated in a pet dog B-cell lymphoma trial for treating canine B-cell lymphomas, a pilot 28-day toxicology study was performed in three naïve Beagles. SH7139 was administered intravenously in three doses injected on days 0, 7 and 14. The dose tested, 50μg/kg, was ten times the dose required to cure 69% of mice carrying Raji xenografts. During the in-life period, animals were observed daily for mortality, moribundity, and food consumption, detailed clinical examinations were conducted on the days of dose, 24 hrs post-dose and weekly thereafter, and individual body weights and temperatures were recorded on the days of dosing and selected days after dosing. Clinical pathology samples (urinalysis, hematology, coagulation, clinical chemistry) were collected prior to dose administration on the days of dose and during the recovery phase (Days 21 and 28). On Day 29, all animals were euthanized and a complete necropsy was conducted with tissue collection and preservation. The key tissues were embedded in paraffin, H&E stained and examined microscopically by a board-certified pathologist. The results of this study show the treatment with SH7139 is well tolerated by healthy, naïve dogs. No treatment-related effects on body weight, body temperature, food consumption or clinical pathology parameters were observed. In addition, the lack of significant changes in hematology, clinical chemistry, urinalysis or coagulation parameters also indicate SH7139 exhibited no apparent systemic toxicity or side effects.
Citation Format: Rod Balhorn, Saphon Hok, Monique Balhorn. Pilot toxicology study of the B-cell lymphoma drug candidate SH7139 demonstrates lack of toxicity in beagles. [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 4419. doi:10.1158/1538-7445.AM2013-4419
Abstract 443: PKC epsilon is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial cells.
Authors: Alam Asim , Rabender Chris , Mikkelsen Ross 
Published: August 2014

Abstract
PKCε is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial cells.
Ionizing radiation (IR) has been shown to increase angiogenic markers and migration in endothelial cells involving reactive oxygen/nitrogen species and eNOS, but the exact mechanism is poorly understood. This activation of endothelial cells can increase angiogenesis post radiation and confer cytoprotection to tumor cells. Thus targeting this IR induced activation of endothelial cells should increase therapeutic efficacy of radiation therapy. Protein Kinase C Epsilon is a molecule that has been shown to be important in cancer cell motility, proliferation, hormone sensitivity and angiogenesis. PKCε activates downstream pathways involved in tumorigenicity such as Akt and Stat3. PKCε has also been shown to be nitrated in response to NO donors and inflammatory conditions in cardiac myocytes. During inflammation, hypoxia and irradiation, levels of reactive nitrogen species are elevated due to uncoupling of Nitric Oxide Synthase (NOS). NOS can be recoupled with tetrahydrobiopterin precursor (sepiapterin) which decreases RNS/ROS in cells. We have shown in 2H11 cells (mouse tumor endothelial cells) that PKCε levels are increased due to exposure to clinically relevant doses of ionizing radiation or levels of NO found in chronic inflammatory conditions. Also in these cells PKCε is nitrated in response to reactive nitrogen species which leads to its activation and activation of Stat3 and Akt. Using sepiapterin, we have shown decreased levels of PKCε, Stat3 and Akt. We have also blocked ionizing radiation induced migration in vitro in 2H11 cells using sepiapterin and a PKCε inhibitor. We hope to show that PKCε is nitrated at specific residue(s) after ionizing radiation and activates tumor endothelial cells to promote the survival of the tumor. We believe sepiapterin with ionizing radiation therapy will result in increase cytotoxicity in a spontaneous mouse model of lung cancer, by decreasing endothelial activation, migration, proliferation and angiogenesis.
Citation Format: Asim Alam, Chris Rabender, Ross Mikkelsen. PKC epsilon is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial 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 443. doi:10.1158/1538-7445.AM2013-443
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4430: Protective effects of rebamipide liquid on radiation-induced glositis in rats.
Authors: Nakashima Takako , Uematsu Naoya , Shibamori Masafumi , Sakurai Kazushi , Sato Masayuki , Matsuda Takakuni , Sako Nobutomo 
Published: August 2014

Abstract
[Background & Aims] Rebamipide is widely used for mucosal protection, healing of gastric ulcers and treatment of gastritis. Recently, it was reported that Rebamipide gargle inhibited oral mucositis induced by chemoradiotherapy in head and neck cancer patients. In this study, we examined protective effects of Rebamipide Liquid on radiation-induced glossitis rat model and analyzed the expression level of pro-inflammatory cytokines and chemokines in the injury area of tongue.
[Materials & Methods] Rebamipide Liquid, comprising with Rebamipide crystals less than 500 nm particles, was prepared by a neutralizing crystallization technique. This formulation is a stable homogenous aqueous suspension provided with appropriate viscosity by adding viscosity enhanced agents to improve the retention in the oral cavity.
The glossitis was induced by X-ray with 15Gy irradiation only around the snout (Day 0) in rats. Rebamipide Liquid was administered intraorally at doses of 5, 10 or 20 mg/kg (1, 2 or 4%, respectively), 6 times a day for 14 days from Day -7 to Day 6. These tongue tissue specimens were obtained at Day 7 and their images were recorded by a digital camera for efficacy evaluations. Gene expression analysis was performed with quantitative real-time PCR (ABI) and protein level was evaluated with Bio-Plex system(BioRad) or ELISA in a different study which was conducted at the two doses of 0 and 20 mg/kg (0 and 4%).
[Result & Conclusions] The ulcer-like areas (10.8 ± 1.2, 7.9 ± 1.1 and 7.0 ± 0.7%) at doses of 5 - 20 mg/kg (1 - 4%) of Rebamipide Liquid administration, were statistically smaller than the vehicle control at 14.7±1.6%. Another study revealed that the expression of pro-inflammatory cytokines (TNF-α, IL-6 and Il-1β) and chemokines (MCP-1 and Gro-α) were dramatically elevated in the irradiated tongue at Day7, as compared to normal. But these elevated expressions were significantly suppressed by the 4% Rebamipide treatment. These immuoassays elucidated that the production of these cytokines and chemokines were significantly suppressed by the Rebamipide administration. These results demonstrated that the Rebamipide Liquid has a potent pharmacological action for the radiation-induced oral mucositis mediated by the suppression of pro-inflammatory cytokines (TNF-α, IL-6 and Il-1β) and chemokines (MCP-1 and Gro-α).
Citation Format: Takako Nakashima, Naoya Uematsu, Masafumi Shibamori, Kazushi Sakurai, Masayuki Sato, Takakuni Matsuda, Nobutomo Sako. Protective effects of rebamipide liquid on radiation-induced glositis in rats. [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 4430. doi:10.1158/1538-7445.AM2013-4430
Abstract 4432: MMP9 reinforces radiation-induced delayed invasion and metastasis of neuroblastoma through second-signaling positive feedback with NFκB via both ERK and IKK activation.
Authors: Major Ryan , Aravindan Sheeja , Natarajan Mohan , Herman Terence S. , Aravindan Natarajan 
Published: August 2014

Abstract
Tumor recurrences continue to remain high in neuroblastoma (NB), and a substantial fraction of those develop metastatic disease with only 10% survival in systemic recurrences. Efficient and improved therapeutic strategy can be developed through targeted drug delivery approach and by intervening molecular pathways operating in response to tumor recurrence. Herein, we investigated the onset and maintenance of metastatic signal transduction in neuroblastoma (SH-SY-5Y, MC-IXC, SK-PN-DW and IMR-32) cells that survive after radiotherapy. Gelatin zymography revealed that exposure to radiation induces significant and consistent increase in MMP2 and MMP9 activity. Further, muting radiation induced NFκB with dominant negative mutant IkB and/or forced expression of NFκB (p50/p65 sub-units) in these cells affirmed the influence of radiation-induced NFκB in MMP9 transactivation (QPCR), translation (immunoblotting) and activity (sequence specific substrate based high sensitive fluorogenic assay). Interestingly, blocking radiation-induced MMP9 with GM-6001 profoundly inhibited p65 transactivation and nuclear localization. More importantly, blocking radiation-induced MMP9 greatly introverted radiation-induced phosphorylation of IKK in these cells. Furthermore, radiation increased both transactivation and activity of ERK-1 (active ERK/phosphor-transferase immunoprecipitation) in neuroblastoma cells. This pathway was further defined (MMP9 blocking and activation, PMA studies) to show that radiation-induced functional MMP9 is necessary for activation of ERK- and NFκB-dependent onset of metastasis (tumor invasion and metastasis transcriptome profiling) in surviving NB cells. Selective MMP9-dependent ERK regulation was confirmed with futile inhibition of ERK activity in aprotinin treated cells. Together, these data strongly suggest that radiation induced NFκB-dependent MMP9 reinforces radiation-induced delayed invasion and metastasis. Further, these results imply that the MMP9 dependent reinforcement may involve dual signaling feedback activation of NFκB though ERK and IKK phosphorylation.
Citation Format: Ryan Major, Sheeja Aravindan, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. MMP9 reinforces radiation-induced delayed invasion and metastasis of neuroblastoma through second-signaling positive feedback with NFκB via both ERK and IKK activation. [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 4432. doi:10.1158/1538-7445.AM2013-4432
Abstract 4436: The down-regulation of ferritin heavy chain as an adjuvant therapy in human glioma.
Authors: Pang Min , Madhankumar A.B. , Webb Becky , Liu Xiaoli , Connor James R. 
Published: August 2014

Abstract
Increased iron requirements and heightened iron metabolism is among the key characteristics of highly proliferative cancer cells. As the major iron storage protein, ferritin expression is elevated in cancer cells and we have previously shown that ferritin down-regulation in human glioblastoma cells increases their sensitivity to chemotherapeutic agent both in vitro and in vivo. In this study, we report that the sensitization of H-ferritin down-regulation in glioma cells against radiation and suggest the potential of H-ferritin down-regulation as an adjuvant therapy in human glioma.
Down-regulation of H-ferritin was performed in human glioma cell line U251 through a nanotechnology-based transfection platform and effective knockdown efficiency was achieved. A transient decrease in transferrin receptor level was also observed, suggesting a release of intracellular iron with loss of ferritin. This iron release in turn produced intracellular oxidative stress, demonstrated by protein oxidation damage, as well as a decrease in the stability of hypoxia-inducible factors (HIFs), which is an indicator of radioresistance. In U251 cells, exposure to radiation resulted in protein oxidation which could be exacerbated by H-ferritin down-regulation.
Previously we have demonstrated a DNA protection role for H-ferritin. Here we report that the down-regulation of H-ferritin is associated with increased DNA vulnerability when cells were exposed to ionizing radiation. Moreover, the activation of DNA repair mechanisms was impaired when H-ferritin was absent. The in vitro data suggest a synergistic effect of radiation and H-ferritin down-regulation.
Additionally, we expand our research into CD133-positive glioma stem cells (GSCs), which are notoriously resistant to anti-cancer treatment. Down-regulation of H-ferritin in these cells inhibited cell proliferation in vitro. With an intracranial glioma model established by GSC implantation, we demonstrated that the survival was significantly prolonged by H-ferritin siRNA transfection through intravenous injection, in tumor bearing mice treated with first-line drug Temodar. This study supports the potential of H-ferritin siRNA as an adjuvant therapy in glioma treatment.
Citation Format: Min Pang, A.B. Madhankumar, Becky Webb, Xiaoli Liu, James R. Connor. The down-regulation of ferritin heavy chain as an adjuvant therapy in human glioma. [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 4436. doi:10.1158/1538-7445.AM2013-4436
Abstract 444: Mitochondrial metabolism and phosphorylation of Stat3 in radioresistant cancer stem cells isolated from glioma U87 cells.
Authors: Fan Ming , Shi Yan , Li Jian Jian 
Published: August 2014

Abstract
Abstract
Radiation therapy continues to play a central role in the management of brain tumors. The radioresistance of high-grade gliomas remains one of the reasons for the failure of treatment, which would otherwise require tumoricidal doses beyond the normal tissue tolerance and beyond safe clinical practice. Thus, determining the cellular, molecular and biochemical mechanisms underlying radiation resistance becomes critical for successful treatment of these tumors. For this purpose, glioma cell line U87 were treated with fractionated doses of radiation and the resistant clones isolated from the surviving tumor cells were characterized. The radioresistant U87 cells showed enhanced aggressiveness and clonogenic survival with an increased expression of HER2 and CD133, glioma cancer stem cell surface markers, as well as elevated mitochondrial membrane potential but lower oxygen consumption and ATP generation. In addition, compared with the wild type U87 cells, the phosphorylation of mitochondrial Stat3 at Serine 727 was decreased in the radioresistant U87 cells, indicating a role for mitochondrial Stat3 in the radioresistance mechanisms. Additionally, mutation of Serine 727 of Stat3 into Alanine resulted in increased radiosensitivity. These results demonstrate that the radioresistant glioma cells surviving routine radiotherapy are enriched with cancer stem cells expressing CD133 and HER2. The radioresistant phenotype is linked with a lowered mitochondrial metabolism and increased anti-apoptotic function due to inhibition of mitochondrial Stat3 phosphorylation. Thus, improving the mitochondrial metabolism by enhancing mitochondrial Stat3 phosphorylation may serve as an effective approach to re-sensitize the radioresistant glioma tumors.
Citation Format: Ming Fan, Yan Shi, Jian Jian Li. Mitochondrial metabolism and phosphorylation of Stat3 in radioresistant cancer stem cells isolated from glioma U87 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 444. doi:10.1158/1538-7445.AM2013-444
Abstract 4443: Small cell transformation of lung adenocarcinoma in acquired resistance to EGFR-TKI.
Authors: So Kwang Sup , Choi Yun Jung , Kim Sun Ye , Choi Chang-Min , Lee Jae Cheol , Kim Woo Sung , Rho Jin Kyung 
Published: August 2014

Abstract
Small cell transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistant mechanisms. We evaluated whether such phenomenon can be found in the cell line model. In addition, its effect on response to conventional chemotherapeutic drugs for small cell lung cancer treatment was investigated. We established resistant cells to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines. Among them, two resistant cells, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expression of CD56 while increased synaptophysin was found in A549/GR in Western blotting, suggesting that small cell transformation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, most commonly using drugs for treatment of small cell lung cancer, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A459 cells, which also made them more sensitive to etoposide and cisplatin. Further, we found a patient showing increased expression of CD56 and synaptophysin after development of resistance to erlotinib. In conclusion, small cell transformation of lung adenocarcinoma can occur during EGFR-TKI treatment leading to resistance.
Citation Format: Kwang Sup So, Yun Jung Choi, Sun Ye Kim, Chang-Min Choi, Jae Cheol Lee, Woo Sung Kim, Jin Kyung Rho. Small cell transformation of lung adenocarcinoma in acquired resistance to EGFR-TKI. [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 4443. doi:10.1158/1538-7445.AM2013-4443
Abstract 4446: Activation of HER Family signaling as a mechanism of acquired resistance to ALK Inhibitors in EML4-ALK-positive Non-Small Cell Lung Cancer.
Authors: Tanizaki Junko , Okamoto Isamu , Okabe Takafumi , Sakai Kazuko , Tanaka Kaoru , Hayashi Hidetoshi , Kaneda Hiroyasu , Takezawa Ken , Nishio Kazuto , Nakagawa Kazuhiko 
Published: August 2014

Abstract
Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown.
Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristic.
Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of the epidermal growth factor receptor (EGFR), HER2, and HER3 was up-regulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion.
Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK.
Citation Format: Junko Tanizaki, Isamu Okamoto, Takafumi Okabe, Kazuko Sakai, Kaoru Tanaka, Hidetoshi Hayashi, Hiroyasu Kaneda, Ken Takezawa, Kazuto Nishio, Kazuhiko Nakagawa. Activation of HER Family signaling as a mechanism of acquired resistance to ALK Inhibitors in EML4-ALK-positive Non-Small Cell 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 4446. doi:10.1158/1538-7445.AM2013-4446
Abstract 4449: Resistance to insulin-like growth factor 1 receptor antibody associated with downregulated IGFBP2.
Authors: Yu Yunkai , Kang Zhigang , Helman Lee , Meltzer Paul , Cao Liang 
Published: August 2014

Abstract
Agents targeting the insulin-like growth factor 1 receptor are in various stages of clinical development. Despite some initial response with single agent trials, the responses are limited and durations are short. It is important to understand the mechanics of innate and adaptive responses of the tumors that lead to resistance. An in vivo mouse model was used for the development of IGF1R antibody-resistant rhabdomyosarcoma tumor. All tumors, despite remarkable initial response, all eventually grow in the presence of the antibody. The isolated cell lines show cross-resistance to IGF1R antibodies, and are presented with increased AKT activity in the presence of an IGF1R antibody. Expression analysis indicates that IGFBP2 is the most affected gene in the IGF signaling process that is significantly down-regulated in two independently generated resistant lines. In addition, the recombinant IGFBP2 is capable of inhibiting of IGF1R phosphorylation and AKT signaling. Further, the inhibitory activity is amplified in the presence of an IGF1R antibody, against both sensitive and resistant RMS cells. Finally, the addition of antibodies against IGF1/2 or IGF2 enhances the activity of an IGF1R antibody against RMS cells. The findings suggest that IGFBP2 down-regulation may represent a novel mechanism to escape the blockage of IGF1R signaling by a therapeutic antibody.
Citation Format: Yunkai Yu, Zhigang Kang, Lee Helman, Paul Meltzer, Liang Cao. Resistance to insulin-like growth factor 1 receptor antibody associated with downregulated IGFBP2. [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 4449. doi:10.1158/1538-7445.AM2013-4449