bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 708: Overcoming the cisplatin resistance of HNSCC cells through Chk1/2 inhibition.
Authors: Gadhikar Mayur A. , Sciuto Maria Rita , Ortega Marcus Vinicus Alves , Pickering Curtis , Monroe Marcus , Osman Abdullah , Neskey David , Sturgis Erich M. , Myers Jeffrey N. , Frederick Mitchell J. 
Published: August 2014

Abstract
Despite the use of multimodality therapy employing cisplatin to treat patients with advanced stage head and neck squamous cell carcinoma (HNSCC), there is an unacceptably high rate of treatment failure. TP53 is the most commonly mutated gene in HNSCC, and the impact of p53 mutation on response to cisplatin treatment is poorly understood. Here we show unambiguously that wild type TP53 (wtp53) is associated with sensitivity of HNSCC cells to cisplatin treatment while mutation or loss of TP53 is associated with cisplatin resistance. We also demonstrate that senescence is the major mode of cell death that accounts for the cisplatin responses in wtp53 HNSCC cells and that cisplatin resistance in p53 null or mutant TP53 cells is due their resistance to senescence induction. Given the dependence on Chk1/2 kinases to mediate the DNA damage response in p53 deficient cells, there is potential to exploit this to therapeutic advantage through targeted inhibition of the Chk1/2 kinases. Treatment of p53 deficient HNSCC cells with the Chk inhibitor leads to sensitization to cisplatin treatment through the induction of mitotic cell death. Therefore, the most common genomic alteration in HNSCC, p53 mutation, can lead to a decreased therapeutic response to cisplatin that can be overcome using a synthetic lethal approach with Chk inhibition. These pre-clinical data provide evidence that a personalized approach to the treatment of HNSCC based on Chk inhibition in p53 mutant tumors may be feasible. The is the first report presenting unambiguous evidence that HNSCC cells respond to cisplatin in a p53 dependent manner. In addition, we clarify that in the presence of wtp53 the major mode of cell death in response to cisplatin in HNSCC cells is senescence, and not apoptosis. TP53 mutations have been identified in 60% of HNSCC cases and many of these patients’ tumors are resistant non-surgical treatment options. By showing dramatic sensitization to cisplatin through addition of Chk1/2 kinase inhibitor in cells with different HNSCC p53 mutations, we present a promising therapeutic approach that warrants further pre-clinical and clinical investigation.
Citation Format: Mayur A. Gadhikar, Maria Rita Sciuto, Marcus Vinicus Alves Ortega, Curtis Pickering, Marcus Monroe, Abdullah Osman, David Neskey, Erich M. Sturgis, Jeffrey N. Myers, Mitchell J. Frederick. Overcoming the cisplatin resistance of HNSCC cells through Chk1/2 inhibition. [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 708. doi:10.1158/1538-7445.AM2013-708
Abstract 718: Optical molecular imaging of HER1-positive cancer using near-infrared PEGylated indocyanine green-labeled panitumumab.
Authors: Zhou Yang , Kim Young-Seung , Milenic Diane E. , Baidoo Kwamena E. , Brechbiel Martin W. 
Published: August 2014

Abstract
Optical molecular imaging has attracted remarkable attention in recent years for cancer visualization and localization due to its characteristics of real-time, high sensitivity and specificity, cost-effectiveness and non-ionization. Indocyanine green (ICG) is the only clinically approved near-infrared fluorescent dye, and has been frequently employed to conjugate with antibodies or their fragments in the development of new cancer-targeted optical imaging agents. However, ICG molecules tend to form aggregates which cannot be removed by dialysis after antibody conjugation because of their high molecular weight. Previous data from our group has demonstrated that an amine-reactive PEGylated analogue of ICG (PEG-ICG) could successfully label an anti-HER1 antibody panitumumab with little aggregation compared with the non-PEGylated ICG. In this study, we present three higher equivalents (5×, 10×, and 20×) of PEG-ICG for panitumumab conjugation to yield ICG-PEG-panitumumab conjugates. Similar to previous studies, conjugation with PEG-ICG (5×) did not cause significant aggregates; whereas higher percentage of aggregates were observed for higher equivalents of PEG-ICG (∼10% and ∼20% for 10× and 20×, respectively). Collected PEG-ICG aggregates showed altered shape of absorbance spectra but not emission profile. In addition, the final molar ratios of ICG to panitumumab of the conjugates were 0.7, 2.3 and 6.0 for 5×, 10×, and 20×, respectively. Competitive radioimmunoassay demonstrated that the targeting moiety of the PEGylated bioconjugates was conserved. Fluorescence microscopy also demonstrated strong cellular binding and excellent fluorescent intensity of the bioconjugate (20×) in HER1-expressing A431 and SKOV3 cells. Comparatively, the conjugates with 5× and 10× PEG-ICG showed little or weaker fluorescent signal under the same exposure time. Hence, purified ICG-PEG-panitumumab bioconjugates are suitable candidates for the in vivo optical imaging of HER1-expressing tumors.
Citation Format: Yang Zhou, Young-Seung Kim, Diane E. Milenic, Kwamena E. Baidoo, Martin W. Brechbiel. Optical molecular imaging of HER1-positive cancer using near-infrared PEGylated indocyanine green-labeled panitumumab. [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 718. doi:10.1158/1538-7445.AM2013-718
Abstract 719: Accumulation of amino acids in metastatic foci of human colon cancer xenografts revealed by newly developed method for imaging mass spectrometry of amino acids.
Authors: Toue Sakino , Sugiura Yuki , Kubo Akiko , Ohmura Mitsuyo , Karakawa Sachise , Mizukoshi Toshimi , Yoneda Junya , Miyano Hiroshi , Noguchi Yasushi , Kobayashi Tsuyoshi , Kabe Yasuaki , Suematsu Makoto 
Published: August 2014

Abstract
MALDI imaging mass spectrometry (IMS) provides information about the spatial distribution of metabolites within thin slices of tissue, and has been used to elucidate complex phenotypes under various physiological conditions. Previously, our group reported distinct spatial distribution of a variety of metabolites in experimental model of hepatic micrometastasis of the solid tumor. However the metabolic properties in tumor and host tissues are not fully characterized, because of difficulty in visualizing most amino acids, due to their lower ionization efficiency.
Here, by using of p-N,N,N-trimethylammonioanily N’-hydroxysuccinimidyl carbamate iodide (TAHS) as a derivatizing reagent, we have successfully developed the method for the detection of various amino acids simultaneously by MALDI-MS on tissue section. We prepared liver section from hepatic metastasis model of human colon cancer, and then performed MALDI-IMS. To compare the signal intensities of amino acids among the different sections, we normalized the MALDI-IMS data with the quantified value of each amino acid obtained from capillary electrophoresis-mass spectrometry. The result indicated the amount of glycine, phenylalanine, leucine, glutamate, and glutamine were significantly elevated in metastatic foci compared to liver parenchyma. Other metabolites such as ATP and glutathione also accumulated in metastatic foci, and these results suggested that increased amino acid pool were required to maintain ATP and GSH levels in tumor.
In conclusion, we have demonstrated that novel imaging technique by using of IMS combined with on-tissue TAHS derivatization enables the visualization of amino acid distribution in tissue. The current method could be powerful tool to elucidate the mechanism for metabolic changes of cancer disease in vivo.
Citation Format: Sakino Toue, Yuki Sugiura, Akiko Kubo, Mitsuyo Ohmura, Sachise Karakawa, Toshimi Mizukoshi, Junya Yoneda, Hiroshi Miyano, Yasushi Noguchi, Tsuyoshi Kobayashi, Yasuaki Kabe, Makoto Suematsu. Accumulation of amino acids in metastatic foci of human colon cancer xenografts revealed by newly developed method for imaging mass spectrometry of amino acids. [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 719. doi:10.1158/1538-7445.AM2013-719
Abstract 720: A validation study on photoacoustics imaging of fluorescent pyroporphysome in vivo.
Authors: Lakshman Minalini , Bu James , Maeda Azusa , Zheng Gang , Needles Andrew , Theodoropoulos Catherine , Da Costa Ralph 
Published: August 2014

Abstract
Photoacoustics (PA) is a hybrid in vivo imaging modality that combines the temporal resolution of optics, and low acoustic scattering and high spatial resolution of micro-ultrasound. This innovation can discern optical absorption of endogenous and exogenous contrast agent(s) in the tumor micro-environment. This advancement is made possible by precise control of optical wavelength using a tunable pulsed laser, ranging from 680-970nm. In this study, we demonstrate fluorescent pyroporphysome, a nanoparticle, to be a photoacoustic contrast agent by which we can monitor its accumulation locally within the tumor.
Approach: Co-registered ultrasound (anatomical) and PA imaging of subcutaneous tumors was accomplished with a LZ250 21 MHz transducer on the Vevo® LAZR system (FUJIFILM VisualSonics, Inc.). Mammary tumors were generated by implanting from MDA-MB-231H2N cell line under the skin line. Pyroporphysomes (120 nm in size) were administered by tail vein at a dose of 300 nmoles. Multiwavelength photoacoustic scans were acquired and quantified over 24 hours using Vevo Spectro (FUJIFILM VisualSonics, Inc.), an ensuite absorbance spectrum quantification tool. Cri Maestro (Quorum Technologies, Inc.) was used for concurrent whole body fluorescence imaging.
Results: Multi-wavelength analyses identified an in vivo PA absorbance of 680 nm to pyroporphysome. Earliest detection was at 20 minutes post bolus in the tumor and PA signal for pyroporphysomes persisted at 24 h. Signal accumulation is supported by a 22 fold change in signal intensity per 3D volume (3.8% post bolus vs 87% at 24h). Fluorescence analyses validate this accumulation in the tumor. Taken together, photoacoustic imaging identifies pyroporphysome as a bimodal contrast agent. Additional evidence includes a shift in signal localization in the PA scans wherein pyroporphysomes were first detected at the tumor periphery (&lt;1mm below the skin line), and as deep as 2mm towards the tumor core at 24 hours. In conclusion, data herein presents photoacoustic imaging as the next generation imaging modality for concurrent molecular and anatomical information to better understand mechanistic changes in the tumor microenvironment.
Citation Format: Minalini Lakshman, James Bu, Azusa Maeda, Gang Zheng, Andrew Needles, Catherine Theodoropoulos, Ralph Da Costa. A validation study on photoacoustics imaging of fluorescent pyroporphysome in vivo. [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 720. doi:10.1158/1538-7445.AM2013-720
Abstract 74: Mitochondrial MKP1-mediated radioresistance in breast cancer stem cells.
Authors: Candas Demet , Chuang Frank , Fan Ming , Shen Rulong , Sweeney Colleen , Borowsky Alexander , Vaughan Andrew , Li Jian Jian 
Published: August 2014

Abstract
The overall cure rate of primary tumors has been significantly improved in the last three decades; however, metastatic and recurrent tumors with aggressive growth and therapy-resistance remain as the major factors shortening breast cancer patients’ survival. MKP1, a mitogen-activated protein kinase (MAPK) phosphatase, was shown to be linked with chemoresistance in breast cancer cells and was overexpressed in radioresistant breast cancer cells that survived long-term fractionated irradiation. Herein, we showed that MKP1 is present in the mitochondria and mitochondrial MKP1 levels are significantly enhanced in irradiated cells, suggesting that increased MKP1 translocation into the mitochondria may function to attenuate pro-apoptotic signals that were initiated from mitochondria-localized MAPK, c-Jun N-terminal kinase (JNK). We found that increased mitochondrial MKP1 levels correlated with the reduced level of phosphorylated active JNK in irradiated cells. Such mitochondrial MKP1-mediated dephosphorylation of JNK was predominantly enhanced in the radioresistant breast cancer cells that can be sensitized by siRNA-mediated inhibition of MKP1. Our results also demonstrated the involvement of extracellular regulated kinase (ERK) as the upstream signal for MKP1 mitochondrial translocation. The identification of cancer stem cells (CSCs) in all human tumors and their involvement in tumor radioresistance encouraged the studies investigating whether MKP1-mediated survival mechanism is present in radioresistant breast cancer cells. Here we showed that MKP1 is overexpressed in irradiated HER2-positive breast CSCs. These data provide critical insights on the aggressive phenotype of breast tumors and define novel diagnostic and therapeutic targets to re-sensitize resistant breast cancer stem cells.
Citation Format: Demet Candas, Frank Chuang, Ming Fan, Rulong Shen, Colleen Sweeney, Alexander Borowsky, Andrew Vaughan, Jian Jian Li. Mitochondrial MKP1-mediated radioresistance in breast cancer 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 74. doi:10.1158/1538-7445.AM2013-74
Abstract 748: Studying the significance of human p53-Sin3B interaction under the condition of DNA damage.
Authors: Kadamb Rama , Mittal Shilpi , Bansal Nidhi , Dwarakanath Bilikere Srinivasa Rao , Saluja Daman 
Published: August 2014

Abstract
Sin3, a global regulator of transcription plays an important role in mediating gene regulation, by binding to various transcription factors through its highly conserved Paired Amphipathic Helices (PAH) domains. Physical association of Sin3 corepressor molecule with human p53, a tumour suppressor protein is now well established. In response to stimuli that activate p53, cells can undergo repair processes, cell cycle arrest or apoptosis. In order to combat the stress, p53 gets activated by posttranslational stabilization and modulate the expression levels of its target genes. There are number of genes which are negatively regulated by p53, but the mechanism of repression is not well characterized. We hereby show that p53 interacts with Sin3/HDAC corepressor complex in-vivo and expression of Sin3B is up regulated in response to DNA damaging stimuli in p53 dependent manner. Increase in the levels of Sin3B upon different kind of DNA damage suggests that Sin3B might be an important protein involved in DNA damage pathway. Sin3/HDAC corepressor complex is recruited by p53 onto the promoters of its target genes, resulting in the down regulation of p53 target genes. In our study we propose that the mechanism of repression of p53 target genes is through recruitment of Sin3/HDAC corepressor complex which leads to context specific chromatin modification. Such modifications results in enrichment of epigenetic marks like H3K9me3, H3K27me3, which are marker of repression under condition of DNA damage induced by Bleomycin. Knockdown of Sin3B using shRNA causes derepression of p53 target genes, suggesting that Sin3B is a key player in p53 mediated transrepression. Based on our studies we propose that Sin3B is an important corepressor molecule recruited by p53 in response to DNA damage and Increased Sin3B expression is an early event in DNA damage induced by Bleomycin. We further provide evidence that p53 regulate its target genes, namely HSPA8, MAD1, CRYZ, ANLN and CDC25c through its interaction with Sin3/HDAC corepressor complex which leads to chromatin modification by recruiting proteins involved in epigenetic modifications.
Citation Format: Rama Kadamb, Shilpi Mittal, Nidhi Bansal, Bilikere Srinivasa Rao Dwarakanath, Daman Saluja. Studying the significance of human p53-Sin3B interaction under the condition of DNA damage. [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 748. doi:10.1158/1538-7445.AM2013-748
Abstract 764: Transient up-regulation of Myc in B-cell lymphomas enhances p53-independent apoptotic responses to chemotherapy.
Authors: Sotillo-Piñeiro Elena , Thomas-Tikhonenko Andrei 
Published: August 2014

Abstract
The c-MYC oncogene deregulation is a common trait in human cancers, with programmed cell death (or apoptosis) among Myc-regulated events. Myc is well-known to induce apoptosis in a p53-dependent manner, via the Myc→ARF ┤MDM2 ┤p53 pathway. We had previously shown that this pathway couldbe exploited to increase sensitivity to anti-cancer drugs. Specifically, small increases in Myc levels obtained by inhibiting Myc-targeting microRNA-34a resulted in enhanced apoptotic response of B-cells to bortezomib (Sotillo et al, Oncogene 2010). Because many Myc-driven tumors are defective for p53 activity, we sought to determine whether transient up-regulation of Myc also increases cell death in response to chemotherapeutic drugs in a p53-deficient background. For this purpose, we used B-lymphoma cells isolated from bone marrows of p53ER™ knock-in mice and subsequently transduced with a Myc-expressing retrovirus (Amaravadi et al, J Clin Inv 2007, Yu et al, Blood 2007). This inducible system allowed us to distinguish between p53-dependent (cells treated with tamoxifen) and independent (no tamoxifen added) cell death. Additionally, instead of modulating Myc levels through miRNA inhibitors, which currently have limited clinical utility, we increased Myc stability with a small molecule inhibitor of GSK3β, which promotes proteosomal degradation of Myc. We observed that the activation of p53 via the addition of tamoxifen is sufficient to induce robust apoptosis, with neither modulation of Myc levels nor additional treatment with doxorubicin being necessary. On the other hand, in the absence of active p53 doxorubicin was needed to kill Myc/p53ER™ cells, but cell killing was rather inefficient. Remarkably, pharmacological stabilization of Myc strongly enhanced p53-independent doxorubicin-induced apoptosis. This enhancement was accompanied by selective activation of pro-apoptotic genes BIM, BAX and BAK, but not PUMA or NOXA, suggesting that the response was indeed p53-independent. To validate this effect in a more relevant setting, we inhibited GSK3β in various Burkitt's lymphoma cell lines and achieved consistent up-regulation of Myc. Most importantly, even in p53mut Ramos cells, Myc stabilization resulted in sharply increased responses to doxorubicin. Our results suggest that transient up-regulation of Myc could be a viable adjuvant therapy even for tumors with p53 loss or MDM2 amplification.
Citation Format: Elena Sotillo-Piñeiro, Andrei Thomas-Tikhonenko. Transient up-regulation of Myc in B-cell lymphomas enhances p53-independent apoptotic responses to chemotherapy. [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 764. doi:10.1158/1538-7445.AM2013-764
Abstract 768: A role for c-Rel in ΔNp63α/v-RASHA-driven carcinogenesis?.
Authors: King Kathryn E. , Ponnamperuma Roshini M. , Park Sa Ra , Jay Steven , Ha Linan , Weinberg Wendy C. 
Published: August 2014

Abstract
The p63 isoform ΔNp63α is expressed in basal keratinocytes and overexpressed in human squamous cell carcinomas, but the mechanisms whereby this p53 homologue contributes to cancer pathogenesis have yet to be elucidated fully. In mimicking the overexpression of ΔNp63α observed in squamous cell carcinomas using transient adenoviral transduction of primary murine kerationcytes, we showed that overexpression of ΔNp63α inhibits Ca2+-mediated growth arrest and biochemical differentiation. We previously reported that this block in growth arrest is mediated via the NF-κB subunit, c-Rel, which accumulates in a phosphorylated form in the nucleus of ΔNp63α-overexpressing cells and physically associates in a phosphorylation-dependent manner with ΔNp63α. Consistent with the observed effects on growth regulation, ΔNp63α:c-Rel complexes bind to a p63 binding site on the cdk inhibitor p21WAF1. To explore the biological impact of long-term ΔNp63α overexpression in primary murine keratinocytes, lentiviruses were developed. Consistent with our transient adenoviral vector studies, keratinocytes expressing lenti-ΔNp63α have enhanced proliferation rates over 15 days in culture relative to lenti-GFP controls. Using a nude mouse grafting model that allows distinction between normal, benign, and malignant growths, we previously reported that lenti-GFP keratinocytes expressing oncogenic v-rasHa form well differentiated papillomas at the graft site, while keratinocytes expressing lenti-ΔNp63α in combination with v-rasHa form undifferentiated carcinomas. To expand this model system to study c-Rel we first confirmed that lentivirus-driven ΔNp63α overexpression results in sustained nuclear accumulation of the NF-kB subunit c-Rel, consistent with our observations using the adenovirally transduced cultures. In the lenti-ΔNp63α expressing cultures, enhancement of c-Rel is observed beginning at day 5 post-infection and is maintained through the latest time point tested, 14 days. Lentiviral c-Rel shRNAs have been developed to assess the contribution of altered nuclear c-Rel expression to ΔNp63α-mediated growth regulation in vitro and in vivo and have been successfully used to knockdown c-Rel to the latest time point tested, 28 days. Taken together, these data support a role for ΔNp63α in facilitating keratinocyte transformation and provide a model system for elucidating the contribution of NFkB/c-rel to ΔNp63α /v-rasHa-driven carcinogenesis.
Citation Format: Kathryn E. King, Roshini M. Ponnamperuma, Sa Ra Park, Steven Jay, Linan Ha, Wendy C. Weinberg. A role for c-Rel in ΔNp63α/v-RASHA-driven carcinogenesis?. [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 768. doi:10.1158/1538-7445.AM2013-768