bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1580: A novel C. elegans animal model for human RET receptor function.
Authors: Zelt Jordan D.S. , Chin-Sang Ian D. , Mulligan Lois M. 
Published: August 2014

Abstract
RET (Rearranged in Transfection) is a receptor tyrosine kinase mutated in the cancer syndrome multiple endocrine neoplasia 2 and linked to many other cancers, including medullary thyroid carcinoma and cancers of the adrenal gland. There are two distinct isoforms of RET, RET9 and RET51, with in vitro evidence indicating isoforms induce unique phosphorylation patterns on select tyrosine residues, possess different cell transforming and differentiation abilities, and bind/activate a unique set of substrates. However, these processes are challenging to dissect in complex organisms because both RET isoforms are ubiquitously co-expressed. We have generated a novel Caenorhabditis elegans model for RET expression to dissect the role of individual RET isoforms. C. elegans do not encompass a homologue of RET, thus we injected chimeric constructs in which human RET isoform sequences were fused to a N-terminal myristoylation signal for membrane targeting and expressed under the control of the C. elegans mechanosensory neuron-specific promoter, mec-4. The resultant transgenic animals were scored for phenotypes of RET-expressing neurons. We found that RET9 expressing animals have near WT phenotype, while RET51 expressing animals exhibited an axon termination phenotype where the PLM mechanosensory neuron of the tail fails to migrate to its correct location. This is indicative of early neuron terminal differentiation attributed to RET downstream signalling. Furthermore, strains harboring constitutively active oncogenic versions of RET9 or RET51 had severe PLM axon defects, with the RET51 phenotype being significantly more penetrant. Through generating strains with point mutations at select tyrosine residues and assessing the resulting phenotype, we have determined Y1062 and Y1096 to be main signalling hubs contributing to the RET-mediated phenotype in C. elegans. We are currently testing known kinase inhibitors, assessing efficacy and toxicity of potential RET inhibiting therapeutics. Using C. elegans as a platform to model RET is a quick and efficient system to gain insight on RET isoforms, delineate molecular events contributing to cancer progression, and investigate therapeutic agents that can be used to treat RET associated cancers.
Citation Format: Jordan D.S. Zelt, Ian D. Chin-Sang, Lois M. Mulligan. A novel C. elegans animal model for human RET receptor function. [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 1580. doi:10.1158/1538-7445.AM2013-1580
Abstract 1587: Loss of LZAP inactivates p53 in head and neck cancer and regulates sensitivity of cells to DNA damage in the p53-dependent manner.
Authors: Liu Dan , Issaeva Natalia , Yarbrough Wendell G. 
Published: August 2014

Abstract
We previously reported that tumor suppressor LZAP is lost in a portion of head and neck squamous cell carcinomas and that LZAP inhibits NF-kB, while activating p53 in ARF-dependent and -independent fashions. The ability of LZAP to regulate p53 in the absence of ARF has been largely unexplored. Here, we show that LZAP depletion diminished expression of mutant and wild-type p53 protein. LZAP activity toward p53 was independent of ARF and the known p53 regulators, Wip1 and HDM2. Loss of LZAP decreased p53 translation and destabilized p53 protein due, at least partially, to increased nucleolin expression. Knockdown of LZAP abrogated p53 stabilization induced by ionizing radiation, and LZAP depletion protected wild-type p53 cells from radiation or chemotherapeutic agents, while rendering cells expressing mutant or no p53 more sensitive. In human HNSCC, LZAP levels correlated with p53 levels, and remarkably, tumors with low LZ were less likely to have p53 mutations. These data suggest that loss of LZAP represents a novel mechanism of p53 inactivation in human cancer. Given these findings, inhibition of LZAP activity toward p53 for patients with tumors harboring p53 mutations may represent a therapeutic strategy to simultaneously sensitize tumors while protecting normal tissues from radiation or chemotherapy.
Citation Format: Dan Liu, Natalia Issaeva, Wendell G. Yarbrough. Loss of LZAP inactivates p53 in head and neck cancer and regulates sensitivity of cells to DNA damage in the p53-dependent manner. [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 1587. doi:10.1158/1538-7445.AM2013-1587
Abstract 1590: Sulfasalazine sensitizes glioblastoma cells to radiation treatment.
Authors: Sleire Linda , Skeie Bente S. , Netland Inger A. , Heggdal Jan , Pedersen Paal-Henning , Enger Per Ø. 
Published: August 2014

Abstract
Glioblastoma (GBM) is a lethal cancer with a limited response to ionizing radiation. Recent studies suggest that Sulfasalazine (SAS), a drug used to treat inflammatory bowel disease, inhibits the Xc− antiporter system in glioma cells, thereby blocking their uptake of cystein. Since the availability of cystein is a rate limiting step in intracellular antioxidant production, we wanted to investigate whether sulfasalazine sensitizes glioma cells to radiation.
Expression of xCT, the catalytic subunit of system Xc−, was found in 30 patient GBM biopsies. SAS effect on glioma cell growth was investigated using an electric cell substrate impedance sensing (ECIS) instrument. All glioma cell lines showed altered growth curves in response to SAS treatment. To assess the effect of blocking the antiporter, intracellular levels of the antioxidant glutathione were measured. With increasing doses of SAS, glutathione levels decreased in a dose response manner. In addition, cysteine was added to the medium to see if the toxic effects of SAS could be counteracted. Furthermore, accumulation of reactive oxygen species upon SAS treatment was measured. Glioma cells were also treated with escalating doses of SAS, alone or in combination with radiation (8 Gy). The presence of double stranded breaks increased markedly in the irradiated samples and also somewhat with increasing doses with SAS. In addition, cell death, viability and clonogenicity were investigated using live/dead staining, the MTS assay and the clonogenic assay.
All treatment groups exhibited increased rates of cell death compared to untreated controls. A combination of SAS and radiation resulted in higher levels of cell death, than radiation or SAS administered alone. Furthermore we continued with implantation of human GBMs into the brain of Nude rats. These animals were treated with Gamma Knife Radiosurgery alone or in combination with SAS. SAS were administered as a pre-treatment for three days before Radiosurgery. The rats receiving the combination treatment lived significantly longer compared to either treatment alone. Interestingly, the animals only receiving pre-treatment with SAS for three days lived significantly longer compared to the untreated controls, although this was not statistically significant. We are currently preparing a clinical trial for patients with GBM recurrences combining pre-treatment with Sulfasalazine and Gamma Knife Radiosurgery.
Citation Format: Linda Sleire, Bente S. Skeie, Inger A. Netland, Jan Heggdal, Paal-Henning Pedersen, Per Ø. Enger. Sulfasalazine sensitizes glioblastoma cells to radiation treatment. [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 1590. doi:10.1158/1538-7445.AM2013-1590
Abstract 1594: Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy.
Authors: Kumar Rajiv , Belz Jodi , Markovic Stacey , Jadhav Tej , Nguyen Paul , Niedre Mark , DAmico Anthony , Makrigiorgos Mike , Cormack Robert , Sridhar Srinivas 
Published: August 2014

Abstract
Systemic chemotherapy is often used with radiation therapy in the management of prostate, cervix and lung cancer patients, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure temporal and spatial properties of diffusion distributions around spacers coated with dye-loaded nanoparticles.
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with &gt;1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation 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 1594. doi:10.1158/1538-7445.AM2013-1594
Abstract 1597: C646, a selective small molecule inhibitor of p300, radiosensitizes cancer cells through enhancement of mitotic catastrophe.
Authors: Oike Takahiro , Komachi Mayumi , Ogiwara Hideaki , Yokota Jun , Nakano Takashi , Kohno Takashi 
Published: August 2014

Abstract
Background: The histone acetyltransferases (HATs) including p300, CBP and TIP60 are transcriptional co-activators implicated in many gene regulatory pathways and protein acetylation events. We have previously shown that siRNA-mediated ablation of p300 and CBP sensitized cancer cells to ionizing radiation (IR) (Ogiwara, Oncogene 2011), and that garcinol, curcumin and anacardic acid, natural compounds with multi-HATs inhibitory activity, had radiosensitizing effect in cancer cells (Oike, Int J Radiat Oncol Biol Phys 2012). However, radiosensitization by selective small molecule inhibitors targeting activity of a specific HAT, that can have much potential for clinical use, have not been well investigated. C646 is a selective small molecule inhibitor of p300 identified by structure-based and active site-directed in silico screening (Bowers, Chem Biol 2010). In this study, we investigated the in vitro effect of C646 on radiosensitization and cell death in human cancer cells.
Materials and Methods: The radiosensitizing effect in A549 (lung adenocarcinoma), H460 (lung squamous cell carcinoma) and H157 (lung large cell carcinoma) cells were assessed by colony formation assay, while that in MRC-5 (fibroblast) cells lacking in colony-forming ability was examined by ATP assay. Cell cycle distribution in A549 cells was analyzed using flow cytometry. The effect on mitotic catastrophe, apoptosis and senescence in A549 cells was evaluated by DAPI, annexin V and senescence-associated β-galactosidase staining, respectively. C646 was used at concentrations less than IC50.
Results: C646 radiosensitized A549, H460 and H157 cancer cells with dose enhancement ratio at 10% surviving fraction of 1.4, 1.2 and 1.2, respectively. Meanwhile, C646 unaffected the radiosensitivity of MRC-5 cells. Cell cycle analysis showed that the hyperploid cell population (&gt; 4N DNA cells) increased in C646-treated A549 cells after IR. Analyses of mode of cell death revealed that C646 enhanced mitotic catastrophe, but not apoptosis nor senescence, induced by IR in A549 cells.
Conclusion: These data indicate that C646 is a radiosensitizer which enhances mitotic catastrophe induced by IR.
Citation Format: Takahiro Oike, Mayumi Komachi, Hideaki Ogiwara, Jun Yokota, Takashi Nakano, Takashi Kohno. C646, a selective small molecule inhibitor of p300, radiosensitizes cancer cells through enhancement of mitotic catastrophe. [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 1597. doi:10.1158/1538-7445.AM2013-1597
Abstract 1606: Photochemical internalization (PCI): a novel technology for site-specific drug delivery.
Authors: Berg Kristian , Hopper Colin , Weyergang Anette , Selbo Pål K. , Høgset Anders 
Published: August 2014

Abstract
The utilization of macromolecules in therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. To achieve the expected biological effect of these macromolecules in many cases internalisation to the cell cytosol is crucial. At an intracellular level, the most fundamental obstruction for cytosolic delivery of therapeutic macromolecule is the membrane-barrier of the endocytic vesicles. Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces rupture of the endocytic vesicles and thereby release of the macromolecules into the cytosol. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides and the chemotherapeutic agent bleomycin. For clinical utilization a novel photosensitizer has been developed and evaluated for PCI of bleomycin. Preclinical results with this combination will be presented. Furthermore, a phase I/II dose-escalating clinical trial has been finalized and results from this trial will also be presented.
Citation Format: Kristian Berg, Colin Hopper, Anette Weyergang, Pål K. Selbo, Anders Høgset. Photochemical internalization (PCI): a novel technology for site-specific drug delivery. [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 1606. doi:10.1158/1538-7445.AM2013-1606
Abstract 1609: IRF1 regulates bevacizumab induced autophagy .
Authors: Liang Ji , Piao Yuji , de Groot John F. 
Published: August 2014

Abstract
Antiangiogenic therapy is commonly being used for the treatment of recurrent glioblastoma. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. Determining the mechanism of treatment failure of the VEGF monoclonal antibody bevacizumab for malignant glioma would provide insight into approaches to overcome therapeutic resistance. In this study, we observed up-regulation of autophagy marker expression and increased autophagosome formation after bevacizumab treatment. In order to determine genes regulating bevacizumab resistance, microarray gene expression analysis was performed on murine xenograft models of glioblastoma. Compared to control tumor tissues, we found increased transcriptional levels of STAT1/IRF1 signaling in bevacizumab resistant tumors, which were further confirmed by immunohistochemistry of bevacizumab treated tissue at the protein level. To determine whether IRF1 contributes to bevacizumab resistance, glioma stem cell lines with stable IRF1 down regulation were injected into the brains of nude mice. H&E staining of
6 week treated tumor tissues showed that bevacizumab markedly reduce tumor size in the shIRF1 group compared to the control shRNA group treated with bevacizumab. We also found a decrease in autophagy marker expression and increased TUNEL staining in shIRF1 cells. These data suggest that IRF1 may regulate bevacizumab-induced autophagy, and may be one important mediator of bevacizumab resistance.
Citation Format: Ji Liang, Yuji Piao, John F. de Groot. IRF1 regulates bevacizumab induced autophagy . [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 1609. doi:10.1158/1538-7445.AM2013-1609
Abstract 1611: Transcriptome analyses of the tumor cell line resistant to anti-VEGF therapy.
Authors: Li Dong , Xie Kun , Ding Guitao , Li Hongwen , Yao Xuejing , Jiang Cizhong , Fang Jianmin 
Published: August 2014

Abstract
Despite overt clinical success of anti-VEGF (vascular endothelial growth factor) agents, such as Avastin, for cancer patients, increasing evidence shows that prolonged treatment of anti-VEGF therapy results in tumor resistance. In order to understand how tumor cells become resistant to anti-VEGF therapy, we developed a mouse Lewis lung carcinoma (LLC) cell line, which was resistant to a potent VEGF blocker, VEGF-Trap. The cell line was established through five rounds of VEGF-Trap treatment and selection in vivo. In each round, C57BL/6 mice were inoculated with LLC cells and subjected to VEGF-Trap or PBS treatment. Tumors grown from treated mice were harvested and the isolated cells were injected to a new batch of mice for the next round of treatment. It was found that tumor cells became insensitive to VEGF-Trap in vivo after five rounds of VEGF-Trap treatment, i.e., VEGF-Trap no longer inhibited tumor growth. In contrast, VEGF-Trap remained efficacious to the LLC cells which underwent five passages in mice but treated with PBS. The resistance phenotype was maintained in LLC cells after the tumor cells were expanded for a number of passages in vitro, indicating that the resistance was due to inherited alterations in tumor cells. To gain insights into the molecular mechanism underlying the resistance to anti-VEGF therapy, we compared transcriptome profiles of the resistant and non-resistant tumor cells using mRNA-seq. The next generation sequencing reads were aligned to mouse genome; gene transcripts were assembled and calculated for relative abundance for individual gene. Results showed that 644 genes were differentially expressed with statistically significances, 317 up-regulated and 327 down-regulated in the resistant tumor cells. Interestingly, VEGF-C was significantly up-regulated in the resistant tumor cells (fold change = 4.91), which was further verified by real-time PCR analysis. Given the stimulatory effects of VEGF-C on both angiogenesis and lymphatic angiogenesis, it is possible that VEGF-C over-expression plays a role in the development of LLC tumor resistance to anti-VEGF therapy.
Citation Format: Dong Li, Kun Xie, Guitao Ding, Hongwen Li, Xuejing Yao, Cizhong Jiang, Jianmin Fang. Transcriptome analyses of the tumor cell line resistant to anti-VEGF 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 1611. doi:10.1158/1538-7445.AM2013-1611
Abstract 1612: Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab .
Authors: Piao Yuji , Liang Ji , Henry Verlene , Holmes Lindsay , de Groot John F. 
Published: August 2014

Abstract
Glioblastoma is the most common malignant brain tumor and is characterized by cellular heterogeneity, vascular proliferation and extensive tissue infiltration.
Analysis of gene expression data from orthotopic glioma stem cells with acquired resistance to bevacizumab therapy identified over expression of intercellular adhesion molecule 1 (ICAM1, CD54) in resistant tumors. ICAM1 is a cell adhesion glycoprotein of the immunoglobulin supergene family which interacts with β2 integrins, mediates leukocyte transendothelial migration and T cell activation during inflammatory processes.
ICAM1 over expression in tumors resistant to antiangiogenic therapy was validated by real time PCR and Western blot. In a panel of glioma stem cell lines, ICAM1 expression was higher in mesenchymal compared to proneural cell lines.
GFP-tagged ICAM1 shRNA lentivirus was used to knockdown ICAM1 in multiple cell lines. We injected shICAM1 NSC11 and scramble glioma stem cells into the brain of nude mice. Mice bearing tumors formed from shICAM1 NSC11 cells survived significantly longer than mice injected with scramble control cells. Tumor size was significantly decreased in mice bearing tumors formed from shICAM1 cells than that in mice bearing tumors from GFP-tagged NSC11 control cells. Knocking-down ICAM1 suppresses tumor invasion both in vitro and in vivo. We next examined the mechanism of ICAM1 over expression after treated with anti-VEGF therapy. We observed that ICAM1 over expression correlated with hypoxia-inducible factor by immnofluorescence analysis in tumor tissue. Furthermore, we found that ICAM1 protein expression was markedly increased after NSC11 and NSC17 cells under hypoxic condition in a time-dependent manner. Furthermore, hypoxia-induced p-STAT3 increased transcription of ICAM1, which was inhibited by an inhibitor of the JAK/STAT3 pathway.
Our studies identify ICAM1 as a potentially important mediator of tumor migration/invasion in glioblastoma. Targeting ICAM1 may provide a new strategy to prolong the efficacy of antiangiogenic therapy and prevent the invasive phenotype.
Citation Format: Yuji Piao, Ji Liang, Verlene Henry, Lindsay Holmes, John F. de Groot. Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab . [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 1612. doi:10.1158/1538-7445.AM2013-1612