bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1712: CAMKV as an immunotherapy target in MYCN-amplified neuroblastoma
Authors: Sussman Robyn T. , Huang Kevin , Raman Pichai , Maris John M. 
Published: August 2015

Abstract
Background: Neuroblastoma is an embryonal tumor of the developing sympathetic nervous system that accounts for 10-15% of pediatric cancer-related deaths. Although an intensive treatment regimen consisting of chemotherapy, surgery, radiation, immunotherapy and autologous stem cell transplant is used for patients with high-risk neuroblastoma, about half of these patients ultimately die. Reliable tumor-specific genomic biomarkers, such as MYCN amplification, have been identified for high-risk neuroblastoma and are used to stratify therapy. Recent clinical studies using immunotherapies to target cell surface molecules such as GD2 in neuroblastoma and CD19 in leukemia have shown impressive results, and have highlighted immunotherapy as a critical strategy in combating childhood cancer.
Methods: As part of the Stand Up 2 Cancer/St. Baldrick's Pediatric Cancer Dream Team's effort to streamline new immunotherapuetics into the clinic, we developed a computation approach to prioritize new targets for immunotherapy for high-risk neuroblastoma. Here we used MYCN as a biomarker for the most aggressive subset of neuroblastoma to define candidate cell-surface targets that are differentially expressed in MYCN-amplified neuroblastoma. We used RNAi to manipulate gene expression levels of MYCN to determine if these cell-surface targets are under the control of MYCN in neuroblastoma cells.
Results: The most significant differentially expressed cell surface molecule in high-risk neuroblastoma based on MYCN-amplification status was the calmodulin kinase-like vesicle-associated gene (CAMKV, p = 1×10-6), which encodes a protein that binds calmodulin in the presence of calcium, but lacks the kinase activity of other calmodulin kinase family members. We have confirmed that CAMKV protein is selectively expressed in MYCN-amplified neuroblastoma cell lines. From membrane fractionation and immunohistochemistry, we have verified that CAMKV is membranous in MYCN-amplified neuroblastoma cell lines and xeongraft tumors. Immunohistochemistry also revealed that CAMKV is not highly expressed in human pediatric normal tissues with the exception of neural tissues. Depletion of MYCN using RNAi resulted in a significant reduction in CAMKV RNA and protein expression (p = 2.3×10-6).
Conclusions: These results provide a template for the discovery and validation of immunotherapeutic targets in MYCN-amplified neuroblastoma and have the potential to lead to the development of a new immunotherapy targeting CAMKV.
Citation Format: Robyn T. Sussman, Kevin Huang, Pichai Raman, John M. Maris. CAMKV as an immunotherapy target in MYCN-amplified neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1712. doi:10.1158/1538-7445.AM2015-1712
Abstract 1714: The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer
Authors: Nam Ah-Rong , Kang Kyo Hwa , Park Ji Eun , Bang Ju-Hee , Jin Ling , Jin Mei Hua , Kim Tae Yong , Han Sae-Won , Song Sang-Hyun , Im Seock-Ah , Kim Tae-You , Oh Do-Youn , Bang Yung-Jue 
Published: August 2015

Abstract
Background: JAB1 (c-Jun activation domain binding protein-1) is a c-Jun coactivator, also known as COP9 signalosome subunit 5 (CSN5). Jab1 has an important role in cell proliferation and apoptosis. Overexpression of Jab1 is correlated with poor prognosis in various cancers. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. The role of Jab1 has not been studied in BTC. We investigated the role and mechanism of Jab1 as a potential therapeutic target in BTC.
Methods: We used 8 kinds of BTC cells and designed Jab1 siRNA. MTT assay and colony formation assay were done to determine growth inhibitory effect of Jab1 knockdown. Cell cycle analysis was done by FACS Calibur flow cytometer and cell migration was evaluated by wound healing assay. We used cycloheximide chase assay for measuring of protein half-life.
Results: BTC cell lines showed high level of Jab1 expression. Among them, SNU478, SNU869 and SNU 1196 were indicated with especially higher level of Jab1 expression. Cell growth and proliferation of BTC cells were decreased by Jab1 knockdown. Depletion of Jab1 induced G1 arrest, as well as decreased CyclinD/CyclinA and increased p27. Cell migration was also inhibited by Jab1 knockdown. Inhibition of Jab1 showed the decrease of pSrc, pAkt. Interestingly, depletion of Jab1 led to the elevation of PTEN protein levels without change of PTEN mRNA levels. PTEN half-life was longer in Jab1 siRNA-transfected cells. Suppression of Jab1 increased the sensitivity of BTC cells to the cytotoxic chemotherapeutic agent.
Conclusion: Suppression of Jab1 shows antitumor effects in BTC cells by inhibiting cell proliferation, migration, cell cycle and increase of chemosensitivity. Taken together, Jab1 might be a potential therapeutic target in BTC.
Citation Format: Ah-Rong Nam, Kyo Hwa Kang, Ji Eun Park, Ju-Hee Bang, Ling Jin, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1714. doi:10.1158/1538-7445.AM2015-1714
Abstract 1715: IRES-transactivating factors (ITAFs) as therapeutic targets in breast and colorectal cancer
Authors: Ward Toby M. , Bockhorn Jessica , Harrell J C. , Liu Xiaofei , Pegram Mark D. 
Published: August 2015

Abstract
Background: The majority of cellular mRNAs are translated in a cap-dependent manner, via ribosome assembly at 5′ methylguanosine caps followed by initiation at a nearby favorable AUG codon. Alternatively, internal ribosome entry sites (IRESs) facilitate translation in a cap-independent manner, particularly during cell stress, and have been identified in mRNAs encoding many canonical cellular oncogenes, including c-MYC, c-SRC, XIAP, Aurora-A kinase, and IGF1R. IRES trans-activating factors (ITAFs) are accessory proteins that augment or inhibit translation of client IRES-containing mRNAs, and were found to be upregulated in many cancer types including breast and colorectal cancers.
Methods and Results: Analysis of microarray datasets from cancer and normal tissue specimens (The Cancer Genome Atlas, METABRIC, and University of North Carolina datasets) revealed that expression of several ITAFs is upregulated in malignant tissues compared to normal controls. mRNAs encoding ITAFs were significantly upregulated (p &lt; 0.05) in cancer specimens, and ITAF protein levels were increased as measured by immunohistochemistry on tissue microarrays made up of malignant and healthy tissue specimens.
To investigate biological impact of ITAF silencing, gene knockdown was accomplished using pGIPZ and pTRIPZ lentiviral shRNA vectors. Silencing of ITAFs and concomitant reduction in protein levels (measured by western blot) led to significant proliferation impairment in MDA-MB-231, MCF7 and DLD1 cancer cells in 2-D culture (as measured by counting assays, p&lt;0.05) as well as in soft agar assays (p&lt; 0.05). In cancer cell lines, treatment with TNF-related apoptosis inducing ligand (TRAIL) led relocalization of ITAFs from cell nuclei to the endoplasmic reticulum (assayed by immunofluorescence), with increased translation of client IRES-harboring mRNAs encoding BAG-1 and c-MYC oncoproteins, despite impaired global cap-dependent translation.
Conclusions and future directions: Future experiments will include expanded investigation of protein-level ITAF expression in archival human specimens using immunohistochemistry, as well as investigation of the effects of ITAF silencing in cancer cell xenografts in immunocompromised mice. Based on their increased expression in malignant tissues and activity in translation of oncoproteins, cellular ITAF genes may represent novel therapeutic targets for intervention.
Citation Format: Toby M. Ward, Jessica Bockhorn, J C. Harrell, Xiaofei Liu, Mark D. Pegram. IRES-transactivating factors (ITAFs) as therapeutic targets in breast and colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1715. doi:10.1158/1538-7445.AM2015-1715
Abstract 1749: Bortezomib and JQ1 hold promise for human and canine osteosarcoma
Authors: Yang Yating , Yuzbasiyan-Gurkan Vilma 
Published: August 2015

Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor of both humans and dogs. Despite advances in treatment of other cancers, the clinical outcome of OS remains poor for the past decades. Therefore, there is a great need to identify novel and effective treatments for osteosarcoma. Several classes of novel small molecules with anti-tumor activities have become available in the last few years. Among these are tyrosine kinase inhibitors (TKIs) which are able to inhibit kinase activity of many receptor tyrosine kinases. Another class of molecules target bromodomains which modify chromatin and block transcription of key factors, another class of molecules target inhibition of the proteasome which induces cell death through various mechanisms. Previous findings from our lab identified two TKIs (sunitinib, sorafenib), a bromodomain inhibitor (JQ1), and a proteasome inhibitor (bortezomib) as having good growth inhibition effects in low concentrations on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS) in a series of drug screening assay. Among these candidates, we hypothesized that bortezomib and JQ1 would be effective against canine and human OS cell lines. We then determined the exact IC50 values of these two drugs, the concentration capable of inhibiting proliferation by 50%. The IC50 values of bortezomib varied in cells from 0.01 to 0.22 μM and JQ1 from 0.5 μM to 12.5 μM, which all within achievable plasma concentration and tolerable levels. In addition, these two drugs shown to decrease cell migration ability in wound healing assay as well as invasion ability in matrigel assay. With the promising results from in vitro studies, we further exam JQ1 as therapeutic strategy in an orthotopic tumor xenograft mouse model. However, the evaluation of JQ1 efficiency need to be evaluated before human and canine OS clinical trials.
Citation Format: Yating Yang, Vilma Yuzbasiyan-Gurkan. Bortezomib and JQ1 hold promise for human and canine osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1749. doi:10.1158/1538-7445.AM2015-1749
Abstract 1780: Targeted inactivation of CRL4-CDT2 E3 ubiquitin ligase as a novel therapeutic strategy for malignant melanoma
Authors: Benamar Mouadh , Guessous Fadila , Corbett Patrick , Slingluff Craig L. , Abbas Tarek 
Published: August 2015

Abstract
The CRL4CDT2 E3 ubiquitin ligase is emerging as a critical regulator cell cycle progression, primarily through the targeted ubiquitylation and degradation of critical cell cycle regulators including CDT1, p21 and SET8 via the 26S proteasome. CDT2, the substrate receptor of the CRL4CDT2 E3 ligase is overexpressed or amplified in several human malignancies, but its role in the development or progression of these cancers remains elusive. We show that CDT2 is overexpressed in primary and metastatic melanoma. Targeted depletion of CDT2 by si-RNA or its pharmacological inhibition by MLN4924, a selective NEDD8-activating enzyme (NAE) inhibitor, suppressed the proliferation of melanoma cancer cells in vitro and inhibited tumor growth of human melanoma xenografts in mice, irrespective of the BRAF mutation status. Inhibition of CRL4CDT2 in melanoma cells with various genetic backgrounds, but not in immortalized human melanocytes, resulted in robust p21- and SET8-dependent rereplication. These results identify the CRL4CDT2 E3 ubiquitin ligase as a promising new therapeutic target for cutaneous melanoma, and demonstrate the efficacy of MLN4924 as a promising anti-melanoma agent.
Citation Format: Mouadh Benamar, Fadila Guessous, Patrick Corbett, Craig L. Slingluff, Tarek Abbas. Targeted inactivation of CRL4-CDT2 E3 ubiquitin ligase as a novel therapeutic strategy for malignant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2015-1780
Abstract 1792: Radiation-induced downregulation of GLT-1 glutamate transporter mRNA expression is reversed by renin-angiotensin system inhibitors
Authors: Kooshki Mitra , Naczki Christine , Robbins Michael E. , Metheny-Barlow Linda J. 
Published: August 2015

Abstract
Fractionated partial or whole brain irradiation (fWBI) is often required to treat metastatic brain cancer. Unfortunately, fWBI can lead to the development of a progressive, irreversible cognitive impairment in patients who survive longer than six months following treatment. Prior studies suggest that neuroinflammation and alterations in neuronal plasticity may play a role in this treatment-related side effect. In the current study we determined that radiation-induced inflammatory activation of primary rat cortical astrocytes results in downregulation of mRNA and protein for the GLT-1 glutamate transporter, which functions to regulate glutamate signaling at excitatory synapses. Furthermore, we show that delivery of clinically-relevant fWBI (40Gy, 5Gy/fraction, 2x/week) to young adult male rats results in 51% decrease in Glt-1 mRNA in the cortex at 48 hours. Two months after completion of fWBI, cortical GLT-1 mRNA is further decreased to 25% the levels observed in sham controls, while at six months following fWBI GLT-1 levels remain 43% decreased compared to controls. We have previously identified two classes of compounds, the renin-angiotensin system inhibitors and PPAR agonists, which ameliorate the fWBI-induced cognitive impairment in this rodent model, although the full mechanisms by which these compounds protect cognition remain unknown. We found that dietary administration of the angiotensin receptor blocker L-158-809, but not the ACE inhibitor Ramipril, prevents fWBI-induced loss of cortical GLT-1 mRNA at 48 hours, while both cognition-sparing compounds restored GLT-1 expression at 2 months post-fWBI. Similarly, administration of the PPARδ agonist GW0742 prevented the fWBI-induced decrease of GLT-1 mRNA observed 6 months post-fWBI. Together these data suggest that radiation-induced downregulation of GLT-1 is a potential mechanism contributing to the development of radiation-induced brain injury, including cognitive impairment, and that GLT-1 may represent a druggable target to prevent this treatment-related cognitive decline. (Supported by NIH CA112593)
Citation Format: Mitra Kooshki, Christine Naczki, Michael E. Robbins, Linda J. Metheny-Barlow. Radiation-induced downregulation of GLT-1 glutamate transporter mRNA expression is reversed by renin-angiotensin system inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1792. doi:10.1158/1538-7445.AM2015-1792
Abstract 1805: DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT)
Authors: Nguyan Duc , Parekh Palak R. , Chang Elizabeth T. , Sharma Navesh , Carrier France 
Published: August 2015

Abstract
The most conventional therapy for solid tumors is radiotherapy. Still there is a challenge when it comes to managing highly disseminated gastrointestinal cancers because of the toxicity issues. Earlier, low dose fractionated radiotherapy (LDFRT) was considered to be ineffective for tumor removal, rather believed to cause cancer. There are few improvements with the use of novel approach in few cases of solid malignancy. This paradigm exploits the advantage of LDFRT with the combination of chemotherapy. Because now it's known that LDFRT causes hyper-radiosensitivity (HRS). The aim of our study is to determine the efficacy of LDFRT in combination with modified regimen of docetaxel, cisplatin and 5′-fluorouracil (mDCF) and their mechanism of action in gastric cancer cells. Our data indicate that consecutive three days radiation with daily fraction of 0.15 Gy produced HRS in gastric cancer cells and potentiated the effect of chemotherapeutic drugs (mDCF). Colony survival assays showed only 10% of gastric cancer cell survival when LDFRT was combined with mDCF while ten times higher dose (1.35 Gy) of radiation alone was required to achieve the same results. RT2-PCR profiler array analysis showed marked upregulation of dual oxidase-2 (DUOX2), an enzyme of NADPH- oxidase family, without inducing the genes involved in DNA repair. This was evident from 3.5 fold increase in reactive oxygen species (ROS) in cells exposed to LDFRT and mDCF. Further, this was confirmed by increase in cancer cell survival hence radioresistance with downregulation of DUOX2 expression. In addition to this inhibition of DUOX2 activity also abrogated the efficacy of the combination therapy. Taken together these data suggest that chemopotentiation by LDFRT in gastric cancer cells may be partly due to increased ROS production by DUOX2 without inducing the DNA repair machinery. These data thus provide a rationale for further explorations of potential clinical applications of LDFRT as a chemopotentiator for advanced and metastatic gastric cancers. (* = Equally Contributed)
Citation Format: Duc Nguyan, Palak R. Parekh, Elizabeth T. Chang, Navesh Sharma, France Carrier. DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1805. doi:10.1158/1538-7445.AM2015-1805
Abstract 1823: A novel web interface to facilitate pathology directed mass spectrometry
Authors: Seeley Erin H. , Dunkerley R. Ryan , Moreira Andre L. , Downey Robert J. , Kilby Greg W. 
Published: August 2015

Abstract
Clinical proteomics studies often involve multiple investigators located at different physical locations necessitating a centralized platform for joint access to data and other information pertinent to the study. To help communicate pathology targets of interests from remote researchers to the on-site technical team, the Pathology Directed Mass Spectrometry (PDMS) web application was developed. PDMS was designed to be a secure, online digital pathology platform specifically configured for down-stream mass spectrometry imaging (MSI) analysis. Hosting ultra-high resolution digital microscopy images of stained serial tissue sections, PDMS allows researchers to zoom into their samples to review and annotate specific areas for analysis. Once finalized, annotated images are exported from PDMS for MSI targeting. Built for HTML5 browsers, PDMS was deployed in a secure LAMP (Linux, Apache, MySQL, PHP) environment, utilizing a Javascript visualization engine and server-side conversion tools.
In a pathology directed mass spectrometry profiling experiment, two sections of a tissue specimen are collected, one on a mass spectrometry target and one that is stained for histological evaluation. A pathologist annotates a digital microscopy image to indicate areas of interest for mass spectral analysis. The annotated image is then merged with an image of the unstained section and after appropriate sample preparation, mass spectra are collected from the annotated areas. A major advantage to this type of analysis is that it is high throughput and is conducive to downstream biostatistical analysis for biomarker discovery.
The PDMS software has been successfully used in the molecular differentiation of histological patterns in stage I pulmonary carcinomas as part of a joint collaboration with Memorial Sloan Kettering Cancer Center. Image annotation was carried out remotely prior to mass spectral analysis in house. Statistical analyses of the mass spectral data resulted in over 85% classification accuracies in differentiating histological tumor subtypes within individual pulmonary carcinoma patient samples.
Citation Format: Erin H. Seeley, R. Ryan Dunkerley, Andre L. Moreira, Robert J. Downey, Greg W. Kilby. A novel web interface to facilitate pathology directed mass spectrometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2015-1823
Abstract 1832: Quantification of metabolic changes by magnetic resonance and mechanism of cell death in ovarian cancer
Authors: Belkacemi Louiza 
Published: August 2015

Abstract
Quantification of metabolic changes by magnetic resonance and mechanism of cell death in ovarian cancer Louiza Belkacemia*, Leila Maurmannb and Rathindra N Bosea
aDepartment of Biology and Biochemistry, University of Houston, Houston, TX 77204
bDepartment of Chemistry, Kansas State University, Manhattan, KS 6650
Ovarian cancer is the most frequent cause of death from gynecologic malignancy. Presently most ovarian cancers are diagnosed when the disease has progressed to stage III or IV. Therefore there is an urgent need for the identification of new biomarkers for early diagnosis and drug efficacy. Changes in metabolite concentrations have been associated with tumor regression or progression. Nuclear magnetic resonance (NMR) has been used to identify molecular markers during cell death (apoptosis), especially the onset of membrane disintegration. Cisplatin is the most commonly used drug in chemotherapy of ovarian cancer. To date, most research has been focused on the cisplatin-DNA reaction. Thus it is essential to evaluate the effect of cisplatin on binding to other biomolecules in the cell. Chinese hamster ovarian (CHO) cells, which, like resistant ovarian cancer cells, require high cisplatin concentrations to induce cell death, were treated with 50 μM cisplatin at different time intervals. Metabolite concentrations were determined by one and two dimensional 31P and 1H NMR. Moreover, the A2780 cisplatin-sensitive cell line and its resistant variant were evaluated for the mechanism of cell death. Analysis revealed that enhanced apoptosis was associated with significantly increased phosphocholine and glycerophosphocholine metabolites and marked elevation of cellular phosphocreatine and nucleoside triphosphate concentrations at 6 hrs and decreased thereafter. Plasma membrane alterations were paralleled by an upregulation of expression of Fas and related proapoptotic Bax and PUMA genes, and Fas and caspase-3 and -9 proteins. These findings suggest that NMR may be used as a tool to monitor tumors and drug efficacy in humans using for instance tissue biopsies. Further, NMR measurements of cell extracts may provide significant insight on pathways to apoptosis.
Citation Format: Louiza Belkacemi. Quantification of metabolic changes by magnetic resonance and mechanism of cell death in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1832. doi:10.1158/1538-7445.AM2015-1832