bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 66: Pharmacologic tobacco cessation agents and response to radiotherapy.
Authors: Sobus Samantha L. , Romano Michelle A. , Mackowiak Janelle , Pundt Krista , Warren Graham W. 
Published: August 2014

Abstract
Purpose: Tobacco use is associated with poor therapeutic outcomes in cancer patients in part due to decreased therapeutic response to conventional cancer treatment such as chemotherapy and/or radiotherapy (RT). Tobacco cessation is warranted to improve cancer treatment outcomes, but preclinical data suggest that nicotine may decrease the biologic effectiveness of cancer treatment. The purpose of this study is to evaluate if nicotinic acetylcholine receptor (nAChR) and non-nAChR based tobacco cessation pharmacotherapy agents alter response to radiotherapy.
Methods: Human lung cancer (A549, H460) and oropharyngeal cancer (FaDu) cell lines were treated with nicotine, a7-nAChR agonists, varenicline, or bupropion alone or in combination with RT. Mice xenografts were used to assess the effect of nicotine administration during RT. Cell survival and downstream activation of radioprotective pathways (Akt, ERK, mTOR, MMP, and hypoxia inducible factor 1-alpha [HIF-1a]) were analyzed.
Results: Nicotine administration increased survival in all cell lines. Similarly, administration of the selective a7-nAChR agonists LY 2087101 and PHA 54613 was also found to increase cell survival with RT. Nicotine, LY 2087101, and PHA 54613 were all found to activate p-ERK 1/2, p-AKT (Ser-473), mTOR (S2448), and hypoxia inducible factor 1-alpha (HIF-1a) in a dose and time dependent manner. Tumor xenografts receiving nicotine administration during RT showed evidence of increased tumor regrowth in comparison non-nicotine treated controls. Treatment with varenicline also increased cell survival following RT at doses lower than with nicotine treatment; however, treatment with bupropion (an FDA approved non-nAChR based tobacco cessation agent) did not increase cell survival and exhibited a moderate cytotoxic effect following RT at high doses. Dose escalated bupropion did not increase activation of radioprotective pathways.
Conclusions: These are the first data to suggest that bupropion may be an ideal FDA approved tobacco cessation agent in cancer patients to prevent potential biologic changes in therapeutic response associated with nAChR based cessation strategies.
Citation Format: Samantha L. Sobus, Michelle A. Romano, Janelle Mackowiak, Krista Pundt, Graham W. Warren. Pharmacologic tobacco cessation agents and response to radiotherapy. [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 66. doi:10.1158/1538-7445.AM2013-66
Abstract 666: Validation of nucleolar protein 4 as a novel methylated tumor suppressor gene in head and neck cancer.
Authors: Demokan Semra , Chuang Alice Y. , Pattani Kavita M. , Sidransky David , Koch Wayne , Califano Joseph A. 
Published: August 2014

Abstract
Purpose: Methylation of CpG islands in the promoter region of genes acts as a significant mechanism of epigenetic gene silencing in head and neck cancer. In this study, we assessed the utility of epigenetic alterations of a panel of twelve genes (NOL4, IRX1, SLC5A8, LRRC3B, FUSSEL18, EBF3, GBX2, HMX2, SEPT9, ALX3, SOCS3, LHX6) previously reported.
Experimental Design: In this study we investigated methylation of the 12 gene promoters via a candidate gene approach. After the initial screening of methylated CpG islands on the promoter regions by bisulfite sequencing using salivary rinse samples, only two genes had methylated CpG dinucleotides on their promoter regions in tumor samples and absence of methylated CpGs were found in normal salivary rinse samples after bisulfite modification and bisulfite sequencing. We then performed quantitative methylation specific PCR (Q-MSP) on 16 salivary rinse and 14 normal mucosal samples from healthy people and 33 HNSCC tumor samples for two genes selected.
Results: After validation with QMSP, one gene, nucleolar protein 4 (NOL4), was highly methylated (91%) in tumor samples and unmethylated in normal salivary rinse samples and minimally methylated in normal mucosal samples demonstrating cancer specific methylation in HNSCC tissues. Although iroquois homeobox 1 (IRX1) gene was observed as methylated in normal mucosal and salivary rinse samples, indeed, the methylation values of these normal samples were very low (less than 10%).
Conclusions: We identified NOL4, as a highly specific promoter methylated gene was associated with HNSCC. IRX1 which may have a potential as a biomarker for HNSCC and should also be assessed in a larger cohort.
Citation Format: Semra Demokan, Alice Y. Chuang, Kavita M. Pattani, David Sidransky, Wayne Koch, Joseph A. Califano. Validation of nucleolar protein 4 as a novel methylated tumor suppressor gene in head and neck 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 666. doi:10.1158/1538-7445.AM2013-666
Abstract 700: Gene expression profiling of cyclin-dependent kinase (CDK) inhibition in cancer cells.
Authors: Ottaviani Silvia , Delaney Sean , Patel Hetal , Periyasamy Manikandan , Bondke Alexander , Slafer Brian , Starkey Richard , Kroll Sebastian H.B. , Fuchter Matthew J. , Barrett Anthony G.M. , Coombes R. Charles , Ali Simak 
Published: August 2014

Abstract
Cyclin-dependent kinases (CDKs) form complexes with partner cyclins to regulate cell cycle progression and transcription. CDK1, CDK2, CDK4 and CDK6 all regulate cell cycle progression and CDK8 and CDK9 are regulators of transcription. CDK7 is a unique member of this family because it can regulate the cell cycle CDKs as part of the CDK-activating kinase (CAK) and also transcription in conjunction with the TFIIH transcription factor by phosphorylating the COOH-terminal domain of RNA polymerase II (Pol II CTD). A hallmark of cancer is deregulated cell cycle progression and many cancers have abnormal CDK activity which makes CDKs a good target for cancer therapy. Here we show BS-194, a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7 and CDK9 (IC50 = 3, 30, 30, 250 and 90nmol/L, respectively). In vitro cell based assays have shown that BS-194 inhibits the phosphorylation of CDK substrates, Rb and RNA Poll II, down regulation of cyclins A, E and D1 and cell cycle arrest in the S and G2/M phases. BS-194 also has potent anti-proliferative activity in 60 cancer cell lines tested (mean GI50 = 28nmol/L). BS-194 is orally bioavailable and shows potent in vivo tumour growth inhibition of xenograft models of MCF7 and HCT116 cells.
We have used BS-194 as a potent inhibitor of CDK activity in HCT116 cells and performed gene microarray analysis to determine novel pathways and identify novel biomarkers associated with CDK inhibition. In summary, the gene microarray has identified genes differentially expressed in response to BS-194 treatment that are primarily involved in cell cycle, apoptosis and transcription pathways.
Citation Format: Silvia Ottaviani, Sean Delaney, Hetal Patel, Manikandan Periyasamy, Alexander Bondke, Brian Slafer, Richard Starkey, Sebastian H.B. Kroll, Matthew J. Fuchter, Anthony G.M. Barrett, R. Charles Coombes, Simak Ali. Gene expression profiling of cyclin-dependent kinase (CDK) inhibition in cancer 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 700. doi:10.1158/1538-7445.AM2013-700
Abstract 702: Chinese Medicine formulation LQ inhibits FUCCI-expressing HeLa cells at the G0/G1 phase in 2D and 3D culture and invasion with Gelfoam® 3D culture.
Authors: Zhang Lei , Wu Chengyu , Yano Shuya , Hoffman Robert M. 
Published: August 2014

Abstract
Traditional Chinese Medicine formula LQ has previously demonstrated anti-tumor and anti-metastasis efficacy. Here, we used fluorescence ubiquitination-based cell cycle indicator (FUCCI) to monitor cell cycle arrest after LQ treatment. FUCCI-HeLa cells were cultured in two dimensional (2D) monolayer, 3D Matrigel®, and 3D Gelform®. Changes of cell cycle status after 24 hours LQ treatment (90mg/ml) were observed using the Olympus FV1000 confocal imaging system. Paclitaxel (Taxol) was used as the positive control which induced a G2/M block of cell cycle. LQ blocked FUCCI-HeLa cells in the G0/G1 phase of the cell cycle in all cultures. In monolayer culture, the control had approximately 45% of the cells in G2/M phase. In contrast, the LQ-treated cells were mostly in the G0/G1 phase (&gt;90%). In 3D dimensional culture (Matrigel®), cancer cells formed spheres. The colonies in control group had 40% of the cells in G2/M phase, but only 15% in LQ-treated culture. The cancer cells at the surface of the sphere were mostly in G2/M phase, and the cancer cells in the center of colonies were in G0/G1 phase. In 3D Gelform® culture, cells grew along the structures of the Gelform®. The control culture had approximately 45% of cells in G2/M phase. In contrast, the cells in LQ-treated culture were mostly in G0/G1 phase (&gt;80%). The cells in control group migrated to 250∼300 μm deep in the Gelfoam®, but only 150∼200 μm deep in LQ-treated culture. FUCCI-HeLa cells in different culture systems demonstrated the efficacy of LQ on the cell cycle and migration.
Citation Format: Lei Zhang, Chengyu Wu, Shuya Yano, Robert M. Hoffman. Chinese Medicine formulation LQ inhibits FUCCI-expressing HeLa cells at the G0/G1 phase in 2D and 3D culture and invasion with Gelfoam® 3D culture. [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 702. doi:10.1158/1538-7445.AM2013-702
Abstract 723: Anticancer ERK kinase inhibitor screening with molecular imaging.
Authors: Zhou Lanlan , Zhang Shengliang , Dicker David T. , Rehemtulla Alnawaz , El-Deiry Wafik S. 
Published: August 2014

Abstract
Extracellular signal-regulated kinase (ERK, also known as the 42-/44-kDa MAPK) signaling pathway controls cell growth, differentiation and survival. ERK is activated by dual phosphorylation on tyrosine and threonine residues (pERK) as a result of genetic alterations in key components of the ERK pathway or upstream activators, or in response to signals from a variety of cell surface receptors. This pro-survival pathway is often upregulated in tumors and is a target for cancer therapy. To screen for ERK inhibitors in small molecule library, an ERK reporter molecule was used to determine ERK kinase activity by measuring bioluminescence with a Xenogen IVIS Optical Imaging System. ERK kinase inhibition was confirmed with Western Blot for pERK to validate ERK reporter. Drug-like small molecule compound libraries NCI Approved Oncology Drug Set (total 2 Plates, 101 compounds) and NCI Diversity Set II (total 18 Plates, 1364 compounds) were screened with an ERK reporter expressing cell line BxPC3-MBP by using bioluminescent assay at different time points and different dosages. Then top 15 candidates were further tested for cell toxicity IC50, ERK kinase inhibition, EGFR kinase inhibition, and combinational treatment response with chemotherapy agents in normal cell MRC-5, colorectal cancer cell SW480, and non-small cell lung cancer cell H460 and Calu6. ERK kinase inhibitor candidate number 6 was found to inhibit ERK kinase activity in a dose-dependent manner and have relatively lower toxicity to normal cells than cancer cells. Clinical trials of Sorafenib (an established small molecular inhibitor of several Tyrosine protein kinases and Raf kinases) combined with Cisplatin and Etoposide on small cell lung cancer and non-small cell lung cancer showed not favorable so Etoposide was compared with its similar structure Teniposide in our combination treatment. Combinational treatments were tested here are ERK kinase inhibitor candidate/Sorafenib combined with Cisplatin and Etoposide/Teniposide. Our results demonstrated that comparing with Sorafenib, ERK kinase inhibitor candidate number 6 was more efficient in killing non-small cell lung cancer cells in combinational treatment with Teniposide and Cisplatin. This ERK kinase inhibitor candidate has shown considerable promise for further in vivo study and clinical development.
Citation Format: Lanlan Zhou, Shengliang Zhang, David T. Dicker, Alnawaz Rehemtulla, Wafik S. El-Deiry. Anticancer ERK kinase inhibitor screening with molecular imaging. [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 723. doi:10.1158/1538-7445.AM2013-723
Abstract 73: Preclinical evaluation of chemoradiation with cetuximab HPV-positive head and neck cancer suggests significant radiosensitization.
Authors: Smith Molly A. , Blitzer Grace C. , Torres Alexandra D. , Armstrong Eric A. , Lambert Paul F. , Harari Paul M. , Kimple Randall J. 
Published: August 2014

Abstract
PURPOSE: Whether cetuximab, a monoclonal antibody to the epidermal growth factor receptor, should be combined with radiation in patients with human papillomavirus (HPV) positive locally advanced head and neck cancer (HNC) is not known. Currently available data are inadequate to address this important therapeutic question. We sought to examine the ability of cetuximab to act as a radiosensitizer and to examine the mechanism of action of this combination in a model system of HPV+ HNC.
METHODS: Four cell lines (UD-SCC2, UM-SCC47, UPCI-SCC90, 93-VU-147T) validated for HPV expression were used for all assays. Subcutaneous flank xenografts were performed in Hsd:athymic Nude-Foxn1nu female mice treated with intraperitoneal cetuximab (0.2mg/mouse) or flank radiation (2 Gy/fraction) delivered twice weekly for 2 weeks. Time to tumor quadrupling from baseline was assessed by Kaplan-Meier method. Flow cytometry was used to assess apoptosis by Annexin V staining and cell cycle distribution by propidium iodide staining.
RESULTS: While there was minimal in vitro radiosensitization after treatment with cetuximab (similar to that seen in HPV-negative HNC), cetuximab + radiation resulted in a significant increase in time to tumor quadrupling compared to cetuximab alone (p=0.001) or radiation alone (p&lt;0.0001) in HPV+ HNC xenografts. Increased apoptosis was seen in cetuximab and radiation treated cells. Analysis of cell cycle distribution 24 hours after drug treatment showed that cetuximab induced a modest G1 cell cycle arrest when given prior to radiation, but that 24 hours after combined therapy, a significant G2 arrest was present.
CONCLUSIONS: Using HPV+ HNC cell lines, radiation and cetuximab appear to be beneficial compared to either treatment alone. This combination, currently undergoing study in randomized clinical trial is being further evaluated in a direct from patient tumorgraft model of HPV+ HNC to further understand predictors of response.
Citation Format: Molly A. Smith, Grace C. Blitzer, Alexandra D. Torres, Eric A. Armstrong, Paul F. Lambert, Paul M. Harari, Randall J. Kimple. Preclinical evaluation of chemoradiation with cetuximab HPV-positive head and neck cancer suggests significant radiosensitization. [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 73. doi:10.1158/1538-7445.AM2013-73
Abstract 731: In vivo fluorescence labeling of gastrointestinal stromal tumor (GIST) .
Authors: Metildi Cristina A. , Tang Chih-Min , Kaushal Sharmeela , Leonard Stephanie Y. , Magistri Paolo , Hoffman Robert M. , Bouvet Michael , Sicklick Jason K. 
Published: August 2014

Abstract
Gastrointestinal stromal tumor (GIST), the most common sarcoma, metastasizes hematogenously and peritoneally. Tumor-free margins and complete cytoreduction of metastatic disease are critical for decreasing recurrence. Since most GISTs overexpress KIT (c-KIT, CD117), we hypothesized that fluorescently labeled anti-KIT antibodies can improve detection of GIST. KIT K641E+/− transgenic mice that spontaneously develop cecal GIST, and wild-type C57BL/6 mice were used in this study. Wistar rat anti-mouse monoclonal c-KIT antibody was labeled with the AlexaFluor 488. The conjugated anti-KIT-Alexa 488 antibody (50-100 μg) was delivered via tail vein at 24 hours prior to standard staging laparoscopy. A pediatric laparoscopic grasper was inserted in the left lower quadrant for bowel mobilization in order to visualize the cecum. All 4 quadrants of the peritoneal cavity were examined systematically under both fluorescence and bright light. Post laparoscopy, mice were sacrificed and their abdomens exposed for Olympus OV-100 imaging. All tumors were resected and confirmed by H&E. We divided the mice into 4 groups. KIT K641E+/− mice received anti-KIT antibody (N=4) or control antibody (N=3). Wild-type mice received the same antibodies (N=3 per group). Fluorescence laparoscopy demonstrated a high tumor signal-to-background noise ratio. Upon whole body imaging used to detect gross tumors, there were 2 false positive and 0 false negative results, leading to an accuracy of 92%. The sensitivity, specificity, positive and negative predictive values were: 100%, 87%, 85%, and 100%, respectively. This method has several translatable applications: 1) identification of peritoneal metastases; 2) following disease response; 3) non-radioactive imaging; 4) endoscopic differentiation of gastric GISTs from leiomyomas or schwannomas; 5) laparoscopic staging; and 6) assessment of margin status.
Citation Format: Cristina A. Metildi, Chih-Min Tang, Sharmeela Kaushal, Stephanie Y. Leonard, Paolo Magistri, Robert M. Hoffman, Michael Bouvet, Jason K. Sicklick. In vivo fluorescence labeling of gastrointestinal stromal tumor (GIST) . [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 731. doi:10.1158/1538-7445.AM2013-731
Abstract 737: Multispectral Optoacoustic Tomography (MSOT) imaging and quantification of apoptosis in vivo.
Authors: Driessen Wouter H. , Burton Neal C. , Sardella Thomas , Morscher Stefan , Razansky Daniel , Ntziachristos Vasilis 
Published: August 2014

Abstract
Apoptosis is an important mechanism in cellular homeostasis and imbalances in the apoptotic process are associated with various disease states. An important example is the acquired ability of cancer cells to resist their own programmed cell death and therefore it is the aim of many tumor therapies to either reestablish pro-apoptotic signaling pathways or induce apoptosis through activation of existing mechanisms within the cell. Therefore, visualizing and quantifying the apoptotic process in vivo has great value in monitoring therapy response, diagnosis and staging disease.
By being able to detect subtle changes in perfusion and tissue oxygenation, the small animal Multispectral Optoacoustic Tomography (MSOT) scanner offers unprecedented performance in cross-sectional imaging of tumor heterogeneity as well as a powerful capacity to simultaneously image molecular processes such as apoptosis by utilizing novel molecular probes. In this study, apoptotic regions within a mouse mammary tumor where visualized using a dye-conjugated caspase probe and compared to the hypoxia status of each tumor region.
The temporal resolution of the MSOT small animal scanner (generation of multispectral cross-sectional data in less than 1 second) allows for the dynamic imaging of targeted and control probe simultaneously. To illustrate this point apoptosis probe was co-injected with a control dye with similar physical and chemical properties, but a different absorbance maximum after which the tumor region was imaged over 1 hour with multi-spectral image acquisition. Next, mice were imaged by MSOT immediately before and 24 hours post treatment with the chemotherapeutic Doxorubicin and the induction of apoptosis was visualized and quantified. Doxorubicin treatment led to a significant increase in signal resulting from the DyLight 747-conjugated apoptosis probe. In summary, MSOT can be used to determine the extent of apoptosis in tumors in vivo and thus has great value in monitoring therapy response, diagnosis and staging disease.
Citation Format: Wouter H. Driessen, Neal C. Burton, Thomas Sardella, Stefan Morscher, Daniel Razansky, Vasilis Ntziachristos. Multispectral Optoacoustic Tomography (MSOT) imaging and quantification of apoptosis 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 737. doi:10.1158/1538-7445.AM2013-737
Abstract 747: p53 activation through stress induction mediates differential regulation of target genes.
Authors: Mittal Shilpi , Kadamb Rama , Bansal Nidhi , Saluja Daman 
Published: August 2014

Abstract
p53 is a sequence specific transcription factor that gets up regulated in response to stress such as DNA damage, microtubule disruption or oxidative stress. p53 protein gets stabilized upon stress induction and functions by activating and repressing large number of downstream genes involved in varying functions like cell cycle, DNA repair, apoptosis or senescence depending upon type of stress. Gene activation and repression is crucial for p53 to perform its functions in the cell. p53 mediates its activation functions through its ability to bind to cis-acting DNA elements within regulatory regions. However, p53 regulates negative expression of genes either through direct recruitment on the promoter or through indirect mechanisms. Studies show that genotoxic as well as nongenotoxic stress leads to accumulation of p53 protein in cell, though the downstream effects vary under both conditions. The various cellular mechanisms that take place in the cell following DNA damage are well studied; however less is characterized about agents that disrupt microtubule assembly.
To put an insight into such differential regulation mechanism, we focused to study the difference in cellular fate upon genotoxic and non genotoxic stress. In the present study, we observed that two varying stresses that include DNA damage caused by bleomycin and microtubule disruption by colchicine mediate cell cycle arrest and increased levels of p53. At the gene level, it was observed that upon bleomycin treatment, Sin3/HDAC corepressor complex is docked onto the promoters of p53 target genes whereas colchicine treatment results in dissociation of Sin3/HDAC complex from the same promoters. Moreover, recruitment of Sin3/HDAC complex is reflective of downregulation of p53 target genes and dissociation of this complex from the promoter brings about transactivation of the same genes.
Therefore, our studies highlight that mere activation of p53 in varying kind of stress is not a decisive factor in gene regulation, rather interaction of p53 with corepressor or coactivator directs succeeding processes depending upon the type of stress.
Citation Format: Shilpi Mittal, Rama Kadamb, Nidhi Bansal, Daman Saluja. p53 activation through stress induction mediates differential regulation of target genes. [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 747. doi:10.1158/1538-7445.AM2013-747