bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 04: Caspase-8 is a novel candidate driver gene in head and neck squamous cell carcinoma
Authors: Uzunparmak Burak , Lindemann Antje , Frederick Mitchell J. , Myers Jeffrey N. , Pickering Curtis R. 
Published: December 2017

Abstract
Integrated genomic analysis of head and neck squamous cell carcinoma (HNSCC) has identified a heterogeneous spectrum of alterations dominated by tumor suppressor genes. An interesting new candidate driver gene is Caspase-8 (CASP8), which is mutated in 18% of oral cavity HPV-negative tumors. CASP8 is not obviously a part of any well-characterized driver pathway in HNSCC, and its role in this tumor type is unknown. In TCGA genomic data CAPS8 mutant tumors have a unique spectrum of alterations and expression changes, including a dramatic increase in markers of inflammation, which suggest they are a genomic subtype of HNSCC. CAPS8 is a key component of the extrinsic apoptotic pathway, but it also has a role in necrotic death, inflammation, and other pathways. We have characterized human and mouse CASP8 knock-out cell lines in vitro and in vivo in order to begin to understand the function of this gene in HNSCC. Loss of CASP8 function prevents extrinsic apoptosis and alters proliferation and tumorigenicity. It may also regulate the antitumor immune response. CASP8 is an exciting new candidate driver gene in HNSCC that may offer new opportunities for therapeutic intervention.
Citation Format: Burak Uzunparmak, Antje Lindemann, Mitchell J. Frederick, Jeffrey N. Myers, Curtis R. Pickering. Caspase-8 is a novel candidate driver gene in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 04.
Abstract 28: Identifying mechanisms of PD-L1 regulation in HNSCC
Authors: Mann Jacqueline E. , Ludwig Megan , Kulkarni Aditi , Hoesli Rebecca , Kafelghazal Judy , Nesvizhskii Alexey , Brenner J. Chad 
Published: December 2017

Abstract
Evidence of immunosuppression is frequently reported in head and neck squamous cell carcinoma (HNSCC). Thus, there has been growing interest in advancing therapies for HNSCC that relieving immunosuppression to permit anti-tumor immunity. The immune checkpoint inhibitor Pembrolizumab targets the coinhibitory PD-1/PD-L1 pathway, which serves to shield tumor cells from attack by cytotoxic T lymphocytes. While Pembrolizumab was recently approved for the treatment of metastatic and recurrent HNSCC, the initial trial reported overall response rates of only 18%. A more comprehensive understanding of the intrinsic and extrinsic mechanisms inducing PD-L1 expression on tumor cells may reveal therapeutic targets that improve response to immune modulation. We have employed a high-throughput genetic screen to identify targetable signaling pathways that may regulate PD-L1 expression in patients with specific genetic lesions. The Genome-scale CRISPR Knock-Out (GeCKO) library, established in multiple HNSCC cell lines, consists of a pool of stable knockouts targeting &gt;20,000 genes with representation of approximately 300 gRNAs per target gene. Sub-populations with enhanced or diminished expression of PD-L1 were sequenced to identify gRNA targets whose knockout causes a change in PD-L1 expression. We expect that by performing these screens across multiple cell lines with diverse genetic lesions, pathways consistently regulating PD-L1 expression will be revealed, and that targeting such pathways will provide novel avenues for modulating this immunosuppressive mechanism.
Citation Format: Jacqueline E. Mann, Megan Ludwig, Aditi Kulkarni, Rebecca Hoesli, Judy Kafelghazal, Alexey Nesvizhskii, J. Chad Brenner. Identifying mechanisms of PD-L1 regulation in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 28.
Abstract 30: Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC
Authors: Michmerhuizen Nicole L. , Leonard Elizabeth , Harris Micah , Foltin Susan K. , Kulkarni Aditi , Carey Thomas E. , Bradford Carol R. , Hui Jiang , Brenner J. Chad 
Published: December 2017

Abstract
Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated oncogenic pathway in this cancer type. Although activating mutations or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K) are frequently observed in HNSCC, monotherapies targeting PI3K have shown limited clinical efficacy. We tested a panel of more than 20 patient-derived oral cavity squamous cell carcinoma (OCSCC) cell lines, which were profiled by Nimblegen V3 exome sequencing. Despite PIK3CA copy number amplification and/or mutations, we observed resistance to PI3K inhibitors in these models. Of six inhibitors tested, the only agents with marginal effects were alpha-isoform selective and pan-PI3K agents; these inhibitors, despite on-target and downstream activity, did not cause an appreciable reduction in cell viability when administered at submicromolar concentrations. We hypothesized that other oncogenic pathways, such as the Ras-MEK-ERK pathway, might still be functional in the presence of PI3K inhibitors and serve as compensatory mechanisms of resistance to these drugs. In order to more fully characterize other novel co-dependent pathway in PI3K inhibitor resistant HNSCC models, we have developed a high-throughput screening approach that utilizes a resazurin cell viability assay. This approach is an unbiased means of testing ~1400 inhibitors as monotherapies and in combination with alpha-isoform selective PI3K inhibitor HS-173 and pan-PI3K inhibitor BKM120 and has been utilized in several in vitro models of OCSCC to date. Testing of additional cellular models and validation of “hits” from this screen, which are drugs that are effective in combination but not as monotherapies, may identify additional resistance mechanisms and are currently ongoing. Developing a better understanding of these combination therapies and the patients in which they might be most effective may lead to improved prognosis for this disease.
Citation Format: Nicole L. Michmerhuizen, Elizabeth Leonard, Micah Harris, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Jiang Hui, J. Chad Brenner. Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 30.
Abstract 48: Targeting IL-1 signaling to improve tumor response to erlotinib in HNSCC
Authors: Simons Andrean , Stanam Aditya , Koch Adam , Espinosa-Cotton Madelyn , Gibson-Corley Katherine 
Published: December 2017

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) including erlotinib have demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date compared to the EGFR monoclonal antibody cetuximab. Therefore we seek to identify molecular mechanisms involved in tumor response to erlotinib and ultimately improve the anti-tumor efficacy of erlotinib for HNSCC patients. We have shown that erlotinib-treated HNSCC cell lines induced the expression and secretion of a wide variety of genes involved in inflammation and immune response including interleukin-1 (IL-1) and interleukin-6 (IL-6) compared to control-treated cells. The secretion of IL-6 from HNSCC cells in response to erlotinib was found to be triggered by MyD88-dependent IL-1 signaling and suppression of IL-1 signaling (using a neutralizing IL-1α antibody) significantly enhanced the anti-tumor efficacy of erlotinib in vivo. In erlotinib-resistant HNSCC cell lines, IL-1 signaling was significantly upregulated compared to their respective parental cell lines. Blockade of IL-1 signaling using a neutralizing IL-1α antibody or an IL-1 receptor (IL-1R) antagonist was able to significantly suppress the growth of erlotinib-resistant HNSCC xenografts as a single agent and in combination with erlotinib which was associated with reduced immune cell recruitment and angiogenesis. Altogether, blockade of the IL-1 pathway may represent a novel strategy to improve tumor response to erlotinib and other EGFR TKIs in HNSCC patients.
Citation Format: Andrean Simons, Aditya Stanam, Adam Koch, Madelyn Espinosa-Cotton, Katherine Gibson-Corley. Targeting IL-1 signaling to improve tumor response to erlotinib in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 48.
Abstract 55: SET protein as a therapeutic target in head and neck squamous cell carcinoma
Authors: Goto Renata Nishida , Stringhetta-Padovani Karina , Vitek Michael , Curti Carlos , Leopoldino Andreia Machado 
Published: December 2017

Abstract
Introduction: The study of cancer molecular profiles allowed the development of several targeting agents, such as OP449 and FTY720/Fingolimod drugs, that can act as PP2A activators. OP449 is a synthetic peptide with antineoplastic action and FTY720 is a potent inhibitor of tumor growth and angiogenesis. SET/I2PP2A, a multifunctional protein, is a potent and specific inhibitor of PP2A and is upregulated in head and neck squamous cell carcinoma (HNSCC). SET has been proposed to be an oxidative stress sensor, promoting cell survival and apoptosis. Both OP449 and FTY720 bind to SET and destabilize SET/PP2A complex, reactivating the PP2A function.
Objectives: The aim was to evaluate the antitumoral effect, in vitro and in vivo, of the association OP449 plus FTY720, in HNSCC.
Material and Methods: HNSCC lineages were analyzed for SET protein status by Western blotting and for cancer stem cell population by using aldehyde dehydrogenase 1 (ALDH1) activity assay. Alterations in SET targets were confirmed by Western blotting. The cytotoxic effects of OP449 and/or FTY720, under different concentrations, were determined after 72 hours through the resazurin assay. The coefficient of drug interaction (CDI) was used to analyze the synergistic inhibitory effect of drug combination. Xenograft tumor model in Balb/c nude mice (n=5 per group), by subcutaneous injection of cells into the flank of the mouse, was used to investigate the antitumoral potential of treatment with OP449 and/or FTY720, every 48 h, for 15 days.
Results and Discussion: HN12 cells were selected due to the higher levels of SET and higher ALDH1 activity compared to other HNSCC cells. The treatment of HN12 cells with OP449 altered the levels of SET targets. A significant synergistic effect was observed when cells were pre-treated with 2 μM OP449 followed by 15 μM FTY720 (CDI=0.27 ± 0.088). Nude mice bearing HN12 human xenograft tumors treated with OP449 (5 mg/kg) and/or FTY720 (2 mg/kg) showed reduction in tumor growth compared to either control (vehicle) or compounds isolated.
Conclusion: Our results indicate that OP449 and FTY720 have a synergistic antitumoral effect, opening perspectives for either alternating or combined therapies in HNSCC, having SET protein as a target.
Financial support: FAPESP, CNPq and CAPES.
Citation Format: Renata Nishida Goto, Karina Stringhetta-Padovani, Michael Vitek, Carlos Curti, Andreia Machado Leopoldino. SET protein as a therapeutic target in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 55.
Abstract 66: c-Fos: A new player in promotion of cancer stem-like cell properties in head and neck squamous cell carcinoma
Authors: Ray Ratna B. 
Published: December 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. We have shown that c-Fos was highly up-regulated in the HNSCC sphere forming cells. However, upregulation of c-Fos for the biology of HNSCC-CSCs remains unknown. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.
We demonstrated that c-Fos overexpression enhanced the epithelial-mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2 and Notch1). Ectopic expression of c-Fos in HNSCC cells also display increased number of sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells. Knockdown of c-Fos in Cal27 cells impaired sphere formation. Next we examine the effect of c-Fos expression in vivo. For this, we established stable HNSCC cell line (MDA1386Tu cells) where c-Fos gene is ectopically expressed. Our results demonstrated that exogenous expression of c-Fos in non-tumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Further, subcutaneous transplantation of c-Fos overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared to parental cells. Taken together, our results strongly demonstrated a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells.
Collectively, our results offer that c-Fos may be a new target for developing therapeutic strategies against HNSCC.
Citation Format: Ratna B. Ray. c-Fos: A new player in promotion of cancer stem-like cell properties in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 66.
Abstract IA05: Immunoprevention of oral cancers
Authors: William William N. 
Published: December 2017

Abstract
Oral pre-malignant lesions (OPLs) are usually clinically characterized as leukoplakia or erythhroplakia, and confer an increased risk of oral cancer. Despite decades of clinical investigations with candidate chemopreventive agents such as 13-cis-retinoic acid, beta-carotene, fenretinide, green-tea extract, celecoxib, erlotinib, among others, a standard-of-care chemoprevention strategy for oral cancers has not yet been developed. Importantly, OPLs and oral cavity cancers are not related to HPV, thus HPV vaccines are not expected to be effective in this setting.
One of the greatest challenges in managing patients with OPLs is determining risk for malignant transformation and need for intervention. To that end, retrospective and prospective studies have been completed by our group and others and demonstrate that LOH profiles (primarily at 13p14 and/or 9p21) in OPLs are associated with higher incidence of oral cancers. LOH is now considered the most robust prognostic marker of cancer risk in this setting, and these data now set the stage for development of clinical trials focused on molecularly-defined high risk groups of OPLs.
Immune checkpoint blockade with antibodies directed at programmed cell death protein 1 (PD-1) has recently been successfully developed for the management of advanced head and neck squamous cell carcinomas, validating the importance of immune modulation in the progression of these invasive tumors. Given the favorable toxicity profile, there is interest in studying these agents for prevention of oral cancers in patients with high risk OPLs.
In this presentation, we will review the data that support a role for immune surveillance and immune editing in the development of oral cancers, and describe the rationale and clinical trial design of the Immunoprevention of Oral Cancer (IPOC) study, the first randomized trial to evaluate the PD-1 inhibitor pembrolizumab for oral cancer prevention in patients with molecularly-defined high-risk OPLs.
Citation Format: William N. William, Jr. Immunoprevention of oral cancers [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA05.
Abstract PR04: HER3 crosstalk with HPV16-E6E7 is a feedback resistance mechanism to PI3K-targeted therapies in head and neck cancer
Authors: Brand Toni M. , Hartmann Stefan , Bhola Neil E. , Li Hua , Zeng Yan , O'Keefe Rachel , Ranall Max V. , Bandyopadhyay Sourav , Soucheray Margaret , Swaney Danielle L. , Krogan Nevan , Kemp Carolyn , Duvvuri Umamaheswar , Johnson Daniel E. , Ozbun Michelle A. , Bauman Julie E. , Grandis Jennifer R. 
Published: December 2017

Abstract
Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinoma (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Accumulating evidence indicates that HPV oncoproteins can activate the Phosphoinositol-3-Kinase (PI3K) pathway, which contributes to transformation. Furthermore, PI3K is genomically activated by PIK3CA mutation or amplification in a disproportionately high number of HPV(+) tumors as compared to HPV(-) tumors. Based on this knowledge, we investigated the efficacy of PI3K-targeted therapies in preclinical models of HPV(+) HNSCC. Our results indicate that HPV(+) preclinical models were less sensitive to the PI3K inhibitors BYL719, BKM120, and BEZ235 as compared with HPV(-) models. Sensitivity of HPV(+) cell lines to PI3K inhibitors was increased upon knockdown of the E6 and E7 oncoproteins. Reciprocally, overexpression of E6 and E7 in HPV(-) cells rendered them resistant to PI3K-targeted therapies. Proteomic analyses indicated that treatment of HPV(+) cell lines and patient-derived xenografts (PDXs) with the PI3Kα inhibitor BYL719 induced expression of the receptor tyrosine kinase HER3, as well as E6 and E7. HER3 was found to regulate the abundance of E6 and E7 in the HPV(+) models. Targeting HER3 with siRNAs or the monoclonal antibody, KTN3379, blocked the increase in E6 and E7 protein levels following BYL719 treatment, and enhanced the efficacy of PI3K inhibitors in HPV(+) cell line and PDX models. Taken together, these results suggest that crosstalk between HER3 and HPV16-E6E7 can limit the efficacy of PI3K inhibitors, and that co-targeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.
This abstract is also being presented as Poster 67.
Citation Format: Toni M. Brand, Stefan Hartmann, Neil E. Bhola, Hua Li, Yan Zeng, Rachel O'Keefe, Max V. Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Danielle L. Swaney, Nevan Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Daniel E. Johnson, Michelle A. Ozbun, Julie E. Bauman, Jennifer R. Grandis. HER3 crosstalk with HPV16-E6E7 is a feedback resistance mechanism to PI3K-targeted therapies in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr PR04.
Epilepsy among Systemic Lupus Erythematosus Patients: Insights from a Large Database Analysis
Authors: Watad Abdulla , Tiosano Shmuel , Bragazzi Nicola Luigi , Brigo Francesco , Comaneshter Doron , Cohen Arnon D. , Amital Howard 
Published: December 2017

<b><i>Objective:</i></b> Epilepsy is characterized by a relevant epidemiological and clinical burden. In the extant literature, an increased risk of seizures has been described in several inflammatory/autoimmune disorders, including systemic lupus erythematosus (SLE). However, so far, relatively few and small size-based studies have been conducted. We aimed to investigate the link between seizure and SLE utilizing a large sample of subjects and extensive data analysis. <b><i>Methods:</i></b> Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of epilepsy in a cross-sectional study. Chi-square and <i>t</i> tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. <b><i>Results:</i></b> The study included 5,018 patients with SLE and 25,090 age- and gender-frequency-matched controls. The proportion of epilepsy was found significantly higher among SLE patients (4.03 vs. 0.87%, <i>p</i> &#x3c; 0.001). Using logistic regression, adjusting for multiple confounding factors, older age (≥70 years) resulted as negative predictor (OR 0.42 [95% CI 0.27–0.62], <i>p</i> &#x3c;0.001), whereas the presence of SLE was a positive predictor of epilepsy (OR 4.70 [95% CI 3.94–5.82], <i>p</i> &#x3c; 0.001). Interaction between SLE and elderly age resulted in high OR of 5.47 for epilepsy (95% CI 2.53–11.9). <b><i>Conclusion:</i></b> Our study confirms the higher prevalence of epilepsy in SLE patients. Physicians should be aware of such findings and have a lower threshold for suspecting epileptic seizures in these patients. Further studies are needed to better elucidate the mechanisms by which SLE favors the insurgence of seizures.
Toward a Surface Soil Moisture Product at High Spatiotemporal Resolution: Temporally Interpolated, Spatially Disaggregated SMOS Data
Authors: Malbéteau Y. , Merlin O. , Balsamo G. , Er-Raki S. , Khabba S. , Walker J. P. , Jarlan L. 
Published: December 2017

Abstract
High spatial and temporal resolution surface soil moisture is required for most hydrological and agricultural applications. The recently developed Disaggregation based on Physical and Theoretical Scale Change (DisPATCh) algorithm provides 1-km-resolution surface soil moisture by downscaling the 40-km Soil Moisture Ocean Salinity (SMOS) soil moisture using Moderate Resolution Imaging Spectroradiometer (MODIS) data. However, the temporal resolution of DisPATCh data is constrained by the temporal resolution of SMOS (a global coverage every 3 days) and further limited by gaps in MODIS images due to cloud cover. This paper proposes an approach to overcome these limitations based on the assimilation of the 1-km-resolution DisPATCh data into a simple dynamic soil model forced by (inaccurate) precipitation data. The performance of the approach was assessed using ground measurements of surface soil moisture in the Yanco area in Australia and the Tensift-Haouz region in Morocco during 2014. It was found that the analyzed daily 1-km-resolution surface soil moisture compared slightly better to in situ data for all sites than the original disaggregated soil moisture products. Over the entire year, assimilation increased the correlation coefficient between estimated soil moisture and ground measurements from 0.53 to 0.70, whereas the mean unbiased RMSE (ubRMSE) slightly decreased from 0.07 to 0.06 m3 m−3 compared to the open-loop force–restore model. The proposed assimilation scheme has significant potential for large-scale applications over semiarid areas, since the method is based on data available at the global scale together with a parsimonious land surface model.