bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2579: Identifying pathways that regulate the turnover of gain-of-function p53 mutant proteins in ovarian cancer cells
Authors: Padmanabhan Achuth , Candelaria Nicholes , Wong Kwong-Kwok , Nikolai Bryan C. , Lonard David , O'Malley Bert W. , Richards JoAnne S. 
Published: July 2017

Abstract
Ovarian cancer is the fifth leading cause for cancer-associated deaths among women in the US. High-grade serous ovarian carcinoma is the most common histological subtype and is characterized by frequent (&gt;90%) mutations in the TP53 (p53) gene. Gain-of-function (GOF) p53 mutant proteins form highly stable aggregates that accumulate in ovarian cancer cells and have been shown to have oncogenic activity. Increasing evidence indicates the stabilization of GOF p53 mutants to be important for tumor progression and drug resistance. Therefore, selective degradation of the GOF p53 mutant proteins is a highly attractive therapeutic strategy to specifically target ovarian cancer cells. We identified that a small molecule named MCB-613, originally discovered as a stimulator of steroid receptor coactivator-3 (SRC-3), causes rapid degradation of the usually stable p53R175H conformational mutant aggregates leading to catastrophic cell death in human ovarian cancer cell lines. Our results indicate this effect is independent of SRC-3 mediated gene expression, but rather by post-translational modification of p53 mutant protein. Upon MCB-613 treatment, the p53R175H mutant is rapidly exported from the nucleus, ubiquitinated and degraded through a lysosomal pathway. Interestingly, in contrast to its effect on the p53R175H mutant, MCB-613 causes a slight stabilization of wild type (WT) p53 but had less of an effect on the turnover of other frequently observed p53 mutants (R248Q and R273H) in human ovarian cancer cell lines. MCB-613 also causes a rapid decrease in MDM2 protein but not mRNA. Further, the effect of MCB-613 on p53R175H is phenocopied by multiple deubiquitinase (DUB) inhibitors, confirming the role of ubiquitination in the selective turnover of p53R175H mutant aggregates. Taken together, these results show that different pathways regulate the turnover of WT p53 and the specific GOF p53 mutant proteins. We are currently investigating the precise mechanism by which MCB-613 and the different DUB inhibitors induce selective turnover of p53R175H mutant protein. We anticipate the proposed work to significantly advance our understanding of pathways important in ovarian cancer progression and pave way for the development of new targeted therapies for ovarian cancer patients with specific p53 mutations. This work is funded by NIH-CA-181808, NIH-HD-07857 and NIH-HD-076596.
Citation Format: Achuth Padmanabhan, Nicholes Candelaria, Kwong-Kwok Wong, Bryan C. Nikolai, David Lonard, Bert W. O'Malley, JoAnne S. Richards. Identifying pathways that regulate the turnover of gain-of-function p53 mutant proteins in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2579. doi:10.1158/1538-7445.AM2017-2579
Abstract 2598: Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB)
Authors: Yin Taofei , Patterson Sara E. , Statz Cara M. , Lakshminarayana Anuradha , Durkin Daniel , Mockus Susan M. 
Published: July 2017

Abstract
In the era of personalized medicine, comprehensive cancer genomic databases represent critical tools for interpreting gene variants and their relevant therapies. As the number of cancer genomic databases grow, it is challenging for users to compare and assess the data integrity and validity of such databases. The lack of disclosure of curation processes makes it difficult to cross reference different databases. The JAX Clinical Knowledgebase (CKB) is a comprehensive relational database providing evidence-based information on gene variants, targeted therapies, efficacy evidence, and clinical trials. At the Jackson Laboratory for Genomic Medicine, we have developed a curation paradigm to ensure curation transparency and consistency of the JAX-CKB. First, to ensure standardization of nomenclature, we have integrated standard nomenclature and ontologies, including HGNC approved nomenclatures for genes, HGVS guidelines for variants, and the Disease Ontology for indications/tumor types. Second, we implemented decision matrices to maintain uniformity of our evaluation of scientific and clinical data. For example, evaluation of the effect of gene variants on protein function is solely based on changes in the intrinsic activity of the protein instead of downstream pathway activation or the effects on pathogenesis; the response type of gene variants to therapies are classified based on the evidence of targeting specificity; and the efficacy evidence are further classified as actionable, diagnostic, prognostic, risk factor, emerging, or not active centered on the response type and the strength of the evidence. Third, to provide convenient evaluation of the clinical relevance of efficacy data, we further developed a tier ranking system based on emerging consensus guidelines, which takes response type, evidence type, and approval status into consideration. Finally, all decision matrices are clearly outlined on the JAX-CKB open access website for users’ reference. In summary, we have curated a highly structured and semantically consistent cancer genomic database following a set of specific curation guidelines. As a result, JAX-CKB open access has become a valuable resource for both the clinical and research communities, and is utilized by numerous independent groups for variant interpretation.
Citation Format: Taofei Yin, Sara E. Patterson, Cara M. Statz, Anuradha Lakshminarayana, Daniel Durkin, Susan M. Mockus. Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2598. doi:10.1158/1538-7445.AM2017-2598
Abstract 2600: Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase
Authors: Patterson Sara E. , Statz Cara M. , Yin Taofei , Mockus Susan M. 
Published: July 2017

Abstract
Emergence of resistance to targeted therapies is a critical problem in cancer therapy, and understanding both the mechanisms of resistance and strategies for overcoming resistance are crucial to effective treatment of cancer patients. The JAX Clinical Knowledgebase (JAX-CKB), which incorporates data on therapeutic efficacy in the context of molecular alterations, enables rapid analysis of known therapy resistance mechanisms and current data surrounding strategies for overcoming resistance, both in the preclinical and clinical setting. Using the JAX-CKB, we have identified over 1250 lines of evidence corresponding to therapy resistance across tumor types. Of those lines, 147 correspond to therapy resistance in lung cancer. The JAX-CKB contains 22 variants in ALK associated with ALK therapy resistance. Within ALK fusion-positive lung cancer, evidence lines corresponding to ALK inhibitor resistance are associated primarily with complex molecular profiles containing secondary ALK mutations, and mechanisms for overcoming resistance in this setting were associated with use of novel agents. Within EGFR mutation positive lung cancer, lines associated with resistance to EGFR inhibitor therapy included copy number alterations, primary resistance mutations, secondary resistance mutations, and expression level changes. Strategies for overcoming resistance in these settings include novel agents and/or various combination therapies. The JAX-CKB provides a unique global view into current data on resistance to targeted therapies in oncology, which may enable more rapid assessment of effective therapy options and expose opportunities for additional research into strategies for overcoming resistance.
Citation Format: Sara E. Patterson, Cara M. Statz, Taofei Yin, Susan M. Mockus. Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2600. doi:10.1158/1538-7445.AM2017-2600
Abstract 2606: Accelerating clinical research using cloud technology
Authors: Apte Arun , Paul Shonali , Gade Aditi , Compton Carolyn 
Published: July 2017

Abstract
Introduction: Existing protocols for clinical trials are typically slow and error-prone due to lack of informatics tools for sharing and accessing clinical data in real time. There is an increasing pressure on clinical trial laboratories to change the way clinical research is performed so as to minimize costs and speed up R&D, which in turn will produce better and faster outcomes. Cloud-based technologies are emerging as one of the most viable options for streamlining the heavily regulated clinical research processes.
Description: Cloud-based software tools such as laboratory information management systems (LIMS) are much more capable than traditional paper-based or desktop tools for accelerating a clinical trial life cycle. Cloud-based LIMS enhance collaboration between sponsors and investigators, enabling more timely and accurate sharing of information with pharmaceutical companies.
Summary: Many sponsors are now adopting cloud-based LIMS for conducting clinical trials. The onus is on service providers to keep pace with the demands of the industry, comply with the regulatory framework and at the same time deliver value to CROs and testing labs by reducing costs and maintaining efficiency.
Conclusion: CloudLIMS.com has developed a cloud based software called CloudLIMS Lite for managing clinical research workflows to provide a cost effective solution to the clinical research industry. Being on the cloud, CloudLIMS Lite facilitates users to access and share data in real time, across multiple laboratories in different geographical locations and adhere to the regulatory framework. This in turn improves their operational efficiency. CloudLIMS Lite uses 256-bit AES encryption SSL protocol, thereby enabling secure data transmission. CloudLIMS Lite deploys a separate database layer for each of its customers making it impossible for any third party to view or access data.
Citation Format: Arun Apte, Shonali Paul, Aditi Gade, Carolyn Compton. Accelerating clinical research using cloud technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2017-2606
Abstract 2637: Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma
Authors: Tran Linda , Allen Clint T. , Park So-Jin , Xiao Roy , Waes Carter Van , Schmitt Nicole C. 
Published: July 2017

Abstract
Rationale: Cisplatin, which remains the most commonly used systemic drug for head and neck squamous cell carcinoma (HNSCC), reduces numbers of circulating immune cells. However, recent studies suggest that cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. We previously found that cisplatin increases expression of major histocompatibility (MHC) class I and programmed death ligand 1 (PD-L1) in HNSCC cell lines in vitro.
Methods: In the current study, we investigated other components of the antigen processing machinery (APM) by flow cytometry following treatment with cisplatin. Using the syngeneic mouse oral cancer 1 (MOC1) model of HNSCC, we then investigated the effects of cisplatin and anti-PD-1 antibody, alone or in combination, on tumor growth and survival.
Results: Using three different HNSCC cell lines, we found that levels of the APM components LMP2, ERp57 and calreticulin increased in all cell lines treated with cisplatin, whereas TAP1/2 increased dramatically only in one cisplatin-treated cell line with wildtype TP53 (UMSCC-74A). In MOC1 tumor-bearing mice, tumor growth was partially delayed by treatment with cisplatin and anti-PD-1 antibody alone and substantially delayed when these agents were given in combination, with resultant increased survival. Comparison of different treatment schedules suggested that concurrent administration is more effective than giving cisplatin one day prior to anti-PD-1 or giving anti-PD-1 one day prior to cisplatin.
Conclusions: Despite upregulating PD-L1 on tumor cells and decreasing levels of circulating immune cells, cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. While no mice were cured with concurrent cisplatin and anti-PD-1 antibody, tumor growth was substantially delayed. These results suggest a rationale for combining cisplatin and anti-PD-1 monoclonal antibodies, perhaps with radiation or other therapies, in additional preclinical studies and clinical trials of HNSCC.
Supported by NIDCD intramural project ZIA-DC-DC000090.
Citation Format: Linda Tran, Clint T. Allen, So-Jin Park, Roy Xiao, Carter Van Waes, Nicole C. Schmitt. Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2637. doi:10.1158/1538-7445.AM2017-2637
Abstract 2638: Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma
Authors: Lee Sung Yong , Shim Jae Kyeom , Oh Jee Youn , Min Kyung Hoon , Hur Gyu Young , Shim Jae Jeong , Kang Kyung Ho , Shin Bong Kyung , Lee Young Seok 
Published: July 2017

Abstract
Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) containing a component of spindle cell or giant cell. Because the prevalence of PSC is very rare, there is insufficient data about clinical feature, therapeutic strategy and prognosis.
Method: We reviewed the medical records of 26 patients diagnosed with PSC from January 2009 to June 2015, and analyzed the clincopathological characteristics, treatment modality and their outcome, and risk factors of overall survival (OS). Programmed death ligand 1 (PD-L1) expression was tested in 13 patients by using archival tissues (PD-L1 IHC 22C3 pharmDx assay).
Results: The median age of PSC patients was 69.5 years. 23 patients were male. 25 patients were current or former heavy smokers. Pleomorphic carcinoma was the most common subtype, and epidermal growth receptor mutation (EGFR) was positive in 2 of 11 patients who were tested. Among 13 patients tested for programmed death ligand 1 (PD-L1), eight showed PD-L1 high expression (tumor proportion score, TPS ≥ 50%). Four patients showed low expression (1% ≤ TPS ≤ 49%), and one patient showed no expression (TPS &lt; 1%). The median OS of all patients was 286 days. Age and the time from symptom onset to diagnosis were significantly associated with OS. PD-L1 expression showed the trend of positive prognostic value on OS in univariate analysis but was insignificant in multivariate analysis. 12 patients were treated with chemotherapy: 9 with platinum-based doublet therapy, 2 with tyrosine kinase inhibitor and 1 with docetaxel. 7 patients showed partial response or stable disease. The median OS and progression free survival of patients receiving chemotherapy were 260 days and 85 days, respectively.
Conclusions: It has poor prognosis compared with ordinary NSCLC. However, PSC patients showed comparatively fair response to chemotherapy and generally showed higher PD-L1 expression. Active treatment with cytotoxic chemotherapy, EGFR TKIs or immune checkpoint inhibitors are necessary to achieve a better results of PSC management.
Citation Format: Sung Yong Lee, Jae Kyeom Shim, Jee Youn Oh, Kyung Hoon Min, Gyu Young Hur, Jae Jeong Shim, Kyung Ho Kang, Bong Kyung Shin, Young Seok Lee. Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2638. doi:10.1158/1538-7445.AM2017-2638
Abstract 2654: Resveratrol and piceatannol synergistically induce PDL1 expression
Authors: Lucas Justin P. , Wu Joseph M. , Hsieh TzeChen , Darzynkiewicz Zbigniew , Halicka-Ambroziak Halina Dorota 
Published: July 2017

Abstract
The interaction of programmed cell death-1 (PD-1) and its ligand programed cell death-1 ligand (PD-L1) is a major focus of recent immune oncology therapy efforts. The expression of PD-1 on T lymphocytes and its subsequent interaction with PD-L1, either from antigen presenting or tumor cells, will result in apoptosis-dependent inactivation of the T lymphocytes. This interaction plays an integral role in tumor immunology, specifically augmenting immune evasion. Relatively little is known about the regulation of PD-L1 in either the tumor or normal environment. We investigated the ability of natural dietary compounds to induce PD-L1 expression on normal epithelial cells and various cancer cell lines. These molecules have been evolutionary selected to control inflammation and cancer cell transformation and progression, understanding their mechanism of action could be important to understanding how this system works. Using flow cytometry and immunohistochemistry, we focused our studies on resveratrol and its metabolite piceatannol, key phytochemicals extracted from grapes, after an initial screen of various natural products. Experimental data showed that both compounds can individually up-regulate the expression of PD-L1 on tumor cell lines and normal epithelial cells, by an IFN-γ-independent mechanism. PD-L1 induction by both of these compounds was higher in tumor than in normal epithelium, suggesting greater significance in tumor regulation than inflammation. Additionally, the combination of resveratrol and piceatannol acted synergistically, leading to a significantly greater induction of PD-L1 expression across multiple tumor indications. Understanding whether resveratrol and piceatannol use a common signaling pathway to induce PD-L1 expression in tumor cells, was critical to understand the synergistic induction observed. Studies utilizing specific inhibition of IKK phosphorylation were accompanied by a significant reduction in the ability to induce PD-L1 expression on tumor cells, either as single agents or in combination. These results are consistent with the hypothesis that induction of PD-L1 by resveratrol or piceatannol, or their combination involves molecular determinants down-stream of NF-kB signaling.
Citation Format: Justin P. Lucas, Joseph M. Wu, TzeChen Hsieh, Zbigniew Darzynkiewicz, Halina Dorota Halicka-Ambroziak. Resveratrol and piceatannol synergistically induce PDL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2654. doi:10.1158/1538-7445.AM2017-2654
Abstract 2661: A broad approach for the selection of therapeutic mAbs to TNFR-superfamily members for use in combination with an anti-PD-1 mAb
Authors: Chen Cheng , Miao Xiaoniu , Yan Yao , Tang Liang , Chen Bingliang , Liu Junjian , Liu Xiaolin , Yu Michael , Tsun Andy 
Published: July 2017

Abstract
The rise of therapeutic antibodies directed towards T cell checkpoint inhibitors has paved the way to a novel and exciting frontier of cancer treatments. Spearheaded by anti-CTLA-4 and PD-1/PD-L1 inhibitors, many investigators have strived to uncover combinatory therapies that could synergize with CTLA-4 and PD-1 inhibitors to improve the overall survival of cancer patients. The TNFR-superfamily has been seen as an ideal combinatory target in providing co-stimulatory T cell signals in sync with the unleashing of T cells from their CTLA-4 and PD-1 brakes. The ideal outcome of these combinations is the induction of T cell memory and effector function towards tumour cells. Current clinical-stage agents against TNFR-superfamily targets include conventional or Fc-engineered therapeutic antibodies and multimeric ligands that aim to cluster and activate targets such as OX40, 4-1BB, GITR, and CD27. For OX40 and GITR, wildtype IgG1 variants offer target cell depletion of OX40/GITR-high expressing Treg cells, and also provide agonism through FcgR-mediated crosslinking. We have taken a broad approach of screening IgG1, IgG2, Fc-engineered and tetravalent antibodies to select for potent therapeutic antibody candidates to TNFR-superfamily targets, and conducted humanized mouse studies as a screen for candidate potency.
Citation Format: Cheng Chen, Xiaoniu Miao, Yao Yan, Liang Tang, Bingliang Chen, Junjian Liu, Xiaolin Liu, Michael Yu, Andy Tsun. A broad approach for the selection of therapeutic mAbs to TNFR-superfamily members for use in combination with an anti-PD-1 mAb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2661. doi:10.1158/1538-7445.AM2017-2661
Abstract 2662: Statins modulate MMP-9 and beta catenin in epithelial cells
Authors: Fazal Nadeem , Al-Ghoul Walid 
Published: July 2017

Abstract
The effect of statins (Simvastatins) mediated mechanisms that affect inflammatory or non-inflammatory pathways causing formation and progression of cancer need to be investigated. Currently, sufficient data are lacking to support the use of statins for the prevention of cancer and further research is clearly warranted. We studied these antineoplastic mechanisms in rodent inflammatory model, which might be instrumental in drug discovery research for the development of future cancer therapeutics. MMP9 is a member of the family of zinc-containing endopeptidases, which degrade various components of the extracellular matrix, thereby regulating matrix remodeling. Since matrix remodeling plays an important role during growth and progression of cancer and considering the fact that, tumor cells switch to aerobic glycolysis as its major energy source, this study was designed to analyze the effect of Statins on MMP9 and epithelial cell integrity at gastrointestinal gut barrier. We used an established model of thermal injury (TI) to study the effects of simvastatins. We found that the percentage of stained MMP-9 in the control tissue and TI+SMV tissue was lower than the percentage in thermal injury tissue (P&lt; 0.05). Moreover, fluorescent stained sections of intestinal epithelial from control, thermal injury and thermal injury+SMV. β-catenin determination was performed with fluorescence microscope. β-catenin levels were significantly (p&lt;0.05) decreased in thermal injury tissue, which was reversed by statins. Our studies conclude that statins have anti-neoplastic effects and affect metallopeptidases, β-catenin and e-cadherins.
Note: This abstract was not presented at the meeting.
Citation Format: Nadeem Fazal, Walid Al-Ghoul. Statins modulate MMP-9 and beta catenin in epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2662. doi:10.1158/1538-7445.AM2017-2662