bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1393: Developing a next-generation noninvasive clinical test for non-small cell lung cancer
Authors: Kasbek Christopher , Song Yang , Quintanilha Danielle , Chen Si , Song QingXuan , Wang Tianjiao , Huang Jun T. 
Published: July 2016

Abstract
Significance: Non-Small Cell Lung Cancer (NSCLC) is responsible for the largest number of cancer-related fatalities, accounting for 22.8% of all cancer deaths in the United States in 2015. Targeted therapy precisely treats mutated cancer pathways and has significantly higher response rates compared to chemotherapy. However, tumor heterogeneity is prevalent in NSCLC patients, and the common practice of detecting mutations using tissue biopsy from a fraction of a single tumor can be less than satisfactory. Failure to detect molecular resistance emerging from heterogenic tumor cell population is a major reason that, even though highly effective, targeted therapy has not contributed greatly to prolong patient survival. We aim to develop a cost-effective, highly sensitive and specific liquid biopsy for advanced stage NSCLC patients that is able to capture a comprehensive tumor profile and monitor tumor response to therapy. Innovation: BEST (Blocker-based Enrichment System for Tumor DNA) blocks primer extension of over 90% of wild type DNA and allows preferential amplification of the mutant allele. BEST NSCLC liquid biopsy is highly sensitive (limit of detection of &gt; = 0.005%), comprehensive (detects 56 mutations in the EGFR, KRAS, BRAF, ALK, and ROS1 oncogenes), and rapid (estimated 4-day turnaround time). BEST is comprised of a multiplex of circulating tumor DNA enrichment reaction and a multiplex plasma cDNA enrichment reaction. Our BEST NSCLC liquid biopsy panel enriches &gt;100 fold for the above driver mutations. The ability to detect a myriad of mutations in heterogenic tumor cell populations allows dynamic and personalized treatment during the course of the disease. Summary: Our primary focus is to offer a test to detect actionable mutations and subsequently monitor tumor dynamics and the rise of molecular resistance. Our liquid biopsy will be also ideal for patients in follow-up visits in conjunction with the typical X-ray or CT image scans. Our test is also suitable for vulnerable patients from whom a solid biopsy cannot be obtained due to illness or inaccessibility.
Citation Format: Christopher Kasbek, Yang Song, Danielle Quintanilha, Si Chen, QingXuan Song, Tianjiao Wang, Jun T. Huang. Developing a next-generation noninvasive clinical test for non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1393.
Abstract 1476: A therapeutic antibody that inhibits CD73 activity by dual mechanisms
Authors: Barnhart Bryan C. , Sega Emanuela , Yamniuk Aaron , Hatcher Sandra , Lei Ming , Ghermazien Haben , Lewin Anne , Wang Xi-Tao , Huang Haichun , Zhang Pingping , Korman Alan 
Published: July 2016

Abstract
CD73 has a central role in dictating the adenosine concentration within the tumor as it is the final step in converting extracellular ATP to adenosine. Thus, substantial reduction of CD73 enzymatic activity has the potential to reduce immunosuppression of effector immune cells within the tumor. We present data describing an anti-human CD73 antibody that suppresses CD73 by two mechanisms: 1. direct inhibition of enzymatic activity upon binding to CD73 and 2. rapid, near-complete internalization of the enzyme. Durable reduction of cell-surface CD73 was observed in multiple tumor cell lines both in vitro and in vivo. The unique properties of this antibody are a result of the use of a human IgG2-IgG1 hybrid antibody with effector function eliminated by specific mutations of the Fc. The IgG2 sequence of this antibody drives superior internalization of CD73 and enhanced CD73 inhibition. Syngeneic tumor models demonstrate that CD73 contributes to resistance to anti-tumor therapy. Combination therapy with PD-1 blockade and a surrogate anti-mouse-CD73 antibody resulted in a better anti-tumor efficacy than either treatment alone. Finally, we demonstrate a novel technique for assessing CD73 enzymatic activity in situ that has potential for clinical application. These data support antibody-based anti-CD73 therapy in cancer and highlight a novel mechanism for inhibition of CD73 enzymatic activity.
Citation Format: Bryan C. Barnhart, Emanuela Sega, Aaron Yamniuk, Sandra Hatcher, Ming Lei, Haben Ghermazien, Anne Lewin, Xi-Tao Wang, Haichun Huang, Pingping Zhang, Alan Korman. A therapeutic antibody that inhibits CD73 activity by dual mechanisms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1476.
Abstract 1477: Targeting immunosuppressive myeloid cells in oral cavity cancer with the PI3Kδ/γ isoform inhibitor duvelisib
Authors: Davis Ruth , Moore Ellen , Clavijo Paul E. , Silvin Chris , Van Waes Carter , Chen Zhong , Allen Clint 
Published: July 2016

Abstract
BACKGROUND: IPI-145 (duvelisib) is an oral inhibitor of the p110δ/γ isoforms of phosphinositide 3-kinase (PI3K) that are differentially expressed in leukocytes. IPI-145 is currently under study in phase II/III trials for the treatment of hematologic malignancies, but has not previously been studied in solid tumors. In this study we sought to determine if p110δ/γ inhibition could suppress solid tumor growth through functional inhibition of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment of syngeneic murine oral cavity (MOC) tumor models of head and neck cancer.
METHODS: In pilot experiments, highly immunogenic MOC1 and poorly immunogenic MOC2 tumor-bearing mice were treated with daily oral doses of 15 mg/kg IPI-145 for 14 days and monitored for tumor progression. Flow cytometry was used to study cellular immune correlates in both the periphery and tumor microenvironment. MDSCs were sorted using FACS and functionally evaluated in a carboxyfluorescein succinimidyl ester (CFSE)-based T-cell proliferation assay.
RESULTS: Selective inhibition of p110δ/γ with low-dose IPI-145 resulted in a trend toward growth suppression of established MOC1 tumors, and had no effect on the growth of poorly immunogenic MOC2. IPI-145 increased infiltration and activation of CD8 T-lymphocytes and NK cells along with increased tumor cell expression of MHC class I and PD-L1 in MOC1 tumor bearing mice. MDSCs sorted from IPI-145 treated MOC1 tissues demonstrated a reduction in their capacity to suppress CD3/28 stimulated T-cell proliferation. MOC2 tumor bearing mice demonstrated no immune correlative changes.
CONCLUSION: Daily oral treatment with low-dose IPI-145 resulted in a trend toward inhibition of primary tumor growth and enhanced immune activation in the tumor microenvironment in an immunogenic murine model of head and neck cancer. This data shows promise for future studies of IPI-145 as a monotherapy at higher doses or as a sensitizer for immunotherapies such as checkpoint inhibitors, and these studies are underway.
This work was supported by the NIDCD Intramural Program ZIA-DC-000087-01
Citation Format: Ruth Davis, Ellen Moore, Paul E. Clavijo, Chris Silvin, Carter Van Waes, Zhong Chen, Clint Allen. Targeting immunosuppressive myeloid cells in oral cavity cancer with the PI3Kδ/γ isoform inhibitor duvelisib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1477.
Abstract 15: Metabolomic profiling of cell death in human lung cancer cells by a novel digitoxin analog
Authors: Kulkarni Yogesh , Azad Neelam , Kaushik Vivek , Yakisich Juan Sebastian , Venkatadri Rajkumar , Wright Clayton , Rojanasakul Yon , O’Doherty George , Iyer Anand Krishnan V 
Published: July 2016

Abstract
Background:
Digitoxin, a cardiac glycoside had shown considerable promise as an anti-cancer therapeutic. However, doses of digitoxin required to inhibit cancer cell proliferation lead to cardiotoxic side effects. We have previously shown that a novel analog of digitoxin, MonoD, activates apoptosis in human lung cancer cells at much lower concentrations as compared to digitoxin. We postulate that treatment with MonoD leads to distinct metabolic signatures on lung cancer cells as compared to digitoxin, which will help delineate the pathways that dictate MonoD action.
Experimental Approach:
NCI-H460 cells from identical passages were used for metabolite analysis using an optimized version of the methanol/water (80:20) protocol for metabolite extraction. The supernatant containing metabolites were suspended in 0.1% formic acid spiked with an internal standard for Q-Exactive analysis. The data was analyzed using SIEVETM 2.0 software with the component extraction algorithm that has been specifically designed for optimal data analysis in untargeted metabolomics experiments. Metabolites that were found to be significantly different between treatment groups were detected via Chemspider/HMDB database search.
Results:
We observed several metabolites along the prostaglandin synthesis pathway which were downregulated in MonoD treated lung cancer cells. Prostaglandins play a key role in the generation of the inflammatory response. Chronic inflammation has been shown to be a causative factor in a variety of cancers. Cyclooxygenase-2 (COX-2) derived prostaglandin has been previously shown to promote tumor growth by binding its receptors and activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Using the metabolite profiling data, we posited that COX-2, a key enzyme involved in prostaglandin synthesis, in addition to NFκB, a key transcription factor of proinflammatory signaling pathway are downregulated with MonoD treatment. Immunoblotting confirmed the downregulation of COX-2 and NFκB in MonoD-treated cells.
Conclusion: Using metabolite profiling, we have elucidated an important mode of action for MonoD in lung cancer cells, and shown that MonoD exerts its anti-tumorigenic properties by downregulating key factors involved in inflammatory response.
Citation Format: Yogesh Kulkarni, Neelam Azad, Vivek Kaushik, Juan Sebastian Yakisich, Rajkumar Venkatadri, Clayton Wright, Yon Rojanasakul, George O’Doherty, Anand Krishnan V Iyer. Metabolomic profiling of cell death in human lung cancer cells by a novel digitoxin analog. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 15.
Abstract 1504: Identification of novel kinase fusion transcripts in endometrial cancer
Authors: Tamura Ryo , Yoshihara Kosuke , Suda Kazuaki , Yamawaki Kaoru , Ishiguro Tatsuya , Adachi Sosuke , Enomoto Takayuki 
Published: July 2016

Abstract
The prognosis of patients with advanced stage or recurrent endometrial cancer remains poor and there is at present no effective therapeutic molecular target for this disease. Our aim is to identify therapeutic targetable targets in endometrial cancer. We focused on fusion transcripts whose inhibitors show impressive activity in some tumors and have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts. We have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications but have not detected recurrent fusion transcripts. We performed Sanger sequencing of RT-PCR amplification products and validated 27 (93.1%) of the 29 fusion transcripts that were randomly selected. As targetable fusion candidates, we extracted three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. Western blotting did not show the detectable protein level of the CPQ-PRKDC similar to CAPZA2-MET, and VGLL4-PRKG1. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. In conclusion, we have described the landscape of fusion transcripts in endometrial cancer by using RNA-sequencing data. We could not identify therapeutically targetable kinase fusions in a small set of 25 endometrial cancer cell lines. Our findings suggest that the transcript allele fraction is a good predictor for determining bona fide targetable fusion transcripts when applying fusion detection methods that use RNA-sequencing data.
Citation Format: Ryo Tamura, Kosuke Yoshihara, Kazuaki Suda, Kaoru Yamawaki, Tatsuya Ishiguro, Sosuke Adachi, Takayuki Enomoto. Identification of novel kinase fusion transcripts in endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1504.
Abstract 1528: Selective gene-expression profiling of metastasizing breast tumor cell subpopulations complements the predictive power of Mammaprint Dx and Oncotype Dx
Authors: Karagiannis George S. , Goswami Sumanta , Jones Joan G. , Oktay Maja H. , Condeelis John S. 
Published: July 2016

Abstract
Gene-expression profiling has yielded prognostic tests, such as MammaPrint and Oncotype Dx, which facilitate clinical decision-making in breast cancer patients. These tests are based on signatures constructed from whole tumor tissue, including tumor as well as stromal cells. Since metastatic tumor cells are not uniquely identified in these signatures, these tests may have reduced clinical specificity and sensitivity in predicting risk of metastasis. In contrast, we captured breast cancer cells in the act of migration/dissemination using an in vivo invasion assay and expression profiled these cells to create a distinct signature named the human invasion signature (HIS). A comparison between HIS and MammaPrint in the NKI295 cohort demonstrated that both signatures perform comparably in selecting a group of patients with significantly poorer outcomes. However, when compared to MammaPrint, the initial slope of the high-risk patients identified by the HIS is significantly steeper, suggesting that the HIS may identify patients at higher risk of early distant metastatic recurrence. Therefore HIS carries prognostic information beyond that captured by MammaPrint. Additionally, a more thorough examination of candidate genes present in HIS yielded two predictive tissue-based biomarkers: TMEM score which measures the density of cancer cell intravasation sites, and MenaCalc which measures the expression of invasive isoforms of the actin-regulatory protein Mena (MenaCalc = PanMena-Mena11a), thereby identifying tumor cells that disseminate. Both, TMEM density and MenaCalc independently predict the development of distant metastases in breast cancer patients. Here, we show that in a small patient cohort (n = 58), there is no correlation between TMEM density and the Oncotype recurrence score (RS). In particular, a subgroup of patients had tumors with high-Oncotype DX and low TMEM score while another subgroup had low Oncotype DX and high TMEM score. These findings indicate that TMEM and Oncotype Dx address different tumor biology and could be used in a complementary fashion for more accurate patient stratification, as well as better selection of systemic therapies to avoid over- and under-treatment.
Citation Format: George S. Karagiannis, Sumanta Goswami, Joan G. Jones, Maja H. Oktay, John S. Condeelis. Selective gene-expression profiling of metastasizing breast tumor cell subpopulations complements the predictive power of Mammaprint Dx and Oncotype Dx. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1528.
Abstract 1536: In silico discovery of target genes and pathways associated with breast cancer brain and bone metastases
Authors: Tang Su-Ni , Jiang Peixin , Liu Xinli 
Published: July 2016

Abstract
Metastasis is the primary cause of death from breast cancer. Bone and brain are the most frequent sites for breast cancer metastasis. The aim of this study was to explore candidate genes associated with breast cancer bone and brain metastases. We compared the gene expression profiles of bone and brain metastases with primary tumors by compiling 55 microarray data sets from Gene Expression Omnibus (GEO: GSE12763, primary tumor n = 30; GSE14017, bone metastasis n = 10, brain metastasis n = 15). A total of 160 differentially expressed genes were screened with a two-fold change, among which 109 genes were up-regulated and 51 genes were down-regulated in bone metastasis. Pathway analysis showed these differentially expressed genes were significantly related to bone development and cell adhesion (p&lt;0.01). Similarly, a total of 150 differentially expressed genes were identified in brain metastasis, 36 genes were up-regulated and 114 genes were down-regulated, which were enriched in immune response (p&lt;0.01). Moreover, protein-protein interaction analysis revealed highly connected hub genes that are expected to play an important role in brain and bone metastases. These hub genes were FOS, EGR1, CTNNB1, DCUN1D1, HIST1H4E, VIM, UBD, EGFR in bone metastasis, and HIST1H4E, DCUN1D1, CDC42, ESR1 in brain metastasis. Interestingly, two genes, DCUN1D1 and HIST1H4E were both up-regulated in bone and brain metastases. It is known that DCUN1D1 could induce extracellular matrix invasion while HIST1H4E played a critical role in regulating chromosomal accessibility and stability. These findings reveal potential biomarkers and therapeutic targets of breast cancer bone and brain metastases, which provide a molecular basis for our future in vitro and in vivo studies.
Citation Format: Su-Ni Tang, Peixin Jiang, Xinli Liu. In silico discovery of target genes and pathways associated with breast cancer brain and bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1536.
Abstract 1540: Midkine-raised oral cancer growth, migration and invasion is required for RBPJk modulation
Authors: Chiu Tai-Jan , Chen Yi-Ching , Chen Chang-Han 
Published: July 2016

Abstract
Oral squamous cell carcinoma (OSCC) represents 95% of all forms of head and neck cancer, and its incidence has increased by 50% during the past decade. Despite the nowadays available therapeutic managements, such as surgery, radiotherapy, chemotherapy or in combination, the five-year survival rate is still improved. The current view is to present that the accumulations of genetic and epigenetic alterations in OSCC lead to the progression of cancer. Our previous study indicated that midkine, heparin-binding growth factor, was overexpressed in tumor tissues of head and neck cancer patients and its expression also correlated with poor 5-year survival. In this study, we tried to explore the biological functions and mechanisms of midkine in vitro and in vivo. Established gain-of-function of midkine in two oral cancer cell lines not only promoted cell growth by MTT, soft agar and BrdU assays, but also induced tumor growth in xenograft model. Midkine-overexpressing cells induced cell migration and invasion by wound healing and Transwell assays. Conversely, cell growth, migration and invasion were also inhibited; while endogenous midkine was abolished by midkine-mediated siRNA in oral cancer cells. By using bioinformatics, Q-RT-PCR, Western blotting, promoter assay and ChIP assay, we identified that RBP-Jk, a transcriptional factor, could bind to the promoter regions of midkine and to induce midkine expression in oral cancer cells. In the specimens of oral cancer patients, the expressions of midkine and RBP-Jk had a positive correlation by immunohistochemistry. Taken together, these results demonstrated that RBP-Jk regulates midkine expression and involves in midkine-elicited tumor formation in oral cancer.
Citation Format: Tai-Jan Chiu, Yi-Ching Chen, Chang-Han Chen. Midkine-raised oral cancer growth, migration and invasion is required for RBPJk modulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1540.
Abstract 1604: TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1
Authors: Lee Yunhee , Kim Semi 
Published: July 2016

Abstract
TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.
Citation Format: Yunhee Lee, Semi Kim. TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1604.