tbuckley/cabot-search huggingface dataset:
Abstract 64: Identification and validation of novel therapeutic targets of osteosarcoma using cutting edge technologies
Authors: Branden Smeester, Natalie Wolf, Branden S. Moriarity
Journal: Cancer Research (2016)

Abstract Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. The current treatment options have not changed over the last four decades and rely on tumor resection and nonspecific combination chemotherapy, resulting in a 5-year survival rate of 0-29% if clinically apparent metastases are present. Although these tumors are rare in humans, with ∼900 cases annually, they are highly prevalent in canines, with over 50,000 cases annually, and have seemingly similar genetics. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS- associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR, MAPK, and ERK5 signaling pathways. We identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. We have now begun pre-clinical testing of inhibitors of our top actionable targets to treat osteosarcoma, namely SEMA4D and CSF1R. Further, we have begun to validate top candidate metastasis genes using the CRISPR nuclease system in immortalized osteoblasts and osteosarcoma cell lines. Preliminarily we have found that loss of candidate osteosarcoma metastasis genes ANAPC1 or TOAK1 increases the migration capacity of immortalized osteoblasts, while loss of EXOC1 or GRLF increases their ability for anchorage independent growth in soft agar assay. Results of these ongoing studies will be presented. Citation Format: Branden Smeester, Natalie Wolf, Branden S. Moriarity. Identification and validation of novel therapeutic targets of osteosarcoma using cutting edge technologies. [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 64.
Abstract 407: Functional analysis of discoidin domain receptor 2 mutation and expression in squamous cell lung cancer
Authors: Naomi Kobayashi-Watanabe
Journal: Cancer Research (2016)

Abstract The treatment strategy for lung cancer has been rapidly progressed, especially in molecular targeted therapy. However, most treatments are established for adenocarcinoma of lung, but not squamous cell carcinoma (SQCC). SQCC occupies approximately 30% among entire lung cancer patients, but the prognosis is worse than that of adenocarcinoma patients. Discoidin domain receptor (DDR) 2 mutations have been recently reported as one of the candidates of molecular targets for lung SQCC, and they are associated with sensitivity to dasatinib, which is already applicable to treatment of chronic myeloid leukemia. However, precise roles of DDR2 on SQCCs of lung have not been clarified. We performed Sanger sequencing of DDR2 gene in a set of 44 primary lung SQCC samples and 7 lung SQCC cell lines, and identified a novel mutation (T681I) in a lung SQCC patient and a lung SQCC cell line, EBC-1. Endogenous protein expression level of DDR2 measured by Western blot technique was high in a lung SQCC cell line, PC-1. Overexpression of wild type and T681I of DDR2 promoted cancer cell invasion of a human lung SQCC cell line, H226B. In animal model, lung metastasis was enhanced and survival was shortened after transplantation of DDR2 wild type overexpressing cells into NOD/SCID/Jak3null (NOJ) mice, which exhibit deficiencies in NK cell activity, macrophage and dendritic cell function, and complement activation, as well as T and B cell deficiencies. Using the cDNA microarray and protein phosphorylation array assay, we found that ectopic expression of DDR2 induced TGF-β1 protein and mRNA expression accompanied with phosphorylation of c-Jun, p38 MAP kinase, and MMP1 elevation. During the process of metastasis, TGF-β pathway plays pivotal roles especially on disruption of basement membrane through induction of MMPs from fibroblasts mediated through both Smad and non-Smad pathways. Since phosphorylations of c-Jun and p38 MAPK were reported to be involved in non-Smad pathway, DDR2 would induce TGF-β mainly through non-Smad pathway, resulting in cancer invasion and metastasis. Taken together, elevation of DDR2 protein might contribute on tumor progression as well as some of DDR2 mutations in lung SQCC. Citation Format: Naomi Kobayashi-Watanabe. Functional analysis of discoidin domain receptor 2 mutation and expression in squamous 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 407.
The influence of heredity versus environment on coeliac disease
Authors: Åsa Torinsson Naluai
Journal: Gut (2016)

For coeliac disease (CD) to manifest itself, certain common gene variants within the human leucocyte antigen (HLA) complex must be present. These HLA gene variants are necessary but not sufficient for the disease to develop, as both environmental factors and other gene variants play their role in CD. In order to determine the effect of environmental factors versus genetic factors in disease development, studies are conducted using twins. One such study of Italian twins suggests that very little of the risk of developing CD is due to environmental factors. In fact, the study indicates that CD is influenced by an unusually strong genetic component (heritability).1 In this issue, Kuja-Halkola et al 2 provide a second evaluation of twin concordance rates and heritability of CD using Swedish twins. They were able to combine the national twin registry with data collected from all pathology departments in Sweden. This comprehensive data collection includes virtually every case of CD diagnosed in Sweden between the years 1969 and 2013, which allows for an accurate estimate as to the prevalence of diagnosed CD.

The results from Kuja-Halkola et al differ noticeably from the earlier Italian study. While Kuja-Halkola et al show a concordance rate in Swedish monozygotic twins of 49% and in …
Abstract 3883: Variant peptide identification system for bottom-up proteomics: Finding hidden sequence alterations in MS data
Authors: Marian Hajduch, Miroslav Hruska, Lakshman Varanasi, Jiri Voller, Petr Dzubak
Journal: Cancer Research (2016)

Abstract In database search, acquired spectra are matched with theoretical spectra of database peptides. Peptides from large databases are likely to match to more than one spectrum, but only a small proportion of peptide interpretations are correct. Incorrect interpretations are likely to arise for two reasons: random matches and non-random matches to homologous peptides. The former is often eliminated by selection of an appropriate similarity threshold or by utilization of the statistical significance of a spectral match. The match to homologous peptide poses a challenge as there is often large similarity in their fragmentation spectra as well. Non-random, but incorrect matches occur surprisingly often in the identification of peptide sequence variants. For this reason, a high identification score does not imply correctness of interpretation. Increasing spectral score threshold enhances specificity in general, but results in significant loss of sensitivity. Therefore, a single spectral criterion is inadequate for distinguishing between homologous peptides. In this study, we reconceive the system for elimination of incorrect interpretations. We propose a system that uses multidimensional LC/MS information in combination with a priori knowledge of sample content to filter out unlikely interpretations. The system calculates retention time of candidate peptides, performs isotopic analysis of precursors and constructs preliminary protein assembly to increase separation between correct and incorrect matches. The approach is used for reevaluation of database search results and is generally applicable to the analysis of standard bottom-up proteomic data. The system was used for identification of alterations in MS2 proteomics data and validated against RNA-Seq data from the same sample. The results demonstrate that non-spectral data can be used to efficiently eliminate peptide interpretations that have no correspondence in the RNA and as such are likely false positives. The approach is sensitive and yields a large proportion of altered peptides that have RNA-Seq support. The method can potentially help overcome the problem of the large database search present, e.g., in proteogenomic studies, particularly important in cancer research and diagnostics. In summary, general prior knowledge of sample content and the use of LC and MS1 data improve on the MS2-based identification of peptides. Citation Format: Marian Hajduch, Miroslav Hruska, Lakshman Varanasi, Jiri Voller, Petr Dzubak. Variant peptide identification system for bottom-up proteomics: Finding hidden sequence alterations in MS data. [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 3883.
Abstract 2852: CITED2, an emerging regulator in hypoxia- and anoikis- mediated cancer cell growth
Authors: Ming-Han Kuo, Chia Ee Chan, Yu-Ting Chou
Journal: Cancer Research (2016)

Abstract In solid tumors, hypoxia and anoikis are two common phenomena occurred in the central of region, inducing a series of genes to switch metabolic pathways, prevent apoptosis and promote continuous growth of cancer cells. Herein, we reported that CITED2 (CBP/p300-interacting transactivators with glutamic acid (E)/aspartic acid (D)-rich C-terminal domain 2) responded to hypoxia and anoikis induction, preventing lung cancer cells from cell cycle arrest. We found that hypoxia induced CITED2 through a HIF2α dependent pathway; moreover, three-dimensional (3D) growth of lung cancer cells induced the expression of CITED2. 3D growth condition elicited anoikis-mediated cell cycle arrest, which was further potentiated by hypoxia stimulation. Knockdown of CITED2 or HIF2α in lung cancer cells enhanced anoikis, causing G1/S cell cycle arrest. Soft agar analysis displayed that both HIF2α and CITED2 are necessary for anchorage-independent cell growth under the hypoxic condition. Spheroid assay indicated that HIF2α-CITED2 signaling axis plays an important role in spheroid formation. Pearson correlation analysis showed that CITED2 was associated with HIF2α expression in lung adenocarcinoma. Kaplan Meier analysis revealed that CITED2 expression was correlated with poor survival outcomes in patients with lung adenocarcinoma. Thus, our findings support the notion that CITED2 plays a critical role in hypoxia- and anokis- mediated cancer cell growth with the potential as a prognostic biomarker for predicting lung cancer progression. Citation Format: Ming-Han Kuo, Chia Ee Chan, Yu-Ting Chou. CITED2, an emerging regulator in hypoxia- and anoikis- mediated cancer cell growth. [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 2852.
S14* Cumulative Genetic Risk of Asthma Severity in Children and Young People: Abstract S14 Table 1
Authors: VL Collis, JO Cunningham, S Dumble, R Tavendale, SJH Vijverberg, AH Maitland-van der Zee, HE Smith, SW Turner, CNA Palmer, S Mukhopadhyay
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Single nucleotide polymorphisms (SNPs) in <i>Chitinase 3-like-1</i> (<i>CHI3L1)</i>, <i>Matrix Metalloproteinase 9 (MMP9) </i>and <i>Matrix Metalloproteinase</i> 12 (<i>MMP12) </i>act on the biological process of airway remodelling that is linked to asthma exacerbations. The cumulative presence of these SNPs could help identify patients at increased risk of asthma exacerbations. The aim of this study is to assess whether these genetic variants increase the risk of asthma exacerbations in children and young adults and exert a cumulative effect on this risk. <h3>Methods</h3> Gene-environmental interactions were investigated in three observational asthma cohorts (BREATHE, PAGES, PACMAN), across three European countries (England, Scotland and the Netherlands), and a pooled dataset including, in total 2,701 patients with asthma, aged between 3 and 22 years (recruited between 2003 and 2011). Participants were genotyped for four biologically related SNPs in three genes (<i>CHI3L1, MMP9 and MMP12</i>). <h3>Results</h3> In single SNP analysis all four investigated SNPs were associated with markers of asthma severity. In the BREATHE study the four investigated SNPs showed a cumulative association with exacerbations involving the use of a course of oral steroids, asthma-related absence from school/college/work, overall asthma exacerbations (OR for overall exacerbations with four risk variants compared to zero risk variants = 3.14, p &lt; 0.001) and asthma treatment step (p value for trend = 0.036). Furthermore, a combined meta-regression analysis of the four investigated SNPs in the pooled dataset (n = 2701) replicated this cumulative association with exacerbations requiring hospital admission (OR per genotypic step 1.18; p = 0.046) and exacerbations requiring oral steroids (OR per genotypic step 1.19; p = 0.008). <h3>Conclusions</h3> Analysis of these four SNPs could enable clinicians to identify patients at higher risk of a severe asthma phenotype, potentially helping tailor strategies for improved asthma control. *S14- BTS Medical Student Award Winner
Abstract 32: Inhibition of cancer cell growth by combined treatment with lactate dehydrogenase (LDHA) inhibitors and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3)
Authors: Michael A. Lea, Yolanda Guzman, Charles desBordes.
Journal: Cancer Research (2016)

Abstract The tendency for enhanced glycolysis in cancer cells presents a target for chemotherapy. In previous studies we observed that proliferation of colon and bladder cancer cells can be inhibited by treatment with either phenformin or an inhibitor of PFKFB3 namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work we have examined the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15). The LDHA inhibitors that we chose to study in increasing order of IC50s were methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2) &amp;lt; isosafrole &amp;lt; oxamate. A synergistic anti-cancer effect of phenformin and oxamate has been reported. In the present work with colon and bladder cancer cells, additive but not synergistic growth inhibitory effects were seen with the LDHA inhibitors of which NHI-2 was effective at the lowest concentrations. Growth inhibition with PQP and PFK15 was compared in colon (Caco-2 and HT29) and bladder cancer cells (5637, HT1376, RT4, SW780, T24, TCCSUP and UM-UC-3). Apart from RT4 cells where the effects were similar, the effects were somewhat greater with PFK15 than with PQP and for both compounds the actions were seen at lower concentrations than in previous studies with 3PO. Actions on medium acidification and glucose uptake are more readily observed in the most rapidly growing cell lines. Effects of phenformin on medium pH and glucose concentration were decreased by the PFKFB3 and LDHA inhibitors that were examined. In accord with our previous studies on inhibitors of glycolysis, the increased medium acidification and glucose uptake caused by phenformin could be blocked by combined treatment with PFKFB3 or LDHA inhibitors. At the same time additive growth inhibitory effects were observed. The results supported the concept that combined treatment with phenformin and inhibitors of glycolysis can cause additive inhibition of cell proliferation while mitigating the lactic acidosis caused by phenformin as a single agent. Citation Format: Michael A. Lea, Yolanda Guzman, Charles desBordes. Inhibition of cancer cell growth by combined treatment with lactate dehydrogenase (LDHA) inhibitors and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). [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 32.
Abstract 2013: The PAX3-FOXO1 oncogene drives aneuploidy and overrides aneuploidy-associated proliferative defects in alveolar rhabdomyosarcoma
Authors: Andrew D. Hollenbach, Jacob M. Loupe, Patrick J. Miller, Benjamin P. Bonner, Elaine C. Maggi, Jyothi Vijayaraghavan, Jovanny Zabaleta, Christopher M. Taylor, Fern Miller, Judy S. Crabtree
Journal: Cancer Research (2016)

Abstract Alveolar Rhabdomyosarcoma (ARMS) is primarily defined by the t(2;13)(q35;q14) translocation, which generates the PAX3-FOXO1 oncogene. Despite the fact that ARMS are frequently aneuploid, like a majority of other solid tumors, it is unknown whether PAX3-FOXO1 contributes to the development and/or persistence of aneuploidy. In this study we show that PAX3-FOXO1 serves as the driver mutation to promote aneuploidy by globally altering gene regulatory networks essential for maintaining proper chromosome number and structure. Further, we demonstrate that PAX3-FOXO1 overrides aneuploid-dependent growth arrest by altering the expression of growth factor related regulatory networks. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these gene regulatory network changes. This is the one of the first studies describing how an oncogene and post-translational modifications of the corresponding oncoprotein drive the acquisition of aneuploidy and override proliferation defects in malignant transformation. The mechanism for PAX3-FOXO1 described in this work has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. Citation Format: Andrew D. Hollenbach, Jacob M. Loupe, Patrick J. Miller, Benjamin P. Bonner, Elaine C. Maggi, Jyothi Vijayaraghavan, Jovanny Zabaleta, Christopher M. Taylor, Fern Miller, Judy S. Crabtree. The PAX3-FOXO1 oncogene drives aneuploidy and overrides aneuploidy-associated proliferative defects in alveolar rhabdomyosarcoma. [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 2013.
Abstract LB-296: Multi-target sDNA increases colorectal cancer screening among previously non-compliant patients: The USMD physician services experience
Authors: Mark Prince, Lynn Lester, Rupal Chinawala, Barry M. Berger
Journal: Cancer Research (2016)

Abstract Background: The multi-target stool DNA test (mt-sDNA) is an FDA approved, high sensitivity, colorectal cancer screening test. We evaluated mt-sDNA in non-screening-compliant Medicare patients and assessed compliance and diagnostic colonoscopy usage and correlated positive mt-sDNA results with colonoscopy findings. Methods: We performed a retrospective medical records review (October 2014 - September 2015) to identify mt-sDNA use in average-risk Medicare eligible patients treated by USMD Physician Services (Dallas, Tx) who were not previously compliant with colon cancer screening. We offered mt-sDNA to patients who were either &amp;gt;10 years since last colonoscopy and/or &amp;gt;1 yr. since last fecal occult blood test. Follow-up colonoscopy was advised for all patients with a positive result. Colonoscopy and pathology results were reviewed with patient classification based on the most significant pathology finding (index lesion). Size, location and total number of polyps and adenomas were tabulated. Results: Over 12 months, 77 providers ordered 393 mt-sDNA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sDNA was negative in 85.3% (296/347) and positive in 14.7% (51/347). Follow-up colonoscopy was performed in 46 positive patients (90.2% colonoscopy compliance) with 3 patients refusing colonoscopy and two patients lost to follow up. Index findings included: colon cancer (4/46, 8.7%), advanced adenomas (21/46, 45.6%), non-advanced adenoma (9/46, 19.6%), and negative results (12/46,23.0%). The positive predictive value for advanced colorectal lesions was 54.3% and for any colorectal neoplasia was 73.9%. Conclusions: The availability of mt-sDNA provided significant medical benefit to our previously screening non-compliant Medicare population. Patients with clinically critical advanced colorectal neoplasia were identified in this cohort due to high compliance with both mt-sDNA screening and follow-up diagnostic colonoscopy. Citation Format: Mark Prince, Lynn Lester, Rupal Chinawala, Barry M. Berger. Multi-target sDNA increases colorectal cancer screening among previously non-compliant patients: The USMD physician services experience. [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 LB-296.