tbuckley/cabot-search huggingface dataset:
Abstract 3509: EWS/FLI regulates transcriptional activation via length-dependent GGAA microsatellites
Authors: Kirsten M. Johnson, Cenny Taslim, Stephen L. Lessnick
Journal: Cancer Research (2017)

Abstract Objective: The purpose of this study is to investigate how EWS/FLI transcriptionally activates gene targets via polymorphic GGAA microsatellites. Ewing Sarcoma is a pediatric bone malignancy initiated by a t(11;22) chromosomal translocation that produces the EWS/FLI oncoprotein. EWS/FLI transcriptionally activates and represses its target genes to mediate oncogenic reprogramming. Expression of its up-regulated targets correlates with EWS/FLI binding to associated GGAA microsatellites, which show length polymorphisms. These microsatellite polymorphisms may critically affect EWS/FLI-responsiveness of key gene targets. For example, NR0B1 is necessary for EWS/FLI mediated oncogenic transformation, and we found a “sweet-spot” of 20-25 repeat length as optimal for EWS/FLI mediated transcriptional activity at NR0B1 through clinical observation and in vitro studies. The mechanism underlying this optimal length is unknown. Methods: We explored the stoichiometry and binding affinity of EWS/FLI for different repeat lengths through biochemical studies, including fluorescence polarization, and immunoprecipitation assays, combined with bioinformatics analysis. Additionally, use of EWS/FLI mutant constructs has been critical for elucidating particular binding behavior of EWS/FLI at different microsatellite repeat lengths. Results: Fluorescence anisotropy studies demonstrate that FLI binding affinity is independent of GGAA microsatellite length. In contrast, the stoichiometry of protein to DNA binding increases in specific incremental patterns with increasing microsatellite repeats. EWS/FLI mutants inform on binding, suggesting a complex relationship between microsatellite length and transcriptional activity. Conclusion: Overall our data suggests a model in which the DNA binding domain of multiple FLI monomers function as independent binding units to facilitate transcriptional activity in a length-dependent manner. The EWS portion appears to be critical for in vivo binding of genomic DNA globally. We propose that GGAA microsatellites are necessary and sufficient for EWS/FLI-mediated oncogenic transformation and that repeat length affects optimal DNA binding stoichiometry and transcriptional activity. Citation Format: Kirsten M. Johnson, Cenny Taslim, Stephen L. Lessnick. EWS/FLI regulates transcriptional activation via length-dependent GGAA microsatellites [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 3509. doi:10.1158/1538-7445.AM2017-3509
Abstract 3326: Identification of a novel androgen receptor co-regulator in prostate cancer
Authors: Aymen A. Shatnawi, Sridhar Acharya Malkaram, Efrosini Tsouko, Daniel E. Frigo
Journal: Cancer Research (2017)

Abstract Prostate cancer (PC) is one of the most frequently diagnosed tumors in the United States, affecting one in six men during their lifetime and second only to lung cancer as a cause of cancer death in men. One of the major drivers of prostate cancer is the androgen receptor (AR). It has been shown that deregulation of AR co-regulators play a crucial role in PC through modulating the transcriptional activity of the receptor. While the importance of the AR complex is well established, there is still an incomplete understanding of what all the associated co-regulators are and how they modulate AR signaling. Here, we have identified that the inhibitor of growth family member 4 (ING4), a protein that has been implicated in the pathogenesis of several solid tumors such as gastric and breast cancer, is a novel AR co-regulator. Overexpression of ING4 increased AR activity in an androgen-dependent manner as assessed using luciferase reporter gene assays. Supporting a role as a potential AR co-activator, RNA Next-Generation Sequencing of prostate cancer cells with ING4 knocked down revealed a repression of endogenous AR/R1881-activated genes and expression of AR/R1881 suppressed genes. Further, mining of existing clinical datasets revealed that the ING4 gene expression is de-regulated in PCs compared relative to normal tissue and tracks with poor patient prognosis. Collectively, the current findings strongly support the involvement of ING4 in AR signaling and PC progression and development. Citation Format: Aymen A. Shatnawi, Sridhar Acharya Malkaram, Efrosini Tsouko, Daniel E. Frigo. Identification of a novel androgen receptor co-regulator in prostate cancer [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 3326. doi:10.1158/1538-7445.AM2017-3326
Abstract 4065: Association study between iron and cholesterol for the treatment of drug resistant neuroblastoma
Authors: Sang Y. Lee, Becky Slagle-Webb, Cara-Lynne Schengrund, James Connor
Journal: Cancer Research (2017)

Abstract Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need more iron and lipids for their active cell metabolism, possible links between iron, mutations in genes involved in iron metabolism (e.g., HFE) and lipid metabolism have not been studied well. We determined the HFE genotype in human neuroblastoma cells as well as patients. Neuroblastoma cells and patients have C282Y HFE mutation rates (~12%) that are similar to those of the general Caucasian population. While cultured cells derived from drug resistant neuroblastomas had less cholesterol, they expressed more ferritin, and contained more iron, than cells derived from drug susceptible tumors. In drug resistant neuroblastoma CHLA-171 cells, siRNA induced alteration of HFE expression had no effect on their iron levels but decreased their cholesterol. Results of in vitro experiments indicated that simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), was cytotoxic to drug resistant cells as was the iron chelator di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). In vivo, the anti-tumor effect of simvastatin administered orally was minimal. In summary, we found i) an inverse association between ferritin and HMG-CoAR expression in neuroblastoma cells that was reflected in their iron and cholesterol levels, and ii) that the most cytotoxic cholesterol inhibitor of neuroblastoma cells was simvastatin, while the most cytotoxic iron chelation agent was DpC. Our results indicate that it may be possible to use HFE genotype to develop a precision medicine approach to use certain iron chelators and/or cholesterol decreasing agents in the treatment of drug resistant neuroblastomas. Our results also indicate that alterations in iron and cholesterol metabolism are part of the cell’s drug resistance mechanism in neuroblastomas. Citation Format: Sang Y. Lee, Becky Slagle-Webb, Cara-Lynne Schengrund, James Connor. Association study between iron and cholesterol for the treatment of drug resistant neuroblastoma [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 4065. doi:10.1158/1538-7445.AM2017-4065
Abstract 5477: Hydrogels to study ECM-oxygen gradient interactions for sarcoma cell migration
Authors: Daniel M. Lewis, Sharon Gerecht, T. S. Karin Eisinger-Mathason
Journal: Cancer Research (2017)

Abstract Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients and collagen fibers on sarcoma cell invasion and migration. We begun with O2 gradient measurements and found that large sarcoma mouse tumors (&amp;gt;300 mm3) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1–6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Next, we have developed hypoxic hydrogels where we can control collagen fiber density and cross-linking density independently from oxygen gradients. Using this new platform we show that an increase in fiber density in conjunction with the hypoxic oxygen gradient leads to an increase in sarcoma cell migration. This increase in migration speed was also correlated with quicker stress relaxation times of the collagen gel and larger pore size. Using these platforms we are able to create a novel 3D experimental system with control over mechanical properties (crosslinking density, binding sight density, fiber density, stress relaxation time, and stiffness) independently from oxygen concentration. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and that this migration is modulated by collagen fiber density and pore size, in the surrounding matrix. We propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets. Citation Format: Daniel M. Lewis, Sharon Gerecht, T. S. Karin Eisinger-Mathason. Hydrogels to study ECM-oxygen gradient interactions for sarcoma cell migration [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 5477. doi:10.1158/1538-7445.AM2017-5477
AB1082 Impact of ankylosing spondylitis versus non-radiographic spondyloarthritis on early retirement
Authors: C Cobilinschi, R Ionescu, D Opris-Belinski
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Axial spondyloarthritis include non-radiographic SpA (nr-SpA) and ankylosing spondylitis (AS), suggesting the extent of sacroiliac involvement on imaging techniques (1). The influence of the two conditions on patients9 physical function and their impact on work capacity should be regularly assessed so that we can better contribute to patients9 social integration. <h3>Objectives</h3> The present study aims to assess the differences between AS and nr-SpA patients under anti-TNF therapy regarding disease related retirement (DR) and its contributing factors. <h3>Methods</h3> Over a period of eleven months 136 patients diagnosed with AS or nr-SpA on current biological therapy were included. Demographic data and working status were assessed. Statistical analysis was performed with SPSS 20.0. <h3>Results</h3> In the study cohort 69% of patients were males. The predominant age group was situated between 30 to 40 years old (29.8%), while 20.2% were over 50. Out of the study group, 66% confirm they are active in their work field with a minimum of seven hours per day, whereas 4.3% reached their retirement age. 29.8% of patients were granted a disability retirement and the majority (42.9%) belonged to the 40–50 age group. Surprisingly, 6.8% of early retired patients were under 30. Out of the DR category, 92.9% were diagnosed with AS, while the rest of 7.1% had nr-SpA. The interval from diagnosis to the initiation of biological therapy was 72.5±85.1 months for AS patients and 64.1±71.2 for nr-SpA. 23.2% of patients applied for early retirement before biological therapy and only 3.1% resumed work after anti-TNF introduction. Patient gender did not influence the working capacity. At the time of study inclusion, 12% of patients with AS and 4% of patients with nr-SpA still exhibited signs of highly active disease, according to ASDAS-CRP assessment. <h3>Conclusions</h3> Almost a third of patients in the study group were offered early retirement due to axial SpA. The vast majority of disease related retirement patients were known with AS, thus emphasizing the extent of disability brought on by this entity. However, a significant percentage of patients suffered from nr-SpA, raising doubts as to whether clinicians can promptly diagnose this entity and offer early, appropriate treatment so that inability no longer occurs. <h3>References</h3> Wendling D, Prati C, Claudepierre P, Guillot X, Breban M. Non-radiographic spondyloarthritis: A theoretical concept or a real entity? Jt Bone Spine. 2012. <h3>Disclosure of Interest</h3> None declared
Abstract 2455: Human glioblastoma arises from the distant subventricular zone normal appearing but harboring tumor-initiating mutations
Authors: Joo Ho Lee, Jeong Eun Lee, Jee Ye Kahng, Junseong Park, Seon Jin Yoon, Se Hoon Kim, Jong Hee Chang, Seok-Gu Kang, Jeong Ho Lee
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is the most devastating and incurable brain tumor. Although the identification of cells with tumor initiating mutations or their location can provide the fundamental basis for understanding disease progression, the origin of GBM remains controversial due to the lack of direct evidence in human GBM patients. Here, we performed ultra-deep sequencing of triple-matched tissues of i) radiologically and pathologically normal subventricular zone (SVZ), which is distant from tumor, ii) GBM tumor, and iii) blood (or normal cortical tissues) from patients with GBM (IDH-wildtype), compared to those with other type of brain tumors such as GBM (IDH-mutant), meningioma, oligodendrgolioma, metastatic brain tumor, and GBM (IDH-wildtype) with SVZ-invasion. Surprisingly, we found that in 55.5% of IDH-WT GBM patients (5 of 9), normal appearing and distant SVZ already contained the low level of GBM mutations such as TP53, EGFR, RB1, PDGRF or TERT variations observed in the matched tumor. Single cell sequencing of GBM tumors and laser capture microdissection analysis of the SVZ show that mutations are enriched in the astrocyte ribbon area, which clonally evolved from the SVZ to the distant GBM tumor. Furthermore, using CRISPR-Cas9 system in the postnatal mouse brain, we showed that neural stem cells with TP53, PTEN, EGFR mutations migrated away from the mutated SVZ site and then formed the high grade malignant glioma in the distant cortical region. Taken together, this study provides the direct evidence that human glioblastoma arises from the distant SVZ that is normal-appearing but harboring tumor-initiating mutations. Citation Format: Joo Ho Lee, Jeong Eun Lee, Jee Ye Kahng, Junseong Park, Seon Jin Yoon, Se Hoon Kim, Jong Hee Chang, Seok-Gu Kang, Jeong Ho Lee. Human glioblastoma arises from the distant subventricular zone normal appearing but harboring tumor-initiating mutations [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 2455. doi:10.1158/1538-7445.AM2017-2455
Abstract 2319: Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer
Authors: Weiwei Li, Yiming Ma, Longmei He, Hongying Wang
Journal: Cancer Research (2017)

Abstract Colorectal carcinoma (CRC) patients show resistance to EGFR-TKI (epidermal growth factor receptor -tyrosine kinase inhibitor) treatment. Protease-activated receptor 2 (PAR2) has been shown to transactivate EGFR. We aim to investigate whether PAR2 sensitizes EGFR-TKI-induced apoptosis in CRC. Firstly, inhibition of PAR2 with shRNA or ENMD-1068 (a selective antagonist of PAR2) significantly sensitized EGFR-TKI (gefitinib or AG1478)-induced apoptosis, which was measured with Annexin V/ PI staining and activation of caspase-3 in different CRC cell lines. In xenograft tumor model, gefitinib treatment dramatically reduced the tumor volume in HT-29-shPAR2 compared with HT-29-vector. Mechanism study showed that PAR2 knockdown significantly reduced bcl-xL expression at both mRNA and protein level. Consistently, activation of PAR2 upregulated bcl-xL. Furthermore, inhibition of protein phosphatase (PP) with okadaic acid significantly downregulated bcl-xL. Moreover, knockdown of PP1 with siRNA blocked PAR2-induced accumulation of bcl-xL. In summary, our findings suggest that inhibition of PAR2 sensitizes EGFR-TKI-induced apoptosis via downregulation of bcl-xL in colorectal cancer. Considering the extensive expression of PAR2 and PAR2-activating proteases in colon, it strongly indicates that inhibition of PAR2 may be a potential avenue to overcome EGFR-TKI resistance in patients with CRC. Citation Format: Weiwei Li, Yiming Ma, Longmei He, Hongying Wang. Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer [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 2319. doi:10.1158/1538-7445.AM2017-2319
Abstract 3148: Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer
Authors: Ryohei Yoshida, Takaaki Sasaki, Shunsuke Okumura, Yoshinobu Ohsaki
Journal: Cancer Research (2017)

Abstract Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in around 3%-5% non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, Crizotinib, and recently the more highly potent Alectinib and Ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an Alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in Alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were Ceritinib or Lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK–NSCLC with acquired resistance to ALK inhibitors. Citation Format: Ryohei Yoshida, Takaaki Sasaki, Shunsuke Okumura, Yoshinobu Ohsaki. Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer [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 3148. doi:10.1158/1538-7445.AM2017-3148
Clinical audit to assess quality of service in a newly implemented NCD programme: a cross-sectional survey to review a pilot implementation of the WHO PEN approach in Salfit district, occupied Palestinian territory
Authors: Ramez Dweakat, Nadim Barghouthi, Yaser Bouziyeh, Reem Abu-Hijleh, Asad Ramlawi, Ilhama Shamasnah, Wendy Venter
Journal: The Lancet (2017)
Abstract 5529: CD177 suppresses breast cancer progression by regulating the canonical WNT β-Catenin pathway
Authors: Paige N. Kluz, Ryan Kolb, Qing Xie, Nicholas Borcherding, Linna Wang, James P. De Andrade, Phillip M. Spanheimer, Wei Li, Katherine N. Gibson-Corley, Andy W. Tao, Sonia Sugg, Ronald J. Weigel, Weizhou Zhang
Journal: Cancer Research (2017)

Abstract To better treat breast cancer patients, it is imperative to be able to predict breast cancer relapse and metastasis. Here, we identified the cluster of differentiation 177 (CD177) expression is positively correlated with relapse-free and metastasis-free survival of breast cancer patients. CD177 protein is highly expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Using mouse models, we found that CD177 suppresses breast cancer, primarily by forming a complex with E-Cadherin and b-Catenin at adherens junctions. The physical interaction prevents the activation of b-Catenin-mediated transcription by the canonical WNT signaling as demonstrated by a TOP-flash dual luciferase assay. In conclusion, we have identified CD177 as a novel breast cancer suppressor and uncovered a new regulatory mechanism for the canonical WNT/b-Catenin-mediated oncogenic signaling transduction. Citation Format: Paige N. Kluz, Ryan Kolb, Qing Xie, Nicholas Borcherding, Linna Wang, James P. De Andrade, Phillip M. Spanheimer, Wei Li, Katherine N. Gibson-Corley, Andy W. Tao, Sonia Sugg, Ronald J. Weigel, Weizhou Zhang. CD177 suppresses breast cancer progression by regulating the canonical WNT β-Catenin pathway [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 5529. doi:10.1158/1538-7445.AM2017-5529