tbuckley/cabot-search huggingface dataset:
Abstract 1325: Genome-wide association study of thyroid nodule in Korean population
Authors: Eun Kyung Lee, Yul Hwangbo, Young Joo Park, Jong-Il Kim, Yuh-Seog Jung, Jun Sun Ryu
Journal: Cancer Research (2017)

Abstract Thyroid nodule is very common. Several autopsy surveys reported that 30% or more of patients had thyroid nodule. However, inherited genetic risk factors for thyroid nodule remain unknown. Genome-wide association studies (GWAS) are widely used in human genetics to identify genes associated with various diseases. We aimed to find genetic factors for thyroid nodule and conducted case-control GWAS. Objective: To identify genetic variants associated with susceptibility to thyroid nodules Methods: We performed a two-stage GWAS for thyroid nodule. The discovery stage involved a genome-wide scan of 713 subjects with thyroid nodule and 591 subjects with normal thyroid from a population-based cohort. replication testing was conducted in an additional 600 cases and 600 controls from the participants of a health check-up. Results In discovery stage, 21 candidate single nucleotide polymorphisms (SNP) in 20 loci including NKX2-1, ITGB1 and ZBTB25 were selected for replication. The strongest signal located in NKX2-1 (P = 9x10-7), which is known susceptibility locus for differentiated thyroid cancer. However, no SNP showed significant association in replication test. In joint analysis, no association signals reaching genome-wide significance (P &amp;lt;5x10-8) were detected. Conclusion GWAS for thyroid nodule have failed to identify susceptibility locus. Therefore, genetic effect for development of thyroid nodule could be negligible. Citation Format: Eun Kyung Lee, Yul Hwangbo, Young Joo Park, Jong-Il Kim, Yuh-Seog Jung, Jun Sun Ryu. Genome-wide association study of thyroid nodule in Korean population [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 1325. doi:10.1158/1538-7445.AM2017-1325
Abstract 4117: Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer
Authors: Rabia A. Gilani, Eric J. Lachacz, Sameer Phadke, Li Wei Bao, Xu Cheng, Evelyn M. Jiagge, Matthew B. Soellner, Sofia D. Merajver
Journal: Cancer Research (2017)

Abstract Triple negative breast cancers (TNBCs) are especially lethal due to their high metastatic potential and propensity to recur. TNBCs comprise the only subset of breast cancer for which there are no FDA-approved targeted therapies. We have developed a mechanistically novel dual c-Src/p38 inhibitor, UM-164, that has potent in vivo anti-TNBC activity. However, single-agent targeted therapies are prone to resistance and rational drug combinations can overcome or prevent resistance. We developed TNBC cells lines that are resistant to UM-164. Significant morphology and cell signaling changes occurred in the drug-resistant cell lines. Most crucial is the observation that in drug-resistant cell lines the activation of c-Src and/or p38 does not return in the presence of UM-164, suggesting that resistance is not occurring via constitutive activation enabling mutations of c-Src and/or p38 kinases. However, compared to their drug-sensitive counterparts, the UM-164-resistant cells have significantly hyperactivated MEK1/2 and ERK1/2 signaling when treated with UM-164. Thus, we tested combinations of UM-164 + MEK1/2 inhibitors in several TNBC cell lines and patient derived xenografts. We found that trametinib (Mekinist®, an FDA-approved inhibitor of MEK1/2) is synergistic (Chou-Talalay CI at ED90 = 0.4, CI &amp;lt; 1 denotes synergy) with UM-164 to inhibit the growth of UM-164-resistant MDA-MB-231 and SUM-149 cell lines. These results support our hypothesis that activation of MEK/ERK signaling can act as an escape mechanism that leads to resistance to UM-164. Future research into rational combinations of targeted therapies delivered in data driven schedules may hold the key to improving survival in TNBC. Citation Format: Rabia A. Gilani, Eric J. Lachacz, Sameer Phadke, Li Wei Bao, Xu Cheng, Evelyn M. Jiagge, Matthew B. Soellner, Sofia D. Merajver. Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast 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 4117. doi:10.1158/1538-7445.AM2017-4117
Zika virus directly infects peripheral neurons and induces cell death
Authors: Yohan Oh, Feiran Zhang, Yaqing Wang, Emily M Lee, In Young Choi, Hotae Lim, Fahimeh Mirakhori, Ronghua Li, Luoxiu Huang, Tianlei Xu, Hao Wu, Cui Li, Cheng-Feng Qin, Zhexing Wen, Qing-Feng Wu, Hengli Tang, Zhiheng Xu, Peng Jin, Hongjun Song, Guo-li Ming, Gabsang Lee
Journal: Nature Neuroscience (2017)
Abstract 4762: New device for radiation delivery in breast cancer patients - double balloon applicator for optimal dose distribution
Authors: Manny R. Subramanian, Mike Cutrer, Rohit Mehta
Journal: Cancer Research (2017)

Abstract Currently available applicators for delivery of accelerated partial breast irradiation using a high dose afterloader, have treatment catheters close to the center of the balloon in fixed positions, restricting one’s ability to modify the dose to critical organs. Recently we developed a novel, dual balloon brachytherapy applicator using which one could optimize radiation dose by shaping the resection cavity with an outer balloon and allowing an inner balloon to selectively position the treatment catheters away from the central axis of the balloon based on cavity size. The Double Balloon Breast Brachytherapy applicator offers a unique design with adjustable treatment catheters, allowing for both optimized dose delivery and conformal avoidance of critical structures. This applicator is a single entry (1 cm incision), multi-channel high dose rate afterloader (HDR) accessory device. The treatment catheters can be expanded to an optimal location greater than or equal to 50% of the outer balloon diameter(&amp;gt; 1 cm diameter) - thereby optimizing dose delivery to the patient. The Conformal Double Balloon Breast Brachytherapy Device has the ability to optimize either conformality or homogeneity by allowing expansion of an inner polyurethane balloon to selectively position multiple treatment catheters significantly away from the central axis of an expanded outer polyurethane balloon. A model study of the Double Balloon Breast Brachytherapy Device was performed with a wide range of volumes of the lumpectomy cavity. Each case is scanned in a CT scanner and the data transported to a treatment planning system. Dosimetric parameters such as dose delivered to treatment site, different organs such as skin, ribs, etc are evaluated and compared against existing breast brachytherapy applicator devices. Both ultrasound and CT images clearly indicate that the quality of the Double Balloon Device images are comparable to other commercial devices. All catheters are distinguishable and can be reconstructed for treatment planning, and the balloon volume can be clearly delineated. Planning Treatment Volume (PTV) based on balloon volume can be easily generated and optimized dosimetry performed. Initial patient studies also indicate that using the double balloon applicator optimized dosimetry can be obtained thereby reducing the dose to critical structures such as skin and rib while maintaining the dose to the target. Citation Format: Manny R. Subramanian, Mike Cutrer, Rohit Mehta. New device for radiation delivery in breast cancer patients - double balloon applicator for optimal dose distribution [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 4762. doi:10.1158/1538-7445.AM2017-4762
Abstract 4519: ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor
Authors: Yi Shi, Ze Liu, Xiang-Lei Yang
Journal: Cancer Research (2017)

Abstract Hypoxia-induced angiogenesis is a critical response in multicellular organisms to maintain oxygen homeostasis. It is also an important mechanism to support tumor progression. Hypoxia activates hypoxia-inducible factor (HIF) and HIF-independent pathways to transcriptionally induce the expression of pro-angiogenic genes. However, our knowledge on transcriptional repressors of angiogenesis and how they are regulated during hypoxia are limited. Here we report that seryl-tRNA synthetase (SerRS), a newly identified transcriptional repressor of vascular endothelial growth factor (VEGFA), is a major inhibitor of angiogenesis that is inactivated during hypoxia1-4. Inactivation of SerRS is achieved through its phosphorylation at serine 101 and serine 241 by ataxia telangiectasia mutated (ATM) and the related kinase ATR. Knockdown of HIF is not sufficient to completely block hypoxia-induced VEGFA expression in human cells unless a phosphorylation-deficient form of SerRS (SerRSS101A/S241A) is simultaneously expressed to escape ATM/ATR inactivation. Consistently, in mice, SerRSS101A/S241A can bypass hypoxia response despite HIF activation to strongly inhibit angiogenesis in a matrigel assay and a xenograft model of human breast cancer. These findings reveal ATM/ATR-SerRS pathway as a key negative regulator of angiogenesis related to hypoxia and a new target for cancer therapy. References 1. Fukui, H., Hanaoka, R., and Kawahara, A. (2009). Noncanonical activity of seryl-tRNA synthetase is involved in vascular development. Circ Res 104, 1253-1259. 2. Herzog, W., Muller, K., Huisken, J., and Stainier, D. Y. (2009). Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circ Res 104, 1260-1266. 3. Shi, Y., Xu, X., Zhang, Q., Fu, G., Mo, Z., Wang, G. S., Kishi, S., and Yang, X. L. (2014). tRNA synthetase counteracts c-Myc to develop functional vasculature. Elife 3, e02349. 4. Xu, X., Shi, Y., Zhang, H. M., Swindell, E. C., Marshall, A. G., Guo, M., Kishi, S., and Yang, X. L. (2012). Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun 3, 681. Citation Format: Yi Shi, Ze Liu, Xiang-Lei Yang. ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor [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 4519. doi:10.1158/1538-7445.AM2017-4519
Abstract 1348: GDC-0032, a p110 beta sparing PI3K inhibitor is highly efficient on <i>PIK3CA</i>-mutated and <i>HER2-</i>amplified breast cancer model
Authors: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Casey Williams, Nandini Dey, Brian Leyland-Jones
Journal: Cancer Research (2017)

Abstract Background: HER2 amplification/overexpression frequently co-occurs with PI3K pathway activation in breast tumors. Mutations in PIK3CA are known to be involved in a wide range of human cancers including HER2+ breast cancer, and mutant PIK3CA is thought to act as an oncogene. Here, we evaluate the efficacy of GDC0032, a p110 beta-sparing PI3K inhibitor against HER2+ or HER2+/PIK3CA mutated breast cancer cells. MATERIALS AND METHODS: Four HER2+ breast cancer (BC) cell lines consisting of three activating (either helical or kinase domain) PIK3CA mutation (HER2+/ER+ and HER2+/ER-) were analyzed for proliferation, apoptosis, cell cycle and signaling pathway activation assays. Preclinical efficacy of GDC-0032 was also evaluated in vivo in a mouse model. RESULTS: 1) All HER2+ and HER2+/PIK3CA mutant cell lines exhibited low IC50 values (ranging from 0.1 µM-1.5 µM) irrespective of ER-positive or not. 2) GDC-0032 caused a strong differential growth inhibition in both HER2+ and HER2+/ /PIK3CA mutated breast cancer cell lines when compared to lines that were HER2- and PIK3CA wild type by 3D-ON-TOP clonogenic assay. 3) Administration of GDC-0032 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependent manner. Furthermore, induction of apoptosis was more with GDC-0032 when combined with RAD001. 4) GDC0032 also blocked expression of CYCLIN D1. 5) Investigation of the signal transduction revealed that the treatment of GDC-0032 reduced the level of p-AKT (Ser473 and Thr308), and p-S6 expression is indicating the down-regulation of downstream signaling of PI3K and mTOR pathway. 6) GDC-0032 was highly active at reducing established tumor growth in vivo in BC mouse xenografts harboring PIK3CA mutation and HER2 amplification. CONCLUSION: Our in vitro or in vivo data showed that GDC-0032 was highly efficient either as a single agent as well as with RAD001 in HER2+/PIK3CA mutated breast cancer cell lines. Our data suggest that GDC-0032 represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification in breast cancer. Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Casey Williams, Nandini Dey, Brian Leyland-Jones. GDC-0032, a p110 beta sparing PI3K inhibitor is highly efficient on PIK3CA-mutated and HER2-amplified breast cancer model [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 1348. doi:10.1158/1538-7445.AM2017-1348
Abstract 3542: Coordination of glutamine and glucose metabolism in pancreatic cancer
Authors: Enza Vernucci, Venugopal Gunda, Surendra Shukla, Pankaj K. Singh
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer related deaths in the United States. Due to early metastasis by the time it is diagnosed it advances to advanced stages and becomes unresectable. Oncogene mediated metabolic reprogramming has been shown to promote the growth, maintenance and metastasis of tumors in pancreatic ductal adenocarcinoma. Pancreatic tumors route majority of glucose and glutamine for biomass generation and maintenance of redox potential. The aim of this study was to investigate the link between glutamine and glucose metabolism in pancreatic cancer cells. We primarily focused on the role of glutamine mediated regulation of glucose metabolism. We observed that glutamine deprivation reduces pancreatic cancer cell growth as suggested by the previous studies. We further investigated how pancreatic cancer cells adapt to glutamine deprived conditions. We observed that glucose uptake increases significantly upon glutamine deprivation. However, GLUT1 expression showed a contrasting decreased expression under conditions of glutamine deprivation. Using tandem mass spectrometry based metabolomic analysis we observed that glutamine deprivation does not alter glycolysis. However, the TCA cycle, amino acid metabolism and glutathione metabolism were significantly impacted in glutamine deprived cells. We noticed a significant increase in the levels of hydroxyglutarate and succinyl CoA levels in the TCA cycle. These changes were accompanied with an increase in GSH to GSSG ratio that reflects a possibility for alternative pathways involved in redox maintenance under glutamine deprived conditions. Hence, we conclude that glutamine metabolism significantly impacts the uptake and metabolism of glucose in pancreatic cancer cells. Citation Format: Enza Vernucci, Venugopal Gunda, Surendra Shukla, Pankaj K. Singh. Coordination of glutamine and glucose metabolism in pancreatic 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 3542. doi:10.1158/1538-7445.AM2017-3542
Abstract 893: Systematic assessment of spliceosome components as drivers of breast cancer progression
Authors: Esmee Koedoot, Sylvia Le Dévédec, Bob van de Water
Journal: Cancer Research (2017)

Abstract Accumulating evidence indicates that RNA splicing is involved in different steps of carcinogenesis. Although the critical role of a limited number of splicing factors has been demonstrated in several cancer studies, the function of many spliceosome components is still unknown. In breast cancer samples higher expression levels of a subset of spliceosome components consistently correlated with more aggressive tumor types in patient microarray as well as RNA sequencing data from The Cancer Genome Atlas (TCGA). We further systematically evaluated the effect of siRNA-mediated knockdown of 244 individual splicing factors on both cell migration and proliferation in two aggressive breast cancer cell lines MDA-MB-231 and Hs578T using high throughput microscopy. Primary candidates were validated with four single siRNAs and classified based on their effects on migration and proliferation. Knockdown of validated spliceosome factors such as SNRPG and SNRPA1 affected the levels of small nuclear RNAs, the main catalyzers of the spliceosome. Moreover, high expression of these key candidate hits is associated with poor breast cancer metastasis free survival. To investigate the downstream mechanisms and splicing patterns controlled by our candidate genes we performed RNA sequencing on both control and siRNA mediated knockdown cells. Interestingly, knockdown of our hits affect extracellular matrix pathways that are essential in tumor cell migration and invasion. Altogether our data indicate a key role for spliceosome factors in the control of breast cancer progression which provide new leads for future therapeutic intervention. Citation Format: Esmee Koedoot, Sylvia Le Dévédec, Bob van de Water. Systematic assessment of spliceosome components as drivers of breast cancer progression [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 893. doi:10.1158/1538-7445.AM2017-893
Mammography screening nearly halves breast cancer mortality
Authors: S. Mayor
Journal: BMJ (2003)

Mammography screening has cut the number of deaths from breast cancer by almost half, according to studies of screening programmes in two European countries.

The first study compared deaths from breast cancer diagnosed in two Swedish counties in the 20 years before screening was introduced, 1958 to 1977, with the 20 years after, 1978 to 1997 ( Lancet 2003;361:1405-10). The study, which included 210000 women, showed that the unadjusted risk of death from breast cancer dropped after the introduction of screening by 23% in women aged 40–69 years (relative risk 0.77 (95% confidence interval 0.70 to 0.85; P<0.0001)).

The reduction in this age group was …
Abstract 1166: Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic
Authors: Verónica Alcolea, Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Rosalyn B. Irby, Juan Palop, Shantu Amin, Carmen Sanmartín, Arun K. Sharma
Journal: Cancer Research (2017)

Abstract The prognosis for patients with metastatic melanoma remains very poor. Constitutive STAT3 activation has been correlated to larger tumor size, metastasis, acquired resistance against vemurafenib (PLX-4032), and poor patient survival suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno-/isothio-urea derivatives (compounds 1/3) were studied in a panel of five melanoma cell lines, including B-RAFV600E mutant and wild type (WT) cells. Compound 1 (IC50 range 0.8-3.8 µM) showed lower IC50 values than 3 (IC50 range 8.1-38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 range 0.4-&amp;gt;50 µM), especially at shorter treatment time (24 h). These effects are long-lasting since melanoma cells did not recover their proliferative potential after 14 days of the treatment. In addition, we confirmed that compound 1 induces cell death by apoptosis using Live and Dead, Annexin V and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduces protein levels of STAT3 and its phosphorylation, as well as decreases the expression of STAT3 regulated genes involved in survival and metastasis such as survivin and c-myc. Compound 1 also upregulates the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of 1 with SH2 domain of STAT3 suggesting its activity through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of STAT3 pathway to non-specifically target both B-RAF mutant and WT melanoma cells with much better cytotoxicity than the current therapy PLX-4032. Citation Format: Verónica Alcolea, Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Rosalyn B. Irby, Juan Palop, Shantu Amin, Carmen Sanmartín, Arun K. Sharma. Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic [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 1166. doi:10.1158/1538-7445.AM2017-1166
Abstract 1524: BCL6 modulates the TP53 and STAT pathways in glioma
Authors: Ye Chen, Liang Xu, Marina Dutra-Clarke, Anand Mayakonda, De-Chen Lin, Lynnette Koh, Yuk Kien Chong, Edwin Sandanaraj, Vikas Madan, Henry Yang, Ngan Doan, Jonathan W. Said, William H. Yong, Markus Müschen, Beng Ti Ang, Carol Tang, Joshua J. Breunig, Phillip Koeffler
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) remains the most aggressive brain malignancy with little improvement in prognosis or therapy for decades. Recently, we identified BCL6, also known as ZBTB27, to be a novel oncogene in GBM. In this study, we performed IHC analysis of 153 primary human glioma specimens and 8 normal brain samples. BCL6 expression is robustly elevated in tumor samples and positively correlated with glioma pathological grade. High BCL6 expression strongly predicts a worse prognosis of GBM patients. Depletion of BCL6 in human GBM cells reduced the incorporation of BrdU, promoted the cellular senescence and inhibited the growth of human GBM cells in vivo. Next, genome-wide occupancy of BCL6 in GBM cells was characterized by ChIP-seq assay. Genomic regions centered on BCL6 peaks are co-enriched with RNA-Pol II and flanked with strong H3K27ac and H3K4me3 modifications. MYC and two long non-coding RNAs MALAT1 and NEAT1 were identified as novel BCL6 targets in GBM. Moreover, pathway enrichment analysis of BCL6 peak-associated genes reveals a significant enrichment of JAK-STAT, TP53, ERBB and MAPK pathways. We demostrated further that BCL6 represses the TP53 pathway and promotes the JAK-STAT pathway activation in GBM cells. Together, our findings uncover potential downstream targets and provide a better understanding of BCL6 function in GBM. Citation Format: Ye Chen, Liang Xu, Marina Dutra-Clarke, Anand Mayakonda, De-Chen Lin, Lynnette Koh, Yuk Kien Chong, Edwin Sandanaraj, Vikas Madan, Henry Yang, Ngan Doan, Jonathan W. Said, William H. Yong, Markus Müschen, Beng Ti Ang, Carol Tang, Joshua J. Breunig, Phillip Koeffler. BCL6 modulates the TP53 and STAT pathways in glioma [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 1524. doi:10.1158/1538-7445.AM2017-1524
An in vivo study on the effect of coating stability on osteointegration performance of collagen/hyaluronic acid multilayer modified titanium implants
Authors: Haiyong Ao, Jiajia Zong, Yanjiao Nie, Yizao Wan, Xiebin Zheng
Journal: Bioactive Materials (2017)

Aseptic loosening of implant is one of the main causes of Ti-based implant failure. In our previous work, a novel stable collagen/hyaluronic acid (Col/HA) multilayer modified titanium coatings (TCs) was developed by layer-by-layer (LBL) covalent immobilization technique, which showed enhanced biological properties compared with TCs that were physically absorbed with Col/HA multilayer