tbuckley/cabot-search huggingface dataset:
Abstract 701: Loss of Krupple-like factor 10 enhanced epithelial-mesenchymal transition of pancreatic cancer by modulating glucose metabolism via Sirt 6 and PKM2
Authors: Yi-Chih Tsai, Su-Liang Chen, HS Vincent Chang, Hui-Ju Ch’ang.
Journal: Cancer Research (2016)

Abstract Introduction: Pancreatic Cancer is well known for its deregulated TGFâ signaling. We have reported that the expression level of Krüpple like factor 10 (Klf10), a TGFâ early response transcription factor, is associated with clinical outcomes of pancreatic cancer patients. In this study, we would like to evaluate the mechanisms of Klf10 in promoting distant metastasis of pancreatic cancer. Materials and Methods: Klf10 over-expressing- or depleting-human pancreatic cancer cell lines were established. Western blot was used to evaluate epithelial-mesenchymal transition (EMT) markers and glycolysis related molecules. Cancer cell migration was measured by trans-well assay. Luciferase-labeled Panc-1 cells with or without Klf10 mRNA silencing were injected via tail veins of NOD/SCID mice to evaluate their metastatic ability. The glucose consumption, lactate production and mitochondrial respiration of pancreatic cancer cells were measured by assay kit or XFe Extracellular Flux Analyzers. Results: Down-regulating Klf10 in Panc-1 cells was associated with enhanced migration and invasion ability by in vitro and in vivo studies. Immunoblots of cell lysates revealed decreased expression level of E-cadherin and increased Twist, MMP9. Glycolysis activity was elevated while mitochondrial respiration decreased after silencing Klf10 mRNA in Panc-1 cells. The phenomenon was in parallel with decreased Sirt 6 and increased HIF-1á as well as PKM2 expression. We demonstrated that Klf10 bind to the promoter and transcriptionally regulated Sirt 6. Modulating Sirt 6 and PKM2 reversed the EMT and metastatic phenotype of Panc-1 cells with Klf10mRNA silencing. Discussion: Loss of Klf10 enhanced the migratory ability of pancreatic cancer cells. Klf10 transcriptionally regulated Sirt 6 which modulated glycolytic enzymes including PKM2 via HIF-1á. Elevated PKM2 promoted EMT phenotype and distant metastasis of pancreatic cancer. Klf10 is a potential prognostic and therapeutic biomarker for pancreatic cancer. Citation Format: Yi-Chih Tsai, Su-Liang Chen, HS Vincent Chang, Hui-Ju Ch’ang. Loss of Krupple-like factor 10 enhanced epithelial-mesenchymal transition of pancreatic cancer by modulating glucose metabolism via Sirt 6 and PKM2. [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 701.
A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank–Starling mechanism
Authors: Abdelaziz Beqqali, Ilse A.E. Bollen, Torsten B. Rasmussen, Maarten M. van den Hoogenhof, Hanneke W.M. van Deutekom, Sebastian Schafer, Jan Haas, Benjamin Meder, Keld E. Sørensen, Ralph J. van Oort, Jens Mogensen, Norbert Hubner, Esther E. Creemers, Jolanda van der Velden, Yigal M. Pinto
Journal: Cardiovascular Research (2016)

Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin ( TTN ). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. We identified a family with DCM carrying a mutation (RBM20 E913K/+ ) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20 E913K/+ carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20 E913K/+ carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20 E913K/+ heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank–Starling mechanism (FSM), which was rescued by protein kinase A treatment. A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20 . This leads to disturbed alternative splicing of TTN , resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.
American College of Cardiology/American Heart Association Clinical Competence Statement on Stress Testing
Authors: George P. Rodgers, John Z. Ayanian, Gary Balady, John W. Beasley, Kenneth A. Brown, Ernest V. Gervino, Stephen Paridon, Miguel Quinones, Robert C. Schlant, William L. Winters, James L. Achord, Alan W. Boone, John W. Hirshfeld, Beverly H. Lorell, George P. Rodgers, Cynthia M. Tracy, Howard H. Weitz
Journal: Circulation (2000)

HomeCirculationVol. 102, No. 14American College of Cardiology/American Heart Association Clinical Competence Statement on Stress Testing
Abstract 4036: Prognostic value of infiltrating immune cell profiling in lung adenocarcinoma
Authors: Yutaka Kurebayashi, Katsura Emoto, Yuichiro Hayashi, Ikuo Kamiyama, Takashi Ohtsuka, Hisao Asamura, Michiie Sakamoto
Journal: Cancer Research (2016)

Abstract Neoplastic cancer cells and cancer stroma (including infiltrating immune cells) determine the biology and prognosis of cancer. Various types of adaptive and innate immune cells are known to infiltrate the cancer stroma. However, the patterns and spatial distribution of immune cell infiltration as well as their association with tumor histology remain poorly understood. To address these issues, we comprehensively analyzed the infiltrating immune cells present in lung adenocarcinoma. The principal types of both adaptive and innate infiltrating immune cells were immunohistochemically evaluated in the predominant histological components of 111 lung adenocarcinomas. The same analysis was also carried out on 143 samples of histological subtypes making up more than 20% of tumors. As a result, plasma cells and B cells with interfollicular distribution were almost exclusively observed in invasive histological subtypes, while increased number of mast cells were observed in noninvasive histological subtypes. Cluster analysis revealed four distinct immunosubtypes: those characterized by high CD8/CD3 ratios with low stromal cellularity (CD8 subtype), those with increased mast cell numbers (mast cell subtype), those with increased macrophage/DC infiltration with variable amounts of T cell infiltration (mϕ/DC subtype), and those with increased plasma cell infiltration in addition to increased macrophage/DC infiltration and variable increases in other infiltrating immune cells (T cells, Tregs, pDCs, and neutrophils) (plasma cell subtype). These immunosubtypes correlated with histological subtypes. Univariate and multivariate analyses identified the plasma cell subtype as an independent negative prognostic factor. Furthermore, we found that these plasma cells may be one of the major producers of immunosuppressive cytokine IL-35 in cancer stroma. Consequently, comprehensive immunohistochemistry-based profiling of infiltrating immune cells has potential as a powerful method for analyzing the cancer stroma of various cancer tissues. Citation Format: Yutaka Kurebayashi, Katsura Emoto, Yuichiro Hayashi, Ikuo Kamiyama, Takashi Ohtsuka, Hisao Asamura, Michiie Sakamoto. Prognostic value of infiltrating immune cell profiling in lung adenocarcinoma. [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 4036.
NF10 Project: An International, Prospective, Observational Study Of Patients With Indolent Non-Follicular Lymphoma. Analysis Of First 215 Patients
Authors: Luca Arcaini, Stefano Luminari, Marina Cesaretti, Gianluca Gaidano, Sara Rattotti, Michele Merli, Maria Giuseppina Cabras, Michele Spina, Luca Baldini, Alessandra Tedeschi, Lorella Orsucci, Maria Gomes da Silva, Luigi Marcheselli, Torresan Delamein Marcia, Massimo Federico
Journal: Blood (2013)
Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas
Authors: Davide Calebiro, Elisa S. Grassi, Markus Eszlinger, Cristina L. Ronchi, Amod Godbole, Kerstin Bathon, Fabiana Guizzardi, Tiziana de Filippis, Knut Krohn, Holger Jaeschke, Thomas Schwarzmayr, Rifat Bircan, Hulya Iliksu Gozu, Seda Sancak, Marek Niedziela, Tim M. Strom, Martin Fassnacht, Luca Persani, Ralf Paschke
Journal: Journal of Clinical Investigation (2016)

Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein α subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown. Here, we performed whole-exome sequencing in 19 ATAs that were paired with normal DNA samples and identified a recurrent hot-spot mutation (c.1712A>G; p.Gln571Arg) in the enhancer of zeste homolog 1 (EZH1) gene, which codes for a catalytic subunit of the polycomb complex. Targeted screening in an independent cohort confirmed that this mutation occurs with high frequency (27%) in ATAs. EZH1 mutations were strongly associated with known (TSHR, GNAS) or presumed (adenylate cyclase 9 [ADCY9]) alterations in cAMP pathway genes. Furthermore, functional studies revealed that the p.Gln571Arg EZH1 mutation caused increased histone H3 trimethylation and increased proliferation of thyroid cells. In summary, this study revealed that a hot-spot mutation in EZH1 is the second most frequent genetic alteration in ATAs. The association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells.
Abstract 82: Genomic profiling of PDX models across 14 tumor types reveals novel targeted therapeutic opportunities
Authors: Hua Dong, Zhixiang Zhang, Baoyuan Zhang, Xuzhen Tang, Xiangnan Qiang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Norman Zhang, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2016)

Abstract Introduction: Large efforts have been made to detect somatic alterations and corresponding transcriptome changes in cancer patients, which are expected to bring about significant improvements in precision cancer medicine. Here we report a comprehensive list of driver genes and new targets identified in a large pan-cancer cohort of 550 Patient Derived Xenograft (PDX) models across 14 tumor types. Material and methods: For each PDX model with passages 2-4, we performed comprehensive genomic analyses, including whole exome sequencing (WES), SNP6.0 array, and RNASeq (or microarray). The genomic data were used for extrapolating genomic SNV, CNV, mRNA expression levels, and for identifying gene fusions. Genomic profiling data were generated in internal and analyzed by in-house validated pipelines. Results: 220 PDXs were identified to have actionable driver gene mutations /and/or amplifications among 550 models. We identified novel genomic alterations in a number of the PDX models. Significant portion of the models were validated with targeted therapeutic agents (TKI, Abs etc.) and certain cytotoxic agents. All processed data could be accessed via OncoWuXi database: http://onco.wuxiapptec.com and corresponding OncoWuXi APP (App store or onco.wuxiapptec.com/oncowuxi.apk Conclusions: We have established a large panel of PDX models with comprehensive genomic annotation and identified novel targets, with open access database and App. These models could serve as a platform for Mouse Clinical Trial and for pre-clinical development of next generation targeted therapeutic drugs. Citation Format: Hua Dong, Zhixiang Zhang, Baoyuan Zhang, Xuzhen Tang, Xiangnan Qiang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Norman Zhang, Qingyang Gu, Qunsheng Ji. Genomic profiling of PDX models across 14 tumor types reveals novel targeted therapeutic opportunities. [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 82.
Abstract 3117: Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid carcinoma
Authors: Shaham Beg, Maqbool Ahmed, Azhar Hussein, Rong Bu, Zeeshan Qadri, Saif AlSobhi, Fouad Al Dayel, Abdul K. Siraj, Khawla S. Al-Kuraya
Journal: Cancer Research (2016)

Abstract Pleiotrophin (PTN) is a heparin binding growth factor known to have role in neuronal development. It is highly expressed in embryo but has a very limited expression in adult tissues. PTN is considered a proto-oncogene and has been hypothesized to play role in oncogenesis as its expression is found to be increased in many different cancer subtypes. Its role in cell transformation, cell growth, survival, migration and angiogenesis has also been shown in various different types of cancers. The function of PTN is hypothesized to be carried out by its interaction with cell surface proteoglycans or binding to its selective cell surface receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1). The significance of role of PTN in pathogenesis of thyroid cancer has not been explored especially with the fact that papillary thyroid carcinoma (PTC) originating in this ethnic population is the second most common female malignancy, after breast. So in search for novel druggable molecular target we sought for PTN expression in a large cohort of Saudi PTC. We analysed PTN alteration in more than 1000 primary papillary thyroid carcinoma in a tissue microarray format with clinical follow up data. We found that PTN was overexpressed in 65.5% (658/1006) of PTC and was significantly associated with aggressive clinical parameters such as tall cell variant histological subtype (p = 0.0333), extrathyroidal extension (p = 0.0292), lymphovascular invasion (p = 0.0182) and large tumour size (p = 0.0160). Important significant molecular association was seen with PTPRZ-1 (p = 0.0316), Midkine (p = 0.0008) and pSTAT-3 (p&amp;lt;0.0001). Finally patients showing PTN overexpression have worse disease free survival compared to patients showing low or absent PTN expression (p = 0.0218). On multivariate analysis PTN is found to be an independent marker of poor prognosis taking into consideration parameters such as Age, Stage, Lymph node status and Extrathyroidal extension (p = 0.0430). This study highlights the importance of PTN as druggable molecular target which can be therapeutically exploited by its inhibitors in treatment of PTC. Keywords: Papillary Thyroid Cancer; Pleiotrophin; Pleiotrophin Receptor Citation Format: Shaham Beg, Maqbool Ahmed, Azhar Hussein, Rong Bu, Zeeshan Qadri, Saif AlSobhi, Fouad Al Dayel, Abdul K. Siraj, Khawla S. Al-Kuraya. Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid carcinoma. [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 3117.
Management of Relapsed/Refractory Hodgkin Lymphomas After ASCT in Czech Republic.
Authors: Heidi Mocikova, Robert Pytlik, Ludek Raida, Pavel Zak, Jana Markova, Zdenek Kral, Katerina Steinerova, Veronika Valkova, Marie Trnkova, Blanka Vackova, David Pohlreich, Edgar Faber, Karel Indrak, David Belada, Tomas Kozak, Jiri Mayer, Antonin Vitek, Vladimir Koza, Marek Trneny
Journal: Blood (2009)
Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma
Authors: Mathieu Chicard, Sandrine Boyault, Leo Colmet Daage, Wilfrid Richer, David Gentien, Gaelle Pierron, Eve Lapouble, Angela Bellini, Nathalie Clement, Isabelle Iacono, Stéphanie Bréjon, Marjorie Carrere, Cécile Reyes, Toby Hocking, Virginie Bernard, Michel Peuchmaur, Nadège Corradini, Cécile Faure-Conter, Carole Coze, Dominique Plantaz, Anne Sophie Defachelles, Estelle Thebaud, Marion Gambart, Frédéric Millot, Dominique Valteau-Couanet, Jean Michon, Alain Puisieux, Olivier Delattre, Valérie Combaret, Gudrun Schleiermacher
Journal: Clinical Cancer Research (2016)

The tumor genomic copy number profile is of prognostic significance in neuroblastoma patients. We have studied the genomic copy number profile of cell-free DNA (cfDNA) and compared this with primary tumor arrayCGH (aCGH) at diagnosis.In 70 patients, cfDNA genomic copy number profiling was performed using the OncoScan platform. The profiles were classified according to the overall pattern, including numerical chromosome alterations (NCA), segmental chromosome alterations (SCA), and MYCN amplification (MNA).Interpretable and dynamic cfDNA profiles were obtained in 66 of 70 and 52 of 70 cases, respectively. An overall identical genomic profile between tumor aCGH and cfDNA was observed in 47 cases (3 NCAs, 22 SCAs, 22 MNAs). In one case, cfDNA showed an additional SCA not detected by tumor aCGH. In 4 of 8 cases with a silent tumor aCGH profile, cfDNA analysis revealed a dynamic profile (3 SCAs, 1 NCA). In 14 cases, cfDNA analysis did not reveal any copy number changes. A total of 378 breakpoints common to the primary tumor and cfDNA of any given patient were identified, 27 breakpoints were seen by tumor aCGH, and 54 breakpoints were seen in cfDNA only, including two cases with interstitial IGFR1 gains and two alterations targeting TERT CONCLUSIONS: These results demonstrate the feasibility of cfDNA copy number profiling in neuroblastoma patients, with a concordance of the overall genomic profile in aCGH and cfDNA dynamic cases of 97% and a sensitivity of 77%, respectively. Furthermore, neuroblastoma heterogeneity is highlighted, suggesting that cfDNA might reflect genetic alterations of more aggressive cell clones. Clin Cancer Res; 22(22); 5564-73. ©2016 AACRSee related commentary by Janku and Kurzrock, p. 5400.
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Authors: Luigi Di Biase, J. David Burkhardt, Dhanunjaya Lakkireddy, Corrado Carbucicchio, Sanghamitra Mohanty, Prasant Mohanty, Chintan Trivedi, Pasquale Santangeli, Rong Bai, Giovanni Forleo, Rodney Horton, Shane Bailey, Javier Sanchez, Amin Al-Ahmad, Patrick Hranitzky, G. Joseph Gallinghouse, Gemma Pelargonio, Richard H. Hongo, Salwa Beheiry, Steven C. Hao, Madhu Reddy, Antonio Rossillo, Sakis Themistoclakis, Antonio Dello Russo, Michela Casella, Claudio Tondo, Andrea Natale
Journal: Journal of the American College of Cardiology (2016)
Abstract 1166: The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) invasion and migration
Authors: Hsin-Han Hou, Chong-Jen Yu
Journal: Cancer Research (2016)

Abstract Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, has been shown to be upregulated in multiple cancers, including gastric, lung, breast, and prostate cancers, and the enzymatic activities of its extracellular metalloprotrease domain promote breast cancer proliferation and migration through mediating ErbB signaling pathway. The patients with ADAM15 high-expressing lung tumors have shorter survival time and enzymatic activity of ADAM15 extracellular domain activates MMP-9 and promotes NSCLC migration and invasion. We firstly demonstrated other than extracellular enzymetic activity, the longest isoform of ADAM15 (ADAM15 i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, significantly upregulated in primary lung cancer tissues and promoted NSCLC proliferation via growth factor receptor-bound protein 2 (Grb2) and Src homolog 2 domain containing (Shc) association. In this study, we further explore the roles of ADAM15 cytosolic domain in NSCLC invasion and migration. Overexpression of ADAM15 i6 promoted CL1-0 cell invasion and migration according to the transwell and wound healing assay. Ablation of Ras protein activator (RASA)1 and protein tyrosine kinase (PTK)6 attenuated the ADAM15 i6-promoted invasion and migration respectively. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will shed light on the molecular mechanisms of ADAM proteins, and facilitate development of novel therapy in NSCLC. Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) invasion and migration. [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 1166.
Cathecholamines Differently Regulate Human AML and Normal Hematopoietic Progenitor Cell Motility Via miR126 and RGS16
Authors: Abraham Avigdor, Chiara Medaglia, Alexander Kalinkovich, Tomer Itkin, Menachem Bitan, Arnon Nagler, Tsvee Lapidot
Journal: Blood (2013)