tbuckley/cabot-search huggingface dataset:
Abstract 1332: NOTCH - HEY1 pathway induces EMT in head and neck squamous cell carcinoma
Authors: Takahito Fukusumi, Theresa W. Guo, Shuling Ren, Akihiro Sakai, Mizuo Ando, Sunny Haft, Chao Liu, Joseph A. Califano
Journal: Cancer Research (2017)

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is noted to have a NOTCH mutation rate of 20% within the Cancer Genome Atlas (TCGA) dataset consistent with tumor suppressor gene status. However, NOTCH genes are also upregulated in wild type HNSCC and show signs of downstream activation in a substantial proportion of HNSCC. In this study, we aimed to further explore the potential for NOTCH pathways to be activated in HNSCC. Material and Methods mRNA sequence of TCGA data includes 520 HNSCC tumors and 46 normal tissues. We used 447 HNSCC excluding 73 tumors with NOTCH mutations. The activated groups of NOTCH downstream genes were defined as tumors with expression 1 standard deviation above the mean of normal tissue. We used four HNSCC cell lines (SKN3, Cal27, SCC61, SCC090) to ascertain the results of the TCGA analysis in vitro. Result In TCGA analysis, HEY1 activated HNSCC had significant more expression of NOTCH pathway genes. In particular NOTCH4 had the most significant correlation with HEY1 activation among NOTCH receptors. To confirm this result in vitro, HEY1 expression was compared between si-control and si-NOTCH4 of SKN3, Cal27, SCC61 and SCC090. As expected, HEY1 expression in all si-NOTCH4 treated cell lines were significant decreased. Next, we examined the relationship about NOTCH4 and an epithelial mesenchymal transition phenotype (EMT). Using TCGA data, we found that mesenchymal marker genes were significantly increased in high NOTCH4 group. In vitro experiments, si-NOTCH4 cells decreased mesenchymal marker gene expression such as Fibronectin and TWIST1. We also examined HEY1 function. Similar to NOTCH4, it was found that HEY1 is significantly related to EMT in silico and in vitro. Conclusion The NOTCH4-HEY1 pathway is significantly upregulated in HNSCC and induces EMT. Citation Format: Takahito Fukusumi, Theresa W. Guo, Shuling Ren, Akihiro Sakai, Mizuo Ando, Sunny Haft, Chao Liu, Joseph A. Califano. NOTCH - HEY1 pathway induces EMT in head and neck squamous cell carcinoma [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 1332. doi:10.1158/1538-7445.AM2017-1332
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma
Authors: Koji Shindo, Jun Yu, Masaya Suenaga, Shahriar Fesharakizadeh, Christy Cho, Anne Macgregor-Das, Abdulrehman Siddiqui, P. Dane Witmer, Koji Tamura, Tae Jun Song, Jose Alejandro Navarro Almario, Aaron Brant, Michael Borges, Madeline Ford, Thomas Barkley, Jin He, Matthew J. Weiss, Christopher L. Wolfgang, Nicholas J. Roberts, Ralph H. Hruban, Alison P. Klein, Michael Goggins
Journal: Journal of Clinical Oncology (2017)

Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.
Burden of paediatric respiratory syncytial virus disease and potential effect of different immunisation strategies: a modelling and cost-effectiveness analysis for England
Authors: Deborah Cromer, Albert Jan van Hoek, Anthony T Newall, Andrew J Pollard, Mark Jit
Journal: The Lancet Public Health (2017)

Vaccines and prophylactic antibodies against respiratory syncytial virus (RSV) are in development and likely to be available in the next 5-10 years. The most efficient way to use these products when they become available is an important consideration for public health decision makers.We performed a multivariate regression analysis to estimate the burden of RSV in children younger than 5 years in England (UK), a representative high-income temperate country, and used these results to assess the potential effect of different RSV immunisation strategies (targeting vaccination for infants, or pregnant women, or prophylactic antibodies for neonates). We did a cost-effectiveness analysis for these strategies, implemented either separately or concurrently, and assessed the effect of restricting vaccination to certain months of the year.We estimated that RSV is responsible for 12 primary care consultations (95% CI 11·9-12·1) and 0·9 admissions to hospital annually per 100 children younger than 5 years (95% CI 0·89-0·90), with the major burden occurring in infants younger than 6 months. The most cost-effective strategy was to selectively immunise all children born before the start of the RSV season (maximum price of £220 [95% uncertainty interval (UI) 208-232] per vaccine, for an incremental cost-effectiveness ratio of £20 000 per quality-adjusted life-year). The maximum price per fully protected person that should be paid for the infant, newborn, and maternal strategies without seasonal restrictions was £192 (95% UI 168-219), £81 (76-86), and £54 (51-57), respectively.Nearly double the number of primary care consultations, and nearly five times the number of admissions to hospital occurred with RSV compared with influenza. RSV vaccine and antibody strategies are likely to be cost-effective if they can be priced below around £200 per fully protected person. A seasonal vaccination strategy is likely to provide the most direct benefits. Herd effects might render a year-round infant vaccination strategy more appealing, although it is currently unclear whether such a programme would induce herd effects.UK National Institute for Health Research.
Abstract 2383: Nicotinamide N-methyltransferase inhibits Protein Phosphatase 2A activity by promoting Y307 phosphorylation
Authors: John R. Jacob, Arnab Chakravarti, Kamalakannan Palanichamy
Journal: Cancer Research (2017)

Abstract Recent evidence indicates that suppression of protein phosphatase 2A (PP2A) activity plays an essential role in malignant transformation and cancer cell maintenance. Despite the importance of PP2A as a tumor suppressor in cancer, the mechanisms by which other enzymes regulate PP2A remain largely unknown. We recently identified Nicotinamide N-methyltransferase (NNMT) as a novel regulator of PP2A activity in glioblastoma (GBM). NNMT is a cytosolic N-methyl transferase which utilizes methyl groups from S-Adenosyl methionine (SAM), forming the by-product S-Adenosyl Homocysteine (SAH). PP2A becomes activated following the trimer formation of the three PP2A subunits, which requires the methylation of the catalytic subunit of PP2A (PP2A C) at L309.In cancer, NNMT has been reported to decrease the cellular methylation potential (SAM:SAH) and correspond with decreased PP2A activity. It was hypothesized that the decrease in methylation potential accounts for the decrease in PP2A activity by kinetically disfavoring the methylation of PP2A C. Interestingly, when we overexpressed NNMT in GBM cell lines and used LC-MS/MS (LC-MS Quadrupole Time-of-Flight and LC-MS Triple Quad) to monitor the methylation potential, we discovered that overexpression of NNMT increased methylation potential, however, still lead to a decrease in PP2A activity. As a result, we hypothesized that NNMT suppresses PP2A activity in a methylation-independent manner. In an effort to identify an alternative mechanism by which NNMT decreases PP2A activity, we found that NNMT expression was required for the phosphorylation of PP2A C at residue T307, which inhibits PP2A trimer formation and activation. Further, we found that NNMT expression leads to the constitutive activation of the PP2A target serine/threonine kinases (STKs): Akt, MAPK, and SAPK/JNK. NNMT silencing resulted in the deactivation of these STKs and radiation-induced cellular stress was not sufficient to rescue their activation. This suggests that NNMT-induced PP2A suppression is essential for the activation of these kinases. Overall, this study demonstrates a novel mechanism independent of methylation by which NNMT represses the activity of tumor suppressor PP2A. Citation Format: John R. Jacob, Arnab Chakravarti, Kamalakannan Palanichamy. Nicotinamide N-methyltransferase inhibits Protein Phosphatase 2A activity by promoting Y307 phosphorylation [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 2383. doi:10.1158/1538-7445.AM2017-2383
Abstract 5946: Universal consent for biospecimens: A novel electronic/video consent
Authors: Arash Naeim, Neil Wenger, Antonia Petruse, Liliana Sanchez, Azita Sharif, Sarah Dry
Journal: Cancer Research (2017)

Abstract Background: Developing innovative, efficient and institutionally scalable bio-specimen consent for remnant tissue that meets the NIH consent guidelines for genomic and molecular analysis is essential for precision medicine efforts in cancer. Solutions in this arena need to satisfy the needs of patients, researchers, ethicists, IRB and compliance leadership, while fitting as seamlessly as possible into existing clinical workflows. Methods: UCLA developed a video-application kiosk-based approach for providing universal consent to repurpose clinical remnant bio-specimen for research. The process was designed to be self-service, comprehensive yet fast (mean shorter than 5 minute for completion). The consent additionally asked the patient if they were willing to be contacted directly for future research projects. This approach was piloted with 474 patients who were coming in for routine services in laboratory medicine, radiology, oncology, and hospital admissions. Of the pilot population, 175 individuals had targeted surveys to evaluate drivers for opting-in or opting-out of the consent for allowing the collection and use of their remnant tissue for research. The cognitive survey was online and presented immediately after the consent process was completed. Results: The opt-in rate for the pilot was 90.7%, and 56% agreed to direct contact for future research. Only 7% needed help navigating the online consent process. Of the subgroup of pilot population who completed the targeted survey, there was no difference between individuals who opted in and out regarding ease of use, of the consent application with about 75% stating it provided mostly or very useful information, 90% stating it was mostly or very easy to understand, and 85% stating they trusted the information. However, there were significant differences between those that opted-in and opted-out in their beliefs concerning usefulness of tissue, trusting researchers, importance of contributing to science and privacy risk with those opting in strongly supporting these beliefs (&amp;gt;90%) compared to those that opted out (&amp;lt;40%), p&amp;lt;0.001. Conclusions: Video-application approach for allowing individuals to consent for remnant specimens to be collected and used for research, including cancer research, can be efficient, patient-centric and meet the NIH requirements. This method could increase the availability of blood and tissue for cancer research and should be tested for scalability as an enterprise solution. Citation Format: Arash Naeim, Neil Wenger, Antonia Petruse, Liliana Sanchez, Azita Sharif, Sarah Dry. Universal consent for biospecimens: A novel electronic/video consent [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 5946. doi:10.1158/1538-7445.AM2017-5946
Abstract P192: MicroRNA-199b Targets the Nuclear Kinase Dyrk1a in an Auto-Amplification Loop Promoting Calcineurin/NFAT Signaling
Authors: Kanita Salic, Paula A da Costa Martins, Monika M Gladka, Stefanos Leptidis, Hamid el Azzouzi, Arne Hansen, Gianluigi Condorelli, Maria L Arbones, Thomas Eschenhagen, Leon J De Windt
Journal: Circulation Research (2011)

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of ∼22 nucleotides in length, and growing evidence indicates that miRs are implicated in myocardial disease processes. A key pathway involved in heart failure consists of the phosphatase calcineurin and its downstream transcription factor Nuclear Factor of Activated T-cells (NFAT). We performed microRNA profiling in hearts from calcineurin transgenic mice and demonstrated that microRNA-199b (miR-199b) is a direct calcineurin/NFAT target gene. MiR-199b increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism with impact on calcineurin-responsive gene expression. Interestingly, cardiac miR-199b levels inversely correlated with cardiac Dyrk1a expression in biopsies of failing human hearts secondary to ischemic heart disease or non-ischemic dilated cardiomyopathy. Furthermore, mutant mice overexpressing miR-199b or haploinsufficient for Dyrk1a are sensitized to calcineurin/NFAT signaling or pressure overload and exhibit stress-induced cardiomegaly by reduced Dyrk1a expression. From a therapeutic point of view, in vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity, and caused marked inhibition and even reversal of pre-established hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs impact cardiac cellular signaling and gene expression, and implicate miR-199b as a therapeutic disease target in heart failure.
Abstract 1816: Endogenous ADAMTS-13 regulates angiogenesis in cultured human endothelial cells
Authors: Huiyuan Tang, Manfai Lee, Eun Ho Kim, Daniel Bishop, George M. Rodgers
Journal: Cancer Research (2017)

Abstract ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a zinc-containing metalloprotease that cleaves von Willebrand factor (vWf). Previous publications by our laboratory have shown that ADAMTS-13 may also be involved in angiogenesis; for example; addition of exogenous ADAMTS-13 enhances endothelial cell (Lee et al. Microvascular Res 2012; 84:109) and glioblastoma cell (Lee et al. Blood 2013; 122:#2306) migration and proliferation. For this study, we report the successful transient knockdown of endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) via siRNA. 30pmols of ADAMTS-13 siRNA in a six-well plate inhibited HUVEC ADAMTS-13 expression levels by 90% after 24hr incubation, whereas control siRNA did not affect endogenous ADAMTS-13 levels. The knockdown effect was decreased over time: 72hr after the initial knockdown, ADAMTS-13 expression was reduced by only 50%. The effects of reduced endogenous ADAMTS-13 on HUVEC angiogenesis functions were studied. Transfection of HUVEC with 10pmols of ADAMTS-13 siRNA in a 24-well plate resulted in a 21% and 22% decrease in proliferation after 24hr and 48hr incubation, respectively. The effects of ADAMTS-13 knockdown on migration of HUVEC across a scratch wound were also evaluated. 24hr after transfection with control siRNA, there was robust cell migration across the scratch wound. This dramatic migration did not occur with ADAMTS-13 knockdown cells. Decreased expression of endogenous ADAMTS-13 also affected angiogenesis as measured by endothelial cell tube formation using a Matrigel matrix method. The tube lengths, sizes and junction numbers of the ADAMTS-13 knockdown cells were all significantly lower compared to control cells by about 40%. Activity of the AKT pathway, one of the angiogenesis downstream signaling pathways was down-regulated by ADAMTS-13 siRNA while ERK, a component of the MAP kinase pathway was not affected upon knockdown of ADAMTS-13. These data indicate that in cultured endothelial cells, one role of endogenous ADAMTS-13 is regulation of angiogenesis, mediated through the AKT signaling pathway. Overall, our data suggest an additional model of endogenous ADAMTS-13 functionality, beyond that of cleaving von Willebrand factor. Citation Format: Huiyuan Tang, Manfai Lee, Eun Ho Kim, Daniel Bishop, George M. Rodgers. Endogenous ADAMTS-13 regulates angiogenesis in cultured human endothelial cells [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 1816. doi:10.1158/1538-7445.AM2017-1816
Abstract 2565: VCP/p97 segregase-mediated regulation of chromatin-bound PTEN stability
Authors: Jinshan He, Gulzar Wani, Qianzheng Zhu, Altaf A Wani
Journal: Cancer Research (2017)

Abstract Phosphatase and Tensin homolog (PTEN) tumor suppressor protein is associated with many human cancers. PTEN has been shown to accumulate in the nucleus and control DNA repair in response to genotoxic stress. PTEN down-regulation impairs the capacity of global genomic nucleotide excision repair by suppressing the early DNA damage sensor, Xeroderma pigmentosum C (XPC), protein. Our recent work has demonstrated that the Valosin-containing protein (VCP)/p97 segregase participates in proteolytic processing of XPC and Cockayne syndrome B (CSB) proteins. Here, we show that (i) VCP/p97 segregase, in conjunction with its adaptor proteins, specifically extracts PTEN from damaged chromatin for targeted proteasomal degradation, (ii) inhibition of VCP/p97 activity induces the accumulation of PTEN on chromatin, and (iii) VCP/p97 physically interacts with PTEN. Depletion of VCP/p97, in p97-knockout cells or siRNA-mediated ablation in normal cells, affects the stability of PTEN in response to cellular UV irradiation. Results show that compromising the proteasome and VCP/p97 functions causes the accumulation of PTEN accompanied by an increase of UBXD7, proteasomal RPN2 and Sug1 within the chromatin compartment. To our knowledge, this is the first report to reveal that VCP/p97 segregase extracts tumor suppressor PTEN from damaged chromatin. (This work was supported by NIH grants ES002388 and ES012991 to AAW). Citation Format: Jinshan He, Gulzar Wani, Qianzheng Zhu, Altaf A Wani. VCP/p97 segregase-mediated regulation of chromatin-bound PTEN stability [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 2565. doi:10.1158/1538-7445.AM2017-2565
Guidelines Update on Indications for Transcatheter Aortic Valve Replacement
Authors: Rick A. Nishimura, Patrick T. O’Gara, Robert O. Bonow
Journal: JAMA Cardiology (2017)

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Abstract 1616: S100A4 blockage alleviates agonistic anti-CD137 antibody induced liver pathology without disruption of anti-tumor immunity
Authors: Jinhua Zhang, Kun Song, Zhihai Qin
Journal: Cancer Research (2017)

Abstract Liver-related autoimmune toxicities triggered by anti-CD137 agonist antibodies have greatly limited their use in clinic applications. Here we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4+ macrophages into the liver. Depletion of these cells or deficiency of S100A4 decreased inflammatory cytokine profiles, and drastically reduced the number of liver pathogenic CD8+ T cells. Mechanistically, soluble S100A4 directly activated the Akt pathway and specifically prolonged CD8+ T cell survival. Interestingly, one S100A4 neutralizing monoclonal antibody selectively alleviated liver abnormalities but did not affect the anti-tumor immunity induced by anti-CD137 therapy. Thus, our study presents a novel molecular link to the liver pathology induced by an immune stimulatory antibody, and proposes that combinational immunotherapies targeting those pathways could potentially elicit optimal anti-tumor immunity with minimal side effects. Note: This abstract was not presented at the meeting. Citation Format: Jinhua Zhang, Kun Song, Zhihai Qin. S100A4 blockage alleviates agonistic anti-CD137 antibody induced liver pathology without disruption of anti-tumor immunity [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 1616. doi:10.1158/1538-7445.AM2017-1616
Precision Functional Mapping of Individual Human Brains
Authors: Evan M. Gordon, Timothy O. Laumann, Adrian W. Gilmore, Dillan J. Newbold, Deanna J. Greene, Jeffrey J. Berg, Mario Ortega, Catherine Hoyt-Drazen, Caterina Gratton, Haoxin Sun, Jacqueline M. Hampton, Rebecca S. Coalson, Annie L. Nguyen, Kathleen B. McDermott, Joshua S. Shimony, Abraham Z. Snyder, Bradley L. Schlaggar, Steven E. Petersen, Steven M. Nelson, Nico U.F. Dosenbach
Journal: Neuron (2017)