tbuckley/cabot-search huggingface dataset:
Abstract 2276: Efficient curation and ontology mapping of clinical and phenotypic data
Authors: Henrik Edgren, Beatriz Mano, Maria Laaksonen
Journal: Cancer Research (2018)

Abstract Heterogeneity within and between data sets is one of the primary impediments to sound and efficient data analysis. This heterogeneity can arise from many sources: data collection practices can change over time, even within the same study; rigorous standards for data encoding may be missing, leading to inter-individual heterogeneity in data encoding; or the data may originally have been collected for a different purpose (e.g. EHR data). Additionally, narrative text, such as medical statements, are inherently unstructured and require curation before analysis. No matter which source(s) heterogeneity derives from, curation of the data is necessary for efficient, accurate and reproducible data analysis. This not only includes correcting errors and standardizing encoding, but also extends to enriching the data through mapping it to relevant medical ontologies, such as SNOMED CT, or other standardized terminologies, such as Research Resource Identifiers. To solve the most common issues in clinical and phenotypic data curation, we have developed the AccurateTM data curation and ontology mapping solution. It combines an intuitive web-based user interface for data cleaning with efficient solutions for semi-automated ontology mapping of both structured data and narrative text. For structured data, tokenized and stemmed data items are mapped against ontologies indexed in Elasticsearch. Term names, their synonyms and the local ontology structure are then used to query the target ontology, with a list of best matches returned along with a quality score for the mapping. Ontology tagging of narrative text is based on a sentence-based deep learning approach, analyzing sentences to classify and ontology map identified text units. In practice, combining a bidirectional long short term memory network with a conditional random field model into a named entity recognition system (bio-NER). Preliminary benchmarking of the bio-NER system on the MIMIC III data set suggests good specificity and sensitivity for identification of biomedically relevant concepts. In summary, we here present an intuitive and highly efficient solution for curating clinical and phenotypic data, as well as enriching it using ontology mapping of both structured and narrative data. Citation Format: Henrik Edgren, Beatriz Mano, Maria Laaksonen. Efficient curation and ontology mapping of clinical and phenotypic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2276.
Morphology of Exertion-Triggered Plaque Rupture in Patients With Acute Coronary Syndrome
Authors: AtsushiTanaka, ToshioImanishi, HironoriKitabata, TakashiKubo, ShigehoTakarada, TakashiTanimoto, AkioKuroi, HirotoTsujioka, HideyukiIkejima, SatoshiUeno, HideakiKataiwa, KeishiOkouchi, ManabuKashiwaghi, HirokiMatsumoto, KazushiTakemoto, NobuoNakamura, KumikoHirata, MasatoMizukoshi, TakashiAkasaka
Journal: Circulation (2008)

Background— Plaque rupture and secondary thrombus formation play key roles in the onset of acute coronary syndrome (ACS). One pathological study suggested that the morphologies of plaque rupture differed between rest-onset and exertion-triggered rupture in men who experienced sudden death. The aim of the present study was to use optical coherence tomography to investigate the relationship in patients with ACS between the morphology of a ruptured plaque and the patient’s activity at the onset of ACS. Methods and Results— The study population was drawn from 43 consecutive ACS patients (with or without ST-segment elevation) who underwent optical coherence tomography and presented with a ruptured plaque at the culprit site. Patients were divided into a rest group and an exertion group on the basis of their activities at the onset of ACS. The thickness of the broken fibrous cap correlated positively with activity at the onset of ACS. The culprit plaque ruptured at the shoulder more frequently in the exertion g...
Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension
Authors: NoritoshiNagaya, ToshioNishikimi, MasaakiUematsu, ToruSatoh, ShingoKyotani, FumioSakamaki, MikioKakishita, KengoFukushima, YoshiakiOkano, NorifumiNakanishi, KunioMiyatake, KenjiKangawa
Journal: Circulation (2000)

Background—Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH). Methods and Results—Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (≥150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P<0.05). Plasma BNP in survivors decreased signi...
Loss of MST/Hippo Signaling in a Genetically Engineered Mouse Model of Fusion-Positive Rhabdomyosarcoma Accelerates Tumorigenesis
Authors: Kristianne M. Oristian, Lisa E.S. Crose, Nina Kuprasertkul, Rex C. Bentley, Yi-Tzu Lin, Nerissa Williams, David G. Kirsch, Corinne M. Linardic
Journal: Cancer Research (2018)

A hallmark of fusion-positive alveolar rhabdomyosarcoma (aRMS) is the presence of a chromosomal translocation encoding the PAX3-FOXO1 fusion oncogene. Primary cell-based modeling experiments have shown that PAX3-FOXO1 is necessary, but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously, we showed that PAX3-FOXO1-positive aRMS is promoted by dysregulated Hippo pathway signaling, as demonstrated by increased YAP1 expression and decreased MST activity. We hypothesized that ablating MST/Hippo signaling in a genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis. To this end, MST1/2-floxed (Stk3F/F;Stk4F/F ) mice were crossed with a previously established aRMS GEMM driven by conditional expression of Pax3:Foxo1 from the endogenous Pax3 locus and conditional loss of Cdkn2a in Myf6 (myogenic factor 6)-expressing cells. Compared with Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ controls, Stk3F/F;Stk4F/F;Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ animals displayed accelerated tumorigenesis (P < 0.0001) and increased tumor penetrance (88% vs. 27%). GEMM tumors were histologically consistent with aRMS. GEMM tumor-derived cell lines showed increased proliferation and invasion and decreased senescence and myogenic differentiation. These data suggest that loss of MST/Hippo signaling acts with Pax3:Foxo1 expression and Cdkn2a loss to promote tumorigenesis. The rapid onset and increased penetrance of tumorigenesis in this model provide a powerful tool for interrogating aRMS biology and screening novel therapeutics.Significance: A novel mouse model sheds light on the critical role of Hippo/MST downregulation in PAX3-FOXO1-positive rhabdomyosarcoma tumorigenesis. Cancer Res; 78(19); 5513-20. ©2018 AACR.
Abstract 4637: Tumor treating fields (TTFields) have antiproliferative effects on high-grade pediatric brain tumor cell lines
Authors: Joshua Branter, Maria Estevez-Cebrero, Richard Grundy, Surajit Basu, Stuart Smith
Journal: Cancer Research (2018)

Abstract Introduction Approximately 400 children in the UK are diagnosed with a CNS tumor each year, which represents a quarter of childhood cancer cases in the UK. The 5-year survival rate of paediatric brain tumor patients is approximately 75%, but survival remains much worse for some brain tumor patients, particularly high-grade gliomas. Pre-clinical and clinical studies have demonstrated efficacy of TTFields as a treatment for high-grade glioma leading to the approval of TTFields for adult Glioblastoma multiforme (GBM) patients. The lack of overlapping toxicities associated with TTFields has made electric field therapy an attractive treatment strategy for poor prognosis paediatric brain tumors.Methods The inovitro is the laboratory based testing system used to deliver TTFields to cell cultures. inovitro was used to deliver TTFields over 72 hours at a range of clinically relevant frequencies (100-400kHz) to our panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines. The effects of TTFields on cell viability and cell cycle was assessed using Resazurin based metabolic viability tests and flow cytometry. The determined optimal frequency for each cell line was also combined with a mitotic inhibitor to explore synergistic effects. Gene expression changes of TTFields treated cells was investigated. Results TTFields treatment reduces cell viability of all cell lines tested within the frequency panel. The optimum frequencies were between 100 and 400kHz for all cell lines tested. TTFields treatment had effects on cell cycling with increased G2 accumulation of treated cells being observed. Combining TTFields with mitotic inhibitors increased efficacy in an additive fashion. Conclusions This preliminary study has demonstrated efficacy of TTFields on paediatric brain tumor cell lines. The optimal frequencies for all the paediatric GBM cell lines used did not match the 200kHz as previously reported for U-87 MG cells. This report warrants further study into the potential for TTFields therapy for paediatric brain tumor patients. Citation Format: Joshua Branter, Maria Estevez-Cebrero, Richard Grundy, Surajit Basu, Stuart Smith. Tumor treating fields (TTFields) have antiproliferative effects on high-grade pediatric brain tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4637.
Explaining the Phenomenon of Nitrate Tolerance
Authors: ThomasMünzel, AndreasDaiber, AlexanderMülsch
Journal: Circulation Research (2005)

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase have been proposed as superoxide sources. Superoxide and vascular NO rapidly form peroxynitrite, which aggravates tolerance by promoting NO synthase uncoupling and inhibition of soluble guanylyl cyclase and prostacyclin synthase. This oxidative stress concept may explain why radical scavengers and substances, which redu...
Abstract 1027: Regulatory T-cell genes drive altered immune microenvironment in adult solid cancers and allow for immune contextual patient subtyping
Authors: Jurriaan Brouwer, Wei-Yi Cheng, Anna Bauer-Mehren, Daniela Maisel, Katharina Lechner, Emilia Andersson, Joel T. Dudley, Francesca Milletti
Journal: Cancer Research (2018)

Abstract The tumor microenvironment is an important factor in cancer immunotherapy response. To further understand how a tumor affects the local immune system, we analyzed immune gene expression differences between matching normal and tumor tissues. We analyzed previously published and new gene expression data from solid cancers and isolated immune cell populations. We also determined the correlation between CD8, FoxP3 immunohistochemistry (IHC) and immune-related genes. Across solid TCGA cancers, we observed that regulatory T-cells (Tregs) were one of the main drivers of immune gene expression differences between normal and tumor tissues. A tumor-specific CD8 signature had slightly lower scores in tumor tissues compared to normal of most (12 of 16) cancers, while a Treg signature score was higher in tumor tissues of all cancers except liver. We clustered TCGA colorectal samples (626 patients) and a new separate testing data set (60 patients) into two groups according to Treg gene signature expression. The High Treg cluster had more colorectal tumors that were Consensus Molecular Subtype 1/4, right-sided and microsatellite-instable, compared to the Low Treg cluster. Finally, we determined the correlation between CD8, FoxP3 immunohistochemistry (IHC) and our gene signatures and found that in this small data set correlation between signature and IHC overall was low, but samples in the High Treg cluster had significantly more CD8+ and FoxP3+ cells compared to the Low Treg cluster. We conclude that high Treg signature expression scores correlate with high overall immune gene expression. Using this novel way of classifying patients, more colorectal tumors with high immune activation were identified compared to other colorectal subtyping methods. Further research will reveal if this Treg-based subtyping improves the identification of patients that may benefit from cancer immunotherapy. Citation Format: Jurriaan Brouwer, Wei-Yi Cheng, Anna Bauer-Mehren, Daniela Maisel, Katharina Lechner, Emilia Andersson, Joel T. Dudley, Francesca Milletti. Regulatory T-cell genes drive altered immune microenvironment in adult solid cancers and allow for immune contextual patient subtyping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1027.
Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production
Authors: SvenWassmann, UlrichLaufs, DjordjeStamenkovic, WolfgangLinz, Johannes-PeterStasch, KatjaAhlbory, RenateRösen, MichaelBöhm, GeorgNickenig
Journal: Circulation (2002)

Background— It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens. Methods and Results— To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg · kg−1 · d−1) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced th...
Abstract 3815: Decomposition of parameters contributing to the improved therapeutic index of ADCs obtained by GlycoConnect™ and HydraSpace™ Technologies
Authors: Floris van Delft, Brian Janssen, Remon van Geel, Marloes Wijdeven, Jorge Verkade, Sander van Berkel
Journal: Cancer Research (2018)

Abstract We have found that conjugation of toxic payloads to the native glycan of a monoclonal antibody by chemoenzymatic remodeling (GlycoConnect™ technology) consistently provides antibody-drug conjugates (ADCs) with enhanced therapeutic index (TI) increases versus those of ADCs prepared by mainstream clinical technologies. For example, head-to-head comparison of GlycoConnect™ ADCs -based on the same antibody and payload components- with the marketed drugs Adcetris and Kadcyla revealed an improvement in both efficacy and safety, which is further enhanced by use of a polar HydraSpace™ technology. Importantly, a similar improvement in TI was noted for comparison of a GlycoConnect™ ADC versus or a site-specific ADC derived from a cysteine-engineered antibody, the most important emerging technology in the clinic. With the aim to better understand the superiority of ADCs based on combined GlycoConnect™ and HydraSpace™ technologies, we have performed in-depth in vitro and in vivo investigation into factors contributing to the overall performance of ADCs prepared by glycan conjugation with a polar spacer. For example, it is found that stability is significantly improved versus mainstream technologies in terms of aggregation and linker stability. Rapid aggregation was observed for both Kadcyla and Adcetris, as well as ADC decomposition due to retro-Michael reaction resulting in free payload (for Adcetris) or albumin-conjugated DM1 (for Kadcyla), as indicated by LC-MS and immunoassay analysis. The latter image is confirmed by in vivo pharmacokinetic analysis, showing a dramatic difference in total antibody versus total conjugated antibody by premature release of payload. Finally, analysis with a solid 3D tumoroid model indicates enhanced penetration of site-specific versus randomly conjugated ADC, which may also contribute to better efficacy in solid tumors. The data generated further underline the importance of conjugation and linker technology as critical quality attributes for next-generation ADCs with higher therapeutic index. Citation Format: Floris van Delft, Brian Janssen, Remon van Geel, Marloes Wijdeven, Jorge Verkade, Sander van Berkel. Decomposition of parameters contributing to the improved therapeutic index of ADCs obtained by GlycoConnect™ and HydraSpace™ Technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3815.
Abstract 040: Upregulation Of Cyp Epoxygenase In The Connecting Tubule(cnt)/cortical Collecting Duct (ccd) Is Essential For High Potassium (k) Intake-induced Antihypertensive Effect
Authors: DaohongLin, ChengbiaoZhang, LijunWang, WenhuiWang
Journal: Circulation Research (2013)

Cyp epoxygenase is responsible for metabolizing arachidonic acid to epoxyeicosatrienoic acid (EET) in the kidney and vascular tissues. EET has been shown to cause vasodilation by stimulating Ca2+-activated K channels in vascular smooth muscles and to have natriuretic effect by inhibiting the epithelial Na channel (ENaC) in the kidney. In the present study we used real time PCR technique to examine the effect of high salt intake or high K intake on Cyp2c44 (a major type of Cyp epoxygenase in the mouse kidney) in the proximal tubule (PxT), thick ascending limb (TAL), distal convoluted tubule (DCT) and the CNT/CCD. An increase in dietary Na content stimulates the expression of Cyp2c4 in TAL, DCT and CNT/CCD but not in PxT while an increase in dietary K intake augments the expression of Cyp2c44 only in DCT and CNT/CCD. Neither high salt intake nor high K intake has a significant effect on the blood pressure (BP) in wt mice. However, high K intake increased BP in CNT/CCD specific conditional knockout (KO) mice...
LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis
Authors: David Bauché, Barbara Joyce-Shaikh, Renu Jain, Jeff Grein, Karin S. Ku, Wendy M. Blumenschein, Stephanie C. Ganal-Vonarburg, Douglas C. Wilson, Terrill K. McClanahan, Rene de Waal Malefyt, Andrew J. Macpherson, Lakshmanan Annamalai, Jennifer H. Yearley, Daniel J. Cua
Journal: Immunity (2018)
Transplanting Hepatitis C–Seropositive, Nucleic Acid Test–Negative Donor Organs Into Hepatitis C–Negative Recipients
Authors: Trana Hussaini, Mel Krajden, Robert A. Mitchell, Eric M. Yoshida
Journal: Hepatology (2018)

Dear Editor, To the Editor: We read with interest the paper by Bari and collogues reporting a higher than expected rate of hepatitis C virus (HCV) transmission when using liver allografts from nonviremic HCV‐seropositive donors for HCV‐seronegative recipients.(1) In this small, single‐center, prospective cohort, 25 patients without HCV received allografts from high‐risk donors who were HCV‐seropositive but nucleic acid testing (NAT)–negative. Four recipients (16%) developed HCV viremia posttransplantation, a rate much higher than previously anticipated. It is of note that all 4 donors who transmitted HCV were younger than 35 years with a history of intravenous drug use and that 3 died as a result of drug overdose. In all 4 donors, HCV NAT was performed within the window period of 7 days postexposure, when false‐negative NAT is a real possibility.(2) The 16% HCV transmission rate is higher than expected, even with high‐risk donors, and could simply represent a random cluster in a small cohort. Indeed, larger population‐based studies are needed to truly quantify the risk of HCV transmission with such donors. Although a possible 16% transmission rate may cause transplant centers to hesitate to transplant these organs into noninfected recipients, given the scarcity of suitable organs for transplantation, wait list mortality, and the availability of highly efficacious direct‐acting antiviral agents, the real question should not be "Should we use HCV‐seropositive, NAT‐negative donors for HCV‐negative recipients?" but "How can we best use HCV NAT‐positive donors for HCV‐negative recipients?"(3) As such, the results of this study should not deter the transplant surgeons/physicians from accepting HCV‐seropositive, NAT‐negative organs for HCV‐unexposed recipients when the transplant outcomes are comparable between NAT‐positive and NAT‐negative allografts and the likelihood of death while on the wait list is significant. Potential conflict of interest Dr. Yoshida is on the speakers' bureau for and received grants from Gilead, Merck, AbbVie, and Intercept. He is on the speakers' bureau for Celgene. He received grants from Janssen and Springbank.