tbuckley/cabot-search huggingface dataset:
Abstract 13937: Electrocardiography-Derived Respiratory Rate Detects Clinical Deterioration in Acute Care Patients With Cardiovascular Disease
Authors: Travis J Moss, Matthew T Clark, James Forrest Calland, Kyle B Enfield, Gina Kim, Michelle A Lynch, Marc I Blatt, Douglas E Lake, J Randall Moorman
Journal: Circulation (2016)

Introduction: Clinical deterioration resulting in ICU transfer occurs in 4 to 5 of every 100 acute care admissions. Early Warning Scores (EWS) identify high risk patients, but rely on intermittent assessments. Continuous ECG not only provides heart rate (HR) and rhythm, but can also estimate respiratory rate (RR). Hypothesis: Continuous ECG data improves the predictive validity of EWS prior to acute deterioration leading to ICU transfer or unanticipated death. Methods: Among floor patients admitted with continuous ECG, we identified those with deterioration resulting in ICU transfer or unanticipated death. We analyzed 60 patient-years of ECG data and applied previously validated methodologies for detection of atrial fibrillation (AF) and estimation of RR. We evaluated the predictive validity of common EWS and compared them to models that incorporate ECG data. We excluded observations after DNR/DNI orders or transitions to comfort care. We calculated the fold change in mortality, and the predictive validity (C-statistic). Results: From 8,033 consecutive admissions, we identified 544 instances of clinical deterioration in 508 admissions. Admissions with events had a 50-fold increase in mortality (19.8% vs 0.4%) despite unexpected deaths accounting for only 6% of all events. We analyzed the 274 deteriorations that had ECG data in the 24-hours leading up to events. EWS had C-statistics ranging from 0.63 to 0.70. A model using only ECG-derived measurements had a C-statistic of 0.67 and the strongest predictors included RR, HR, and AF. Addition of the ECG-only model to the best EWS improved its C-statistic to 0.72. Conclusions: Continuous ECG data improves the ability of intermittent EWS to identify the highest risk patients up to 24-hours in advance of acute clinical deterioration.
Lung injury and fibrosis induced by a mutant form of surfactant protein C
Authors: Timothy S. Blackwell
Journal: Journal of Clinical Investigation (2018)

Although mutant forms of the gene encoding surfactant protein C (SFTPC) have been linked to interstitial lung disease, the mechanisms by which the most common of these mutations, SFTPCI73T, results in lung fibrosis are uncertain. In this issue of the JCI, Nureki et al. developed a knockin mouse model and showed that SFTPCI73T is expressed by alveolar type II (AT2) epithelial cells in the lungs. These mice developed an age-related fibrotic phenotype when the mutant allele was expressed at low levels and acute lung inflammation/injury followed by lung fibrosis when mutant SFTPCI73T expression was enhanced. This work provides important information regarding the impact of AT2 cell dysfunction on fibrotic remodeling in the lungs.
Heterogeneous prognosis among KIT mutation types in adult acute myeloid leukemia patients with t(8;21)
Authors: Ya-Zhen Qin, Hong-Hu Zhu, Qian Jiang, Lan-Ping Xu, Hao Jiang, Yu Wang, Xiao-Su Zhao, Yan-Rong Liu, Xiao-Hui Zhang, Kai-Yan Liu, Xiao-Jun Huang
Journal: Blood Cancer Journal (2018)
Anatomic Properties of Myocardial Bridge Predisposing to Myocardial Infarction
Authors: YukioIshikawa, YoshikiyoAkasaka, KoyuSuzuki, MiekoFujiwara, TakafumiOgawa, KazutoYamazaki, HitoshiNiino, MichioTanaka, KentaroOgata, ShojirohMorinaga, YoshiroEbihara, YutakaKawahara, HitoshiSugiura, ToshiroTakimoto, AkioKomatsu, ToshihitoShinagawa, KazuhiroTaki, HideakiSatoh, KazuakiYamada, MakiYanagida-Iida, ReikoShimokawa, KazuyukiShimada, ChiakiNishimura, KinjiIto, ToshiharuIshii
Journal: Circulation (2009)

Background— A myocardial bridge (MB) that partially covers the course of the left anterior descending coronary artery (LAD) sometimes causes myocardial ischemia, primarily because of hemodynamic deterioration, but without atherosclerosis. However, the mechanism of occurrence of myocardial infarction (MI) as a result of an MB in patients with spontaneously developing atherosclerosis is unclear. Methods and Results— One hundred consecutive autopsied MI hearts either with MBs [MI(+)MB(+) group; n=46] or without MBs (n=54) were obtained, as were 200 normal hearts, 100 with MBs [MI(−)MB(+) group] and 100 without MBs. By microscopy on LADs that were consecutively cross-sectioned at 5-mm intervals, the extent and distribution of LAD atherosclerosis were investigated histomorphometrically in conjunction with the anatomic properties of the MB, such as its thickness, length, and location and the MB muscle index (MB thickness multiplied by MB length), according to MI and MB status. In the MI(+)MB(+) group, the MB sh...
Smooth Muscle–Specific Deletion of Nitric Oxide–Sensitive Guanylyl Cyclase Is Sufficient to Induce Hypertension in Mice
Authors: DieterGroneberg, PeterKönig, AngelaWirth, StefanOffermanns, DorisKoesling, AndreasFriebe
Journal: Circulation (2010)

Background— Arterial hypertension is one of the major diseases in industrial countries and a major cause of mortality. One of the main vascular factors responsible for the relaxation of blood vessels and regulation of blood pressure is nitric oxide (NO). NO acts predominantly via NO-sensitive guanylyl cyclase (NO-GC), which is made up of 2 different subunits (α and β). Deletion of the β1 subunit leads to a global NO-GC knockout, and these mice are hypertensive. However, global deletion of NO-GC in mice does not allow identification of the cell/tissue type responsible for the elevated blood pressure. Methods and Results— To determine the relative contribution of smooth muscle cells to the hypertension seen in NO-GC knockout mice, we generated smooth muscle–specific knockout mice for the β1 subunit of NO-GC using a tamoxifen-inducible system. Male mice were investigated because the Cre transgene used is located on the Y chromosome. Tamoxifen injection led to a rapid reduction of NO-GC expression in smooth m...
Response to Letter Regarding Article, “Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects”
Authors: ReneBaudrand, LuminitaPojoga, AnandVaidya, AmandaGarza, PaulVöhringer, XavierJeunemaitre, PaulHopkins, ThamYao, JonathanWilliams, GailAdler, GordonWilliams
Journal: Circulation (2016)
Abstract 17857: Clinical Outcomes in Patients with Takayasu’s Arteritis: Retrospective Analysis From National Inpatient Sample Database
Authors: JalajGarg, ParasuramKrishnamoorthy, ChandrasekarPalaniswamy, AbhishekSharma, DiwakarJain, SunnyGoel, HasanAhmad, GreggLanier
Journal: Circulation (2014)

Background: Takayasu’s arteritis (TA) is an inflammatory condition of unknown etiology involving large cardiac vessels, predominantly the aorta and its major branches.. We aimed to determine the cardiac manifestations and predictors of mortality in patients with TA in the United States. Methods: All patients (≥ 18 years) diagnosed with TA in the Nationwide Inpatient Sample (NIS) 2009 - 2010 database using the International Classification of Diseases 9th revision (ICD 9 code 446.7) were included in the analysis. We analyzed demographics, traditional risk factors, cardiac manifestations and predictors of mortality in patients with TA. Results: TA constituted 0.003% (n=1,411) of all in-hospital admissions. The mean age was 51 years, 78.6% were women, 66.46% whites and only 3.3% were Asian. Traditional risk factors prevalent in our study were hypertension (61.5%), hyperlipidemia (26.2%), diabetes (23%), smoking (18.6%), and obesity (9.8%) with no significant difference between men and women (except dyslipidem...
Abstract 3670: Urine- and blood-based DNA+RNA liquid biopsy tests in prostate, bladder and kidney cancers
Authors: Amy Wang, Zhixin Zhao, Cheng Xie, Tak Cheung, Carlos Montesinos, Phoebe Zhang, Pan Du, Jianjun Yu, Shidong Jia
Journal: Cancer Research (2018)

Abstract The estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths by 2020. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. The recent tremendous success in cell-free DNA (cfDNA) blood test has laid the groundwork for using body fluids such as blood and urine as minimally invasive “liquid biopsies” to identify RNA- and DNA-based molecular biomarkers in urologic malignancies. Here we report the development and clinical application of PrediSeq panel, a urine- and blood-based next generation sequencing-based diagnostics assay that offers integrated genomic cfDNA and cell-free RNA (cfRNA) profiling of genitourinary cancers to detect RNA-based splicing variants (e.g. AR-V7) and rearrangement (e.g. TMPRSS2-ERG), DNA/RNA-based point mutation (e.g. p53, PIK3CA, FGFRs), DNA-based copy number change (e.g. AR) as well as tumor mutation burden (TMB) and microsatellite instability (MSI) using a single tube of blood and/or urine sample in prostate, bladder, and kidney cancers, respectively. In addition to NGS-based multiplex test, we also developed a Bio-Rad digital PCR assay measuring drug response and resistance biomarkers including AR-V7 and PD-L1. Collectively, PrediSeq NGS and ddPCR assays offer comprehensive genomic profiling of both cfDNA and cfRNA using blood and/or urine samples in patients with genitourinary cancers. The successful development and clinical validation of these tests has potential to enable early diagnosis, cancer screening, and precision medicine in genitourinary cancers. Citation Format: Amy Wang, Zhixin Zhao, Cheng Xie, Tak Cheung, Carlos Montesinos, Phoebe Zhang, Pan Du, Jianjun Yu, Shidong Jia. Urine- and blood-based DNA+RNA liquid biopsy tests in prostate, bladder and kidney cancers [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 3670.
Clinical outcomes and emergent circulating tumor (ct)DNA <i>RAS</i> mutations and allele fraction for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study.
Authors: Timothy Jay Price, Marc Peeters, Michael Boedigheimer, Tae Won Kim, Peter Gibbs, Anne L. Thomas, Kristina Hool, Agnes Ang, Bruce A. Bach
Journal: Journal of Clinical Oncology (2017)

3584 Background: ASPECCT was a phase III clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This analysis explores the relationship between circulating levels of mutations and clinical outcomes for panitumumab-treated subjects using univariate and multivariate models that treat total mutational load as a continuous measure. Methods: 238 subjects treated with panitumumab had paired plasma samples at baseline and post-treatment (PT). Samples were analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). The fraction of mutant RAS reads was evaluated for association with tumor response (by RECIST) and overall survival using univariate and multivariate Cox proportional hazards models. Results: 52% of the subjects who were RAS wild-type by plasma at baseline never developed a RAS mutation. For those with mutant RAS ctDNA ( KRAS+ NRAS) detected at baseline or PT, there was an overall increase in RAS mutant DNA fraction at PT compared to baseline. By non-parametric analysis, there was no difference in the distribution of baseline mutant RAS fraction between those who achieved stable disease (SD) or those with progression ( P = 0.09). There was also no difference in the increase in mutant RAS fraction on therapy between subjects with SD or progressive disease (PD). In addition, RAS mutation was not required for progression: 48% of subjects with PD had no RAS mutant DNA detected. Conclusions: In this exploratory analysis, baseline plasma mutant RAS fraction is an unreliable predictor of subsequent tumor response. Subjects with objective response or SD may have stable or rising levels of mutant RAS DNA. Subjects without any detectable RAS mutation still experience PD. These findings suggest that detectable plasma ctDNA RAS mutations do not necessarily predict response to panitumumab and should be interpreted with caution. Further work is needed to establish clinically relevant and validated thresholds. Clinical trial information: NCT01001377.
Abstract 18817: The Four Statin Benefit Groups Defined by the 2013 ACC/AHA Guideline are Characterized by Increased Plasma Level of Electronegative LDL
Authors: Chih-ShengChu, Liang-YinKe, Hua-ChenChan, Hsiu-ChuaChan, Chih-ChiehChen, Kai-HungCheng, Hsiang-ChunLee, Hsuan-FuKuo, Ching-TangChang, Sheng-HsiungSheu, Wen-TerLai, Chu-HuangChen
Journal: Circulation (2014)

Background: Anion-exchange chromatography has identified L5 as the most electronegative entity of charge-defined LDL subfractions, L1-L5. In patients with ST-elevation myocardial infarction, L5 is markedly elevated and can enhance platelet aggregation. To further evaluate its clinical relevance, we examined plasma L5 distributions in patients classified as the 4 statin benefit groups (atherosclerotic cardiovascular disease, LDL cholesterol >190 mg/dL, diabetes mellitus, 10-year cardiovascular risk score >7.5%) by the 2013 ACC/AHA guideline. Methods and results: By examining the medical history and clinical profiles, we divided a cohort of 62 asymptomatic patients (59.4±10.5 yr) with 2 or more components of the metabolic syndrome criteria into the statin benefit (n=44) and non-statin benefit (n=18) groups. Although the plasma LDL cholesterol levels did not differ between groups (147±35 vs. 153±49 mg/dL), the statin benefit group had significantly higher L5/LDL% (5.2±7.3% vs. 2.6±1.9%, P=0.031) and L5 conce...
Abstract 15419: Protective Effects of Hoe-642 on the Neuronal Mitochondria in Asphyxial Cardiac Arrest Model in Rats
Authors: Pengjiao Zhang, Jiaxu Dong, Chaoran Nie, Xintong Liu, Lanying Wei, Fei Han
Journal: Circulation (2016)

Introduction: The opening of mitochondrial permeability transition pore (mPTP) was an important event during ischemia/reperfusion injury. HOE-642, an inhibitor of Na+/H+ exchanger 1, delays the ope...
Diagnostic Value of Electrocardiography and Echocardiography for Familial Hypertrophic Cardiomyopathy in a Genotyped Adult Population
Authors: PhilippeCharron, OlivierDubourg, MichelDesnos, RichardIsnard, AlbertHagege, AlainMillaire, LucieCarrier, GiseleBonne, FrédériqueTesson, PascaleRichard, Jean-BrieucBouhour, KettySchwartz, MichelKomajda
Journal: Circulation (1997)

Background The diagnostic value of ECG and echocardiography for familial hypertrophic cardiomyopathy (FHC) has not been reassessed since the development of molecular genetics. The aim of the study was to evaluate it in adults, with the genetic status used as the criterion of reference. Methods and Results Ten families with previously identified mutations were studied (9 mutations in 3 genes). ECG and echocardiography were analyzed in 155 adults, of whom 77 were genetically affected and 78 unaffected. The major diagnostic criteria were, for echocardiography, a left ventricular wall thickness >13 mm and, for ECG, abnormal Q waves, left ventricular hypertrophy, and marked ST-T changes. Minor ECG and echographic abnormalities were also analyzed. (1) Sensitivity and specificity of major criteria were 61% and 97% for ECG and 62% and 100% for echocardiography. (2) Sensitivity but not specificity was age related (from 50% at  50 years old, P<.01) and sex related (83% in men versus 57% in women...
Abstract 3271: A machine learning approach for somatic mutation discovery
Authors: Derrick Wood, James White, Andrew Georgiadis, Beth Van Emburgh, Sonya Parpart-Li, Jason Mitchell, Valsamo Anagnostou, Noushin Niknafs, Rachel Karchin, Eniko Papp, Christine McCord, Peter Loverso, David Riley, Luis A. Diaz, Sian Jones, Mark Sausen, Victor E. Velculescu, Samuel Angiuoli
Journal: Cancer Research (2018)

Abstract Variability in the accuracy for somatic mutation detection may affect discovery of alterations and therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery method based on machine learning approaches that outperformed other methods using tumor alterations that were experimentally validated (sensitivity of 97% vs 90-99%; positive predictive value of 98% vs 34-92%). Analysis of tumor-normal exome data from 1,376 TCGA samples using this method revealed concordance for 74% of mutation calls but also identified likely false positive and negative changes in TCGA data, including in clinically actionable genes. For melanoma and lung cancer patients treated with immune checkpoint inhibitors, determination of high-quality somatic mutation calls improved mutation load-based predictions of clinical outcome. Integration of high-quality mutation detection in clinical NGS analyses improved the accuracy of test results compared to other clinical sequencing analyses not using these approaches (sensitivity of 100% vs 50-97%; positive predictive value of 100% vs 9-66%). These analyses provide an approach for improved identification of tumor-specific mutations and have important implications for research and clinical management of patients with cancer. Citation Format: Derrick Wood, James White, Andrew Georgiadis, Beth Van Emburgh, Sonya Parpart-Li, Jason Mitchell, Valsamo Anagnostou, Noushin Niknafs, Rachel Karchin, Eniko Papp, Christine McCord, Peter Loverso, David Riley, Luis A. Diaz, Sian Jones, Mark Sausen, Victor E. Velculescu, Samuel Angiuoli. A machine learning approach for somatic mutation discovery [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 3271.
Family history–based colorectal cancer screening in Australia: A modelling study of the costs, benefits, and harms of different participation scenarios
Authors: Mary Dillon, Louisa Flander, Daniel D. Buchanan, Finlay A. Macrae, Jon D. Emery, Ingrid M. Winship, Alex Boussioutas, Graham G. Giles, John L. Hopper, Mark A. Jenkins, Driss Ait Ouakrim
Journal: PLoS Medicine (2018)

The Australian National Bowel Cancer Screening Programme (NBCSP) was introduced in 2006. When fully implemented, the programme will invite people aged 50 to 74 to complete an immunochemical faecal occult blood test (iFOBT) every 2 years.To investigate colorectal cancer (CRC) screening occurring outside of the NBCSP, we classified participants (n = 2,480) in the Australasian Colorectal Cancer Family Registry (ACCFR) into 3 risk categories (average, moderately increased, and potentially high) based on CRC family history and assessed their screening practices according to national guidelines. We developed a microsimulation to compare hypothetical screening scenarios (70% and 100% uptake) to current participation levels (baseline) and evaluated clinical outcomes and cost for each risk category. The 2 main limitations of this study are as follows: first, the fact that our cost-effectiveness analysis was performed from a third-party payer perspective, which does not include indirect costs and results in overestimated cost-effectiveness ratios, and second, that our natural history model of CRC does not include polyp sojourn time, which determines the rate of cancerous transformation. Screening uptake was low across all family history risk categories (64%-56% reported no screening). For participants at average risk, 18% reported overscreening, while 37% of those in the highest risk categories screened according to guidelines. Higher screening levels would substantially reduce CRC mortality across all risk categories (95 to 305 fewer deaths per 100,000 persons in the 70% scenario versus baseline). For those at average risk, a fully implemented NBCSP represented the most cost-effective approach to prevent CRC deaths (AUS$13,000-16,000 per quality-adjusted life year [QALY]). For those at moderately increased risk, higher adherence to recommended screening was also highly cost-effective (AUS$19,000-24,000 per QALY).Investing in public health strategies to increase adherence to appropriate CRC screening will save lives and deliver high value for money.
Abstract 3864: Development of high-specific and sensitive reporter assays for the detection of Wnt/β-catenin signaling activity
Authors: Kiyoshi Yamaguchi, Chi Zhu, Tomoyuki Ohsugi, Akari Saku, Tsuneo Ikenoue, Yoichi Furukawa
Journal: Cancer Research (2018)

Abstract The Wnt/β-catenin signaling pathway is involved in development, tissue homeostasis, and regeneration. Since aberrant activation of this pathway plays a crucial role in human carcinogenesis, inhibition of this pathway has been shown to be a promising therapeutic strategy for cancers with de-regulated Wnt signaling. Although cell-based assays using synthetic TCF/LEF reporters (also known as TOPFLASH) have contributed to the discovery of small molecules that modulate Wnt signaling pathway, these assays often raise a problem of the specificity in the screening. In this study, we aimed to develop a specific reporter for the detection of Wnt signaling activity. We performed integrated transcriptome analysis and found that expression of histidine ammonia-lyase gene (HAL) is negatively regulated by β-catenin/TCF. In addition to TOPFLASH, we leveraged a promoter region of HAL as another transcriptional readout of Wnt signaling. Subsequently, HepG2 cells stably expressing both optimized HAL promoter reporter and TOPFLASH reporter were established. Since inhibition of the β-catenin/TCF transcriptional activity decreased TOPFLASH activity and simultaneously increased HAL reporter activity, we termed this assay as a bidirectional reporter assay. To verify the effectiveness of this assay, we compared the number of hits in the screening of a test library using the bidirectional assay with that using the conventional TOPFLASH/FOPFLASH assay. Among the 361 compounds in the library, the bidirectional reporter assay identified 9 hits, while the TOPFLASH/FOPFLASH assay did 79 hits. Four compounds were overlapped between these assays, suggesting that the bidirectional assay decreased false positives compared with the conventional assay. The concept of bidirectional assay might be useful for the screening of compounds that regulate other transcriptional factors and/or disease-associated signaling pathways. Citation Format: Kiyoshi Yamaguchi, Chi Zhu, Tomoyuki Ohsugi, Akari Saku, Tsuneo Ikenoue, Yoichi Furukawa. Development of high-specific and sensitive reporter assays for the detection of Wnt/β-catenin signaling activity [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 3864.