tbuckley/cabot-search huggingface dataset:
Abstract B15: A cancer-specific detection of serum CA125 improves differential diagnosis of epithelial ovarian cancer from benign conditions
Authors: Kaisa Huhtinen, Kamlesh Gidwani, Henna Kekki, Johanna Hynninen, Liina Salminen, Antti Perheentupa, Matti Poutanen, Annika Auranen, Seija Grenman, Urpo Lamminmäki, Olli Carpén, Kim Pettersson
Journal: Clinical Cancer Research (2018)

Abstract Introduction: We have developed an assay that distinguishes CA125 originating from malignant and benign sources. The assay combines conventional immunoassay with the detection of carbohydrates differentially glycosylated in epithelial ovarian cancer (EOC). These glycans can be detected using carbohydrate-reactive lectins. Our recent data showed that CA125 detection using MGL-lectin improves the discrimination of cancerous CA125 from CA125 of endometriosis patients (Gidwani et al., Clin.Chem 2016). The current study extends CA125MGL measurements to a broader sample set and longitudinal collections during EOC treatment and follow-up. Methods: MGL lectin coated onto fluorescent europium-chelate-doped 97-nm nanoparticles was used for detection of the CA125 that was captured on an anti-CA125 antibody immobilized on microtitration wells. Serum samples from high-grade serous EOC or patients with varying benign conditions and healthy controls were analyzed. Results: CA125MGL specifically recognized the CA125 isoform produced by EOC, whereas the recognition of CA125 from nonmalignant conditions was reduced. Serum CA125MGL measurement discriminated better patients with EOC from benign conditions compared with conventional immunoassay. Importantly, discrimination was particularly improved for marginally increased CA125 values that are common in benign conditions. Our data also showed earlier detection of EOC progression, suggesting that the CA125MGL also has potential to improve earlier diagnosis of EOC. Conclusions: The CA125MGL concept could help reduce the false-positive rates of conventional CA125 immunoassays. It carries further potential to improve early diagnosis of EOC as well as follow-up of treatment response. Finally, using appropriate combinations of lectins and antibodies, applying the test concept presented here can also be explored for other diagnostic targets, where changes in glycosylation are indicative of an ongoing disease process. Citation Format: Kaisa Huhtinen, Kamlesh Gidwani, Henna Kekki, Johanna Hynninen, Liina Salminen, Antti Perheentupa, Matti Poutanen, Annika Auranen, Seija Grenman, Urpo Lamminmäki, Olli Carpén, Kim Pettersson. A cancer-specific detection of serum CA125 improves differential diagnosis of epithelial ovarian cancer from benign conditions. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B15.
Mnk1 Is Required for Angiotensin II–Induced Protein Synthesis in Vascular Smooth Muscle Cells
Authors: MariIshida, TakafumiIshida, HidekatsuNakashima, NarimasaMiho, KiyoshiMiyagawa, KazuakiChayama, TetsuyaOshima, MasayukiKambe, MasaoYoshizumi
Journal: Circulation Research (2003)

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal–integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II–induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II–induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II–induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II–induced Mnk1-eIF4E activat...
Abstract 15107: The Immature Right Ventricle Has Impaired Fatty Acid Metabolic Flexibility During Acute Physiologic Stressors
Authors: Masaki Kajimoto, Nuri Muhammad, Nancy G Isern, Christine Des Rosiers, Aaron K Olson, Michael A Portman
Journal: Circulation (2016)

Introduction: To preserve the high energy phosphate reserves needed to maintain contractile function, myocardial substrate metabolism must adapt to acute stressors. Acute right ventricular (RV) fai...
Abstract 4647: Identifying drug targets in sarcoma using machine learning and cell phenotype-based compound screening
Authors: Eric J. Lachacz, Zhi Fen Wu, John L. Bixby, Vance P. Lemmon, Sofia D. Merajver, Hassan Al-Ali, Matthew B. Soellner
Journal: Cancer Research (2018)

Abstract High-throughput phenotypic screens that incorporate compound biochemical activity annotations are positioned for novel target discovery in cancer. We used machine learning approaches to correlate kinome-wide profiling data of a collection of kinase inhibitors with phenotypic cell proliferation data for the same compounds. We assembled a library of profiled kinase inhibitors with diverse chemotypes and kinome-wide selectivities and determined their anti-proliferative activities in a panel of sarcoma cell lines. Using a previously published machine learning algorithm, we related the compound inhibition profiles across 237 kinases to their abilities to inhibit cell proliferation. This identified Protein Kinase D (PRKD) as a putative novel target kinase selectively in synovial sarcoma cell lines, such that its inhibition leads to a decrease in proliferation in these cells. Next, we reasoned that our approach could be leveraged to identify targets that, when co-inhibited, induce a synergistic phenotype. This would enable rational design of drug combinations for further testing as opposed to the labor-intensive, random, pairwise testing commonly performed. To identify targets synergistic with PRKD, we performed a screen of a synovial sarcoma cell line in the presence of a selective PRKD inhibitor. Several kinases became prioritized as new targets in this “synergy screen.” Combining selective inhibitors for each synergistic target, as defined by Chou-Talalay, (here, CDK and AKT) with PRKD inhibitors synergistically reduced synovial sarcoma cell proliferation. Conversely, combining PRKD inhibitors with a selective inhibitor of a kinase that was deprioritized in the synergy screen (p38 MAPK) resulted in non-synergistic or even antagonistic effects. Overall, our approach provides a promising framework to identify new targets of cancer subtypes and a novel methodology to identify new combinational strategies for treatment. Citation Format: Eric J. Lachacz, Zhi Fen Wu, John L. Bixby, Vance P. Lemmon, Sofia D. Merajver, Hassan Al-Ali, Matthew B. Soellner. Identifying drug targets in sarcoma using machine learning and cell phenotype-based compound screening [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 4647.
Abstract 19239: Patient Outcomes and Quality of Life 15 years or more after the Ross Operation in Adults
Authors: Michael Ibrahim, Ryo Torii, Ismail El-Hamamsy, Tarun Mittal, Julien Gaer, Johanna J Takkenberg, Magdi H Yacoub
Journal: Circulation (2014)

Introduction: The Ross operation provides a living aortic valve substitute with very good results in the medium term. There is continuing concern about its durability in adults. Methods: We reviewed a series of patients operated on (by a single surgeon) and prospectively followed up at our centre who underwent the Ross operation at least 15 years before. Results: Among 84 patients (69 male, median age at operation 37.5 (range 19.8 - 64.4)), there were 1 early and 4 late deaths. Actuarial survival was 94.9% (55 patients at risk (PAR)) at 15 years and 87.6% (10 PAR) at 19 years, compared to 95.6% at 15 years and 92.7% at 19 years for an age and sex matched UK population. Actuarial freedom from aortic or pulmonary reoperation was 89% (51 PAR) at 15 years and 72.1% at 19 years (10 PAR). Serial echocardiographic follow-up demonstrates stable aortic root dimensions over time without ventricular dilatation. Figure 1 shows the degree of aortic regurgitation over time, which has not increased in the large majority of patients. We assessed quality of life using the Short Form-36 point questionnaire which was 50·7 [median score, 2014, IQR 43.4-59.7] vs 51·0 [2009, IQR 45·9-56·1], non-significant). This compares favourably with previously published quality of life scores in patients with prosthetic valves. Of note, our oldest patient (a female aged 64 at operation), is now 80 years old with maintained valve and ventricular function, and leading an active life. Conclusions: It is concluded that the Ross operation provides a durable aortic valve and root substitute with good quality of life for periods of up to twenty years.
NAD(P)H Oxidase–Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease
Authors: HuaCai
Journal: Circulation Research (2005)

Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O2·−) and hydrogen peroxide (H2O2) appear most important in redox signaling. Whereas O2·− predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO·), H2O2 influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H2O2 in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase–derived H2O2 amplifies its own production. Recent studies have shown that H2O2 stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H2O2-dependent pa...
Abstract 4133: Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma
Authors: Yun Wei, Victor Maximov, Anna Kenney
Journal: Cancer Research (2018)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Currently, the standard therapy comprising radiation, surgery and chemotherapy “cures” about 70% of medulloblastoma patients. However, these aggressive and non-differential treatment modalities cause lifelong side effects in patients. Medulloblastoma patients are classified into four different subgroups based on transcriptional and molecular profiles, namely WNT, SHH, Group 3, and Group 4. The SHH subgroup accounts for approximately 30% of all medulloblastoma cases and is further subcategorized into TP53 wild type and TP53 deficient subtypes. The importance of TP53 status in SHH medulloblastoma patients has been recently recognized by the association between TP53 mutation and poor prognosis for these patients. However, research findings illustrating TP53 signaling in preclinical models of SHH medulloblastoma are quite limited. Apart from the fact that TP53 mutation is associated with poor survival, 80% of medulloblastoma cases are TP53 wild type. TP53 protein is a tumor suppressor which acts as a checkpoint protein for all types of cells. Cancer cells either mutate TP53 gene or employ other mechanisms such as overexpressing MDM2 to compromise TP53 protein function. Therefore we hypothesize that TP53 function is compromised by highly active MDM2 in TP53 wild type Shh medulloblastoma. Using the SmoA1 mouse model, which closely recapitulates human SHH medulloblastoma, we aim to investigate whether TP53 signaling has been disrupted in Shh medulloblastoma. Surprisingly, we observed relatively higher TP53 protein levels in tumor tissue lysates as compared to that in neighboring normal cerebellum using SmoA1 mice. However, MDM2, the major suppressor of TP53, showed higher phosphorylation at Ser166, which would stabilize MDM2, resulting in degradation of newly-produced TP53 protein. We also found significantly increased protein levels of I2PP2A, an endogenous inhibitor of phosphatase 2A, which can dephosphorylate MDM2 at Ser166. Using COG112, a small molecule inhibitor of I2PP2A, we showed the reactivation of PP2A, concurrent with a decrease of p-MDM2 and an increase of TP53 in a time-dependent manner. From these experiments, we conclude that 1) TP53 pathway is functional in our SmoA1 mouse model; 2) I2PP2A upregulation could be the reason for rapid degradation of TP53 protein in SmoA1 mice. These findings have translational implications as they suggest that targeting I2PP2A in TP53 wild type SHH medulloblastoma patients could be a method of driving tumor cell death, thus resulting in better clinical outcomes for these patients. Citation Format: Yun Wei, Victor Maximov, Anna Kenney. Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma [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 4133.
The Homeobox Gene Lbx1 Specifies a Subpopulation of Cardiac Neural Crest Necessary for Normal Heart Development
Authors: KonstanzeSchäfer, PetraNeuhaus, JuliaKruse, ThomasBraun
Journal: Circulation Research (2003)

Cardiac neural crest cells are known to play multiple roles during development of the inflow and outflow tract of the heart and the aortic arch. In addition, cardiac neural crest is required for normal heart tube looping and regulation of myocardial cell proliferation, as well as differentiation and function of the myocardium. We show that the homeobox gene Lbx1 is expressed in a subpopulation of the cardiac neural crest during tubular heart formation. Inactivation of the Lbx1 gene in mice resulted in defects in heart looping, changes in gene expression pattern, and increased cell proliferation ensuing in myocardial hyperplasia. We found that the activity of the Lbx1 promoter, as indicated by a LacZ reporter gene, is upregulated in the hearts of Lbx1+/−:splotch1H/splotch1H and Lbx1−/− mice, indicating that Pax3 and Lbx1 participate in a negative regulatory feedback that might be necessary for normal differentiation and function of the myocardium during early heart development. Because migration of Lbx1-ex...
Abstract 16070: Cardiomyocyte-Specific Endothelin Receptor Type B Knockout Mice Confers Cardiac Resistance to Extreme Hypoxia
Authors: Tsering Stobdan, Dan Zhou, Pedro Cabrales, Gabriel G Haddad
Journal: Circulation (2017)

Rationale: To better understand human adaptation to hypoxia, we took advantage of one of the nature’s experiments at high altitude (HA) and studied Ethiopians, a human population that is well adapt...
Abstract 18288: The Total-to-high Density Lipoprotein-cholesterol Ratio Associates With Coronary Atheroma Progression Rates and Reclassifies Disease Progression Across Populations With Varying Metabolic Risk
Authors: Mohamed B Elshazly, Stephen J Nicholls, Steven E Nissen, Julie St. John, Seth S Martin, Steven R Jones, Brian Stegman, Samir R Kapadia, E. Murat Tuzcu, Rishi Puri
Journal: Circulation (2015)

Introduction: Total to high-density lipoprotein cholesterol (TC/HDL-C), routinely available from the standard lipid profile, is postulated to characterize atherogenic lipids beyond low density lipoprotein cholesterol (LDL-C) and non-HDL-C Hypothesis: On-treatment TC/HDL-C significantly associates with coronary atheroma progression rates at variable levels of LDL-C, non-HDL-C, apolipoprotein B (apoB), triglycerides (TG), C-reactive protein (CRP), and irrespective of diabetes status, obesity or intensity of statin therapy Methods: We analyzed data from 9 trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography and assessed the effect of on-treatment levels of TC/HDL-C [&lt;/≥ median: 3.3] on changes in percent atheroma volume (ΔPAV, annualized and controlled for baseline PAV and clinical trial) at variable levels of LDL-C, non-HDL-C, apoB [&lt;/≥ median: 80, 107, and 76 mg/dL, respectively], CRP [&lt;/≥ 2mg/L] and TG [&lt;/≥150 mg/dL], and in patients with/without diabetes or obesity, and in those receiving high-intensity statin therapy (HIST) or not Results: Discordance, defined by median cut points, between TC/HDL-C vs. LDL-C, non-HDL-C and apoB was sizeable at 26, 20 and 27%, respectively. Lower (&lt; median) on-treatment TC/HDL-C associated with PAV regression (ΔPAV &lt;0) while higher (≥median) TC/HDL-C associated with PAV progression across all levels of LDL-C, non-HDL-C, apoB, TG as well as the presence/absence of obesity or HIST. Lower (&lt;median) TC/HDL-C associated with lower PAV progression irrespective of CRP levels or the presence/absence of diabetes Conclusion: TC/HDL-C, available at no extra cost, correlates significantly with coronary atheroma progression rates when discordant with other lipid-metabolic parameters and in clinical scenarios such as diabetes, obesity and in patients receiving HIST. Future studies are needed to determine the implications of applying TC/HDL-C for reducing residual risk
Therapeutic Activation of Signal Transducer and Activator of Transcription 3 by Interleukin-11 Ameliorates Cardiac Fibrosis After Myocardial Infarction
Authors: MasanoriObana, MakikoMaeda, KojiTakeda, AkikoHayama, TomomiMohri, TomomiYamashita, YoshikazuNakaoka, IsseiKomuro, KiyoshiTakeda, GoroMatsumiya, JunichiAzuma, YasushiFujio
Journal: Circulation (2010)

Background— Glycoprotein 130 is the common receptor subunit for the interleukin (IL)-6 cytokine family. Previously, we reported that pretreatment of IL-11, an IL-6 family cytokine, activates the glycoprotein 130 signaling pathway in cardiomyocytes and prevents ischemia/reperfusion injury in vivo; however, its long-term effects on cardiac remodeling after myocardial infarction (MI) remain to be elucidated. Methods and Results— MI was generated by ligating the left coronary artery in C57BL/6 mice. Real-time reverse transcription polymerase chain reaction analyses showed that IL-11 mRNA was remarkably upregulated in the hearts exposed to MI. Intravenous injection of IL-11 activated signal transducer and activator of transcription 3 (STAT3), a downstream signaling molecule of glycoprotein 130, in cardiomyocytes in vivo, suggesting that cardiac myocytes are target cells of IL-11 in the hearts. Twenty-four hours after coronary ligation, IL-11 was administered intravenously, followed by consecutive administratio...
Abstract 397: Systematic functional annotation of somatic mutations in cancer
Authors: Han Liang, Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Yiling Lu, Song Yi, Nidhi Sahni, Gordon Mills
Journal: Cancer Research (2018)

Abstract Recent sequencing studies have identified thousands of unique somatic mutations across patient tumors. However, the functional impact of the vast majority of these mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant open reading frame generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of downstream signaling effects for select aberrations. We apply the platform to annotate &amp;gt;1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. We show that our platform has higher sensitivity for characterizing weak drivers than pooled screening. Our data are accessible through the user-friendly, open-access data portal we created. Our study will facilitate the discovery of novel biomarkers, improvement of existing prediction algorithms, and development of new therapeutic approaches. Citation Format: Han Liang, Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Yiling Lu, Song Yi, Nidhi Sahni, Gordon Mills. Systematic functional annotation of somatic mutations in cancer [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 397.
Hemodialysis Impairs Endothelial Function via Oxidative Stress
Authors: HiroshiMiyazaki, HidehiroMatsuoka, HiroyukiItabe, MichiakiUsui, SeijiUeda, SeiyaOkuda, TsutomuImaizumi
Journal: Circulation (2000)

Background—Patients who undergo hemodialysis experience accelerated atherosclerosis and premature death. Recent evidence suggests that endothelial dysfunction proceeds to and exacerbates atherosclerosis. It remains unknown whether hemodialysis per se causes endothelial dysfunction. Methods and Results—We evaluated endothelial function estimated by flow-mediated vasodilation during reactive hyperemia using high-resolution ultrasound Doppler echocardiography before and after a single session in patients on maintenance hemodialysis. Several studies have shown that the imbalance between pro-oxidant and antioxidant activities in hemodialyzed patients results in high oxidative stress, which causes lipid peroxidation and endothelial injury. Accordingly, we investigated the effects of antioxidative modification during hemodialysis on endothelial function using a vitamin E–coated cellulose membrane dialyzer. Nonspecific endothelium-independent vasodilation was measured after administration of a sublingual glyceryl...