tbuckley/cabot-search huggingface dataset:
Abstract 1432: Deranged tyrosine metabolism drives tumorigenesis in liver cancer
Authors: Man Tong, Tin Lok Wong, Steve Tin-Chi Luk, Noelia Che, Xin Yuan Guan, Yun Fei Yuan, Terence Kin-Wah Lee, Stephanie Ma
Journal: Cancer Research (2018)

Abstract Tyrosine, like other amino acids, is the building block for proteins as well as an alternative energy source for cellular functions. Liver is the major organ where tyrosine degradation takes place to produce intermediates or precursors for gluconeogenesis and ketogenesis. In normal liver, tyrosine can be converted to fumarate and acetoacetate through multiple steps of enzymatic reactions. In patients with liver cancer, an upregulation of serum tyrosine levels has been previously reported, suggesting a deregulated tyrosine catabolism in liver cancer. In this study, we observed a significant down-regulation of the five enzymes involved in tyrosine catabolism (TAT, HPD, HGD, GSTZ1 and FAH) in tumor samples compared with normal liver samples from TCGA database. Further, downregulation of the first three enzymes significantly correlates with overall and disease-free survival in liver cancer patients. Downregulation of these enzymes is also confirmed in a separate liver cancer patient transcriptome cohort of Asian ethnicity, as well as at the proteomic level by both Western blot and immunohistochemistry assays. Our group has previously reported that downregulation of the first tyrosine catabolizing enzyme TAT (tyrosine aminotransferase) could promote liver tumorigenesis. Here, we further investigate if reprogrammed tyrosine metabolism could promote cancer development by modulating gene expression and activity of the second enzyme HPD (4-hydroxyphenylpyruvate dioxygenase) in the tyrosine catabolism pathway. We found blocking HPD gene expression or its enzymatic activity could promote cell proliferation and tumor formation in liver cancer. This could be partially attributed to enhanced mitochondrial respiratory capacity accompanied with reduction in ROS level, NADP/NADPH ratio and DNA damage. Conversely, overexpression of HPD led to an opposing effect. Taken together, this study reveals an unreported alteration of tyrosine metabolism which drives cancer development in liver cancer. Citation Format: Man Tong, Tin Lok Wong, Steve Tin-Chi Luk, Noelia Che, Xin Yuan Guan, Yun Fei Yuan, Terence Kin-Wah Lee, Stephanie Ma. Deranged tyrosine metabolism drives tumorigenesis in liver 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 1432.
Abstract 19852: Depletion of Neurogenesis within Key Neural Stem/Progenitor Cell Pools Contributes to Brain Immaturity in Congenital Heart Disease
Authors: Paul D Morton, Ludmila Korotcova, Bobbi Lewis, Vidhi Kumar, Fizza Shaikh, Elena Short, Jiangyang Zhang, Susumu Mori, Joseph A Frank, Vittorio Gallo, Richard A Jonas, Nobuyuki Ishibashi
Journal: Circulation (2015)

Objectives: Congenital heart disease (CHD) often causes neurological deficits throughout life; primarily due to immature brain development as a consequence of restricted cerebral oxygenation during fetal life. However, the underlying cellular mechanisms remain poorly understood. The primary goal of this study is to model CHD-induced brain injury with a species similar to humans to better understand how the brain responds to these pathologies. Methods: Piglets were used in this study because their brains display highly evolved neocortexes. Newborn pigs were housed in a hypoxic (Hx) chamber (10.5% FiO2) for 11 days, alongside normoxic (Nx) controls. We used MRI to assess cortical folding and volume. Cell tracers (CTG) were injected into the subventricular zone (SVZ), prior to Hx exposure, to label neural stem/progenitor cells (NSPCs). t2* scans were acquired to visualize the migratory paths and destination of labeled cells. Immunostains determined the fate of labeled cells and the cellular composition of the cortex. Findings: Hx reduces cortical volume and folding (gyrification index) (Fig. 1a); a phenomenon commonly seen in CHD patients. The porcine SVZ shares significant anatomical/structural similarities to the human SVZ and a majority of NSPCs in the SVZ generate immature neurons that migrate to the frontal cortex where they mature into GABAergic (Calr+) interneurons. Hx reduces the capacity of neurogenesis (Sox2+Ki67+) within the SVZ and limits the contribution of SVZ-derived neurons (CTG+Dcx+) to postnatal cortical development (Fig. 1b). Finally, Hx reduces the number of immature (Dcx+) as well as mature interneurons (Calr+NeuN+) within the frontal cortex (Fig.1c). Conclusions: Immature brain development seen in CHD patients is due, in part, to a depletion of neuronal producing NSPCs in the SVZ. Therapies aimed at protecting these vulnerable cells or restoring neurogenic potential from the SVZ will likely improve neurological outcomes in CHD.
Abstract 328: Targeting Mcl-1 enhances DNA replication stress sensitivity for cancer therapy
Authors: Guo Chen, Andrew Magis, Ke Xu, Dongkyoo Park, David Yu, Taofeek Owonikoko, Gabriel Sica, Sarah Satola, Suresh Ramalingam, Walter Curran, Paul Doetsch, Xingming Deng
Journal: Cancer Research (2018)

Abstract DNA double-strand breaks (DSBs) are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. Here we report that Mcl-1 acts as a functional switch in pathway choice between HR and NHEJ. Mcl-1 was cell cycle-regulated, with expression peaking in S/G2 phase when HR occurred. Endogenous Mcl-1 depletion reduced HR and enhanced NHEJ. Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with Ku via its BH1 and BH3 domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ and promote Mre11 complex-mediated DNA resection and HR-dependent DSB repair. Using the Mcl-1 BH1 domain (aa256-265) as docking site, we identified a novel small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair leading to a significant sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcome. Citation Format: Guo Chen, Andrew Magis, Ke Xu, Dongkyoo Park, David Yu, Taofeek Owonikoko, Gabriel Sica, Sarah Satola, Suresh Ramalingam, Walter Curran, Paul Doetsch, Xingming Deng. Targeting Mcl-1 enhances DNA replication stress sensitivity for cancer therapy [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 328.
Invasive Approaches to Treatment of Venous Thromboembolism
Authors: PeterAugustinos, KennethOuriel
Journal: Circulation (2004)

Deep vein thrombosis (DVT) occurs in one-quarter of a million individuals annually in the United States and results in significant disability from pulmonary embolism and chronic venous insufficiency, especially when the proximal iliofemoral is involved. Treatment has centered on early institution of adequate anticoagulation to prevent thrombus propagation and embolism, but anticoagulation alone does not always restore venous patency and many patients are left with venous outflow obstruction and valvular incompetence—the anatomic underpinnings of the postthrombotic syndrome. Various strategies have been used to restore patency of thrombosed veins, including open surgical thrombectomy, pharmacological thrombolysis, and percutaneous mechanical thrombectomy. Each modality has benefits and shortcomings. Surgical thrombectomy had previously been abandoned secondary to poor long-term results. More recently, with improved techniques and better patient selection, surgical thrombectomy has regained a therapeutic ro...
Resident PW1+ Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
Authors: FranceDierick, TiphaineHéry, BénédicteHoareau-Coudert, NathalieMougenot, VirginieMonceau, CarolineClaude, MihaelaCrisan, VanessaBesson, PeterDorfmüller, GillesMarodon, ElieFadel, MarcHumbert, ElisaYaniz-Galende, Jean-SébastienHulot, GiovannaMarazzi, DavidSassoon, FlorentSoubrier, SophieNadaud
Journal: Circulation Research (2016)

Rationale:Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1+ progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro. Objective:To determine the role of pulmonary PW1+ progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension. Methods and Results:We investigated their contribution during chronic hypoxia–induced vascular remodeling in Pw1nLacZ+/− mouse expressing β-galactosidase in PW1+ cells and in differentiated cells derived from PW1+ cells. PW1+ progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1+ cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1+ cells and the proportion of β-gal+ vascular SMC were increased, indicating a recruitment of PW1+ cells and their differentiation into vascular SMC during earl...
Abstract 4899: Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance
Authors: Anna Maria Barbuti, Zhe-Sheng Chen
Journal: Cancer Research (2018)

Abstract Despite advances in anticancer drug research, chemotherapy options and response rates for metastatic colorectal cancer (mCRC) are poor. Irinotecan, a topoisomerase I inhibitor, is a commonly used chemotherapy against mCRC as a single agent, or in combination with other anti-cancer drugs such as fluorouracil and leucovorin. However, acquired resistance to chemotherapy, especially in metastatic patients, is a critical cause of treatment failure. Multi-drug resistance (MDR) in cancer is a major challenge to chemotherapy success. Mechanisms of MDR involve deliberate alteration in cellular expression, function, and/or responses of the cancer. One of the most notable mechanism of MDR is an increased cellular drug efflux through up-regulation of membrane ATP-binding cassette (ABC) transporters. To investigate a new and clinically relevant mechanism of MDR in mCRC cells, SN-38 (the potent and active metabolite of irinotecan) was regularly administered to SW620 cells with drug-free intervals to reflect a drug induced resistance to treatment. Through cytotoxicity and western blotting assays on the newly formed SW620/SN100 cells, we discovered ABCG2 (BCRP) to be the main mechanism of SN-38 resistance, with no alterations in the topoisomerase I, ABCB1 (P-gp) or ABCC1 (MRP1). These results confirmed our initial hypothesis, given SN-38 is a known substrate of ABCG2. This discovery of SN-38 induced efflux in mCRC is of a larger importance because this mechanism not only limits the efficacy of the chemotherapy, but also poses a threat to the efficacy of a variety of pharmacologically dissimilar drugs which are substrates of ABCG2. As treatments for mCRC continue to be investigated it is important to also continue investigating resistant mechanisms of these drugs. More discoveries of MDR mechanisms which are specific to cancer patient populations will offer superior diagnosis, proper treatment regimens and greater prognosis for patient success. Citation Format: Anna Maria Barbuti, Zhe-Sheng Chen. Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance [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 4899.
Abstract 5428: Effect of amentoflavone on Nrf2 signaling in HaCaT cells
Authors: Lilik Duwi Wahyudi, Jiwon Jeong, Heejung Yang, Jung-Hwan Kim
Journal: Cancer Research (2018)

Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key mediator of cell response to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against many diseases, aging, inflammation, and cancer. To date, Nrf2 activators from natural products have been widely studied. In this study we investigated the potential effect of Amentoflavone (AFN), a biflavonoid in many natural plants, on Nrf2 signaling in human keratinocytes cells (HaCaT). As results, AFN significantly increased ARE-luciferase activity and nuclear accumulation of Nrf2. Furthermore, a Nrf2 target protein, NQO-1, was significantly increased by AFN in dose- and time-dependent manner. To verify the Nrf2 signaling mechanism by AFN, firstly we measured reactive oxygen species (ROS) using DCFDA because mild intracellular ROS could stimulate Nrf2 activation. Surprisingly AFN triggered the production of ROS in 1 h and AFN-induced Nrf2 was inhibited by N-acetyl cysteine (NAC). Thus, we studied the ROS-related signaling on Nrf2 by measuring the activation of Akt and mitogen-activated protein (MAP) kinase family such as extracellular signal-regulated kinase (ERK) and p38. As results, pharmacology inhibitor of PI3K/Akt (LY294002) or p38 (SB 203580), but not ERK (U0126), abrogated AFN-activated Nrf2. Furthermore, silencing p38 using p38siRNA or inhibition using its pharmacology inhibitor decreased phosphorylation of Akt and attenuated Nrf2 activation. We also confirmed that AFN stabilized Nrf2 by inhibiting the ubiquitination. Taken together, AFN activates Nrf2 through ROS-mediated phosphorylation of p38 and followed by phosphorylation of Akt. Citation Format: Lilik Duwi Wahyudi, Jiwon Jeong, Heejung Yang, Jung-Hwan Kim. Effect of amentoflavone on Nrf2 signaling in HaCaT cells [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 5428.
Abstract 3425: Exome-sequencing derived mutations of endocrine treated ER-positive early breast cancer
Authors: Werner Schroth, Siarhei Kandabarau, Peter Fritz, Thomas Mürdter, Liza Bacchus, German Tamoxifen Study Group, Matthias Schwab, Hiltrud Brauch
Journal: Cancer Research (2018)

Abstract Anti-hormonal treatment of ER-positive early breast cancer with tamoxifen and/or aromatase inhibitors (AI) significantly improves patient outcome, however there is a lack of markers that predict the one third of treated patients who relapse or die. Although ER positive (luminal) tumors are known to be genetically highly diverse, the relevance of somatic mutations with regards to endocrine treatment outcome and course of the patients' disease is not fully understood. We conducted a prospective observational clinical trial for the investigation of treatment outcome determinants including 1219 tamoxifen and/or AI-treated postmenopausal ER-positive early breast cancer patients (DRKS00000605, recruitment between 2005-2010, median follow up 5.1 years). Of these, 40 tumors divided into 20 patients each with and without disease recurrence matched by prognostic variables (age, tumor size, grade, nodal status, treatment) were analyzed for their mutation pattern. We performed whole-exome sequencing of tumor and normal DNA (Agilent SureSelect, Illumina) for the identification of single nucleotide variants and small indels. Somatic mutations were identified following subtraction of germline single nucleotide polymorphisms (SNP), filtering based on raw-read quality parameters, in silico predicted biological function, and disease relatedness using the Ingenuity variant analysis software package (Qiagen). Clinical outcome associations were tested either on gene or on variant level. Somatic mutations with predicted deleterious effects were identified in 18 out of 40 known mutation-driver genes including PIK3CA, GATA3, MAP3K1, and TP53 (45%). Thirteen patients carried a mutation in the most frequently affected PIK3CA (32.5%). Of note, three out of four patients with a E542K mutation belonged to the breast cancer recurrence group, while 5 of 6 tumors with the H1047R mutation originated from patients without recurrence suggesting differential effects of these PIK3CA hotspot mutations. Common germline SNPs at IL17RB, ANK2, POM121, PGR, PTPRB, RAD51D, RFPLA4, and SUMO3 provided first hints for a possible association with relapse status (p&amp;lt;0.05). We will report on the extended genotype-outcome-correlations to further evaluate the relevance of somatic mutations for endocrine treatment outcome of early ER-positive breast cancer. Citation Format: Werner Schroth, Siarhei Kandabarau, Peter Fritz, Thomas Mürdter, Liza Bacchus, German Tamoxifen Study Group, Matthias Schwab, Hiltrud Brauch. Exome-sequencing derived mutations of endocrine treated ER-positive early breast 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 3425.
Non-Respiratory Oscillations in Systemic Arterial Pressure of Dogs
Authors: DavidRace, MauriceRosenbaum
Journal: Circulation Research (1966)

In dogs the condition of the cardiovascular control system was investigated quantitatively during haemorrhage, by using a system of transient inputs and by recording arterial blood pressure. The analysis of our results using standard control system techniques demonstrates a probable increase in open loop gain and a reduction of natural frequency. The implications of these findings are discussed.
Potential Benefit From Implantable Cardioverter-Defibrillator Therapy in Patients With and Without Heart Failure
Authors: DirkBöcker, DietmarBänsch, AchimHeinecke, MaxWeber, JürgenBrunn, DieterHammel, MartinBorggrefe, GünterBreithardt, MichaelBlock
Journal: Circulation (1998)

Background—Whether patients with heart failure derive a benefit from therapy with implantable cardioverter-defibrillators (ICDs) has been questioned. The purpose of this study was to investigate whether New York Heart Association (NYHA) functional class had an impact on the potential benefit from ICD therapy as assessed from data stored in the memory of ICDs. Methods and Results—Between 1989 and 1996, 603 patients (77% men; 59% with coronary artery disease and 16% with dilated cardiomyopathy; age, 57±13 years; ejection fraction, 44±18%) were treated with an ICD with extended memory function (storage of electrograms and/or RR intervals from treated episodes) in combination with endocardial lead systems. The stages of heart failure (NYHA functional class I through III) at implantation were correlated with overall mortality and the recurrence of fast ventricular tachyarrhythmias (>240 bpm) during follow-up. The potential benefit of the device was estimated as the difference between overall mortality and the ...
Abstract 19898: Heightened Sympathetic Activity Related to Masked Uncontrolled Hypertension in Treated Hypertensive Patients
Authors: Mohammed Siddiqui, Hemal Bhatt, Eric K Judd, Tanja Dudenbostel, Suzanne Oparil, David A Calhoun
Journal: Circulation (2016)

Introduction: Masked uncontrolled hypertension in treated hypertensive patients (MUCH) is defined as controlled blood pressure (BP) in clinic (BP < 140/90 mmHg) but uncontrolled BP out-of-clinic as...
Abstract 1060: Longitudinal profiling of plasma derived extracellular vesicles (EVs) from women presenting with metastatic triple-negative breast cancer (mTNBC) informs on metastatic location and treatment outcome
Authors: Sinéad Lindsay, Jennifer McIntyre, Luke Gubbins, Martina Smith, Laura Kerr, Emma Kavanagh, Michaela J. Higgins, Bryan Hennelly, Paul Dowling, Hugh Byrne, Amanda McCann
Journal: Cancer Research (2018)

Abstract Background: Women presenting with Triple Negative Breast Cancer (TNBC) have an increased risk of recurring at distant visceral metastatic sites such as brain, lungs and liver rather than bone compared to oestrogen-receptor-positive breast cancer. (Rakha et al., 2011, Wood 2004). The preferential homing of TNBC cancer cells to these sites is not clearly understood, but is increasingly being attributed to the ability of extracellular vesicles (EVs) released by chemoresistant cancer cells to circulate to distant sites creating metastatic niches and paving the way for organ-specific metastases. Hypothesis: We hypothesise that the physical EV properties, macromolecular and proteomic content of these EVs could potentially determine the risk of metastasis and align with these “preferred” metastatic locations. Methodology: This project uses nanoparticle tracking analysis (NTA), infra-red and mass spectroscopy to generate unique patient-specific EV longitudinal signatures of women diagnosed with organ defined metastatic TNBC. These signatures hold potential as “unique identifiers” of clinically documented organ-specific metastases. All profiles generated are compared longitudinally to the patient's initial baseline sample and also to age matched female control plasma samples. Results and Conclusions: Preliminary results have developed SOPs to (i) successfully enrich for EVs from patient plasma samples and (ii) employ nanoparticle tracking analysis, infra-red and mass spectroscopic profiling to develop unique longitudinal patient specific EV signatures. The longitudinal profiling of EV signatures from patients with metastatic TNBC will potentially (a) predict response to therapy, (b) uniquely identify risk of and potential location of metastatic site/sites and (c) inform on patient outcome. Following this multidisciplinary profiling of our mTNBC, our remit is to recapitulate this profiling into the primary TNBC setting to identify potential sites of organ specific metastases ahead of any detection on an x-ray or scan, thereby informing on clinical management. Citation Format: Sinéad Lindsay, Jennifer McIntyre, Luke Gubbins, Martina Smith, Laura Kerr, Emma Kavanagh, Michaela J. Higgins, Bryan Hennelly, Paul Dowling, Hugh Byrne, Amanda McCann. Longitudinal profiling of plasma derived extracellular vesicles (EVs) from women presenting with metastatic triple-negative breast cancer (mTNBC) informs on metastatic location and treatment outcome [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 1060.