tbuckley/cabot-search huggingface dataset:
Abstract 5484: Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer
Authors: Masakazu Yashiro, Kishu Kitayama
Journal: Cancer Research (2018)

Abstract Glycolysis is the primary mode of glucose metabolism, not only in normal cells but also in cancer cells. The Warburg effect, known as anaerobic glycolysis even in the presence of ample oxygen, might contribute to tumor development in such hypoxic environments. It has been suggested that some kinds of glucose metabolism-related enzymes—including pyruvate kinase isozyme M2 (PKM2), PKM1, enolase 1 (ENO1), and glucose-6-phosphate dehydrogenase (G6PDH)—might be associated with the anaerobic glycolysis of cancer cells. Glutamine is also associated with the proliferation of cancer cells by an alternate source of biosynthesis from the TCA cycle, namely glutaminolysis. In the present study we evaluated the significance of the enzymes for glycolysis and glutaminolysis in relation to the proliferation of gastric cancer cells in hypoxic environments. The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: PKM2, GLS, ENO1, G6PDH, and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all of hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment by Shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either one of the two agents. The in vivo study indicated that the tumor size treated by the combination of Shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors might be therapeutically promising for the treatment of gastric cancer. Citation Format: Masakazu Yashiro, Kishu Kitayama. Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric 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 5484.
The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila
Authors: Akira Goto, Kiyoshi Okado, Nelson Martins, Hua Cai, Vincent Barbier, Olivier Lamiable, Laurent Troxler, Estelle Santiago, Lauriane Kuhn, Donggi Paik, Neal Silverman, Andreas Holleufer, Rune Hartmann, Jiyong Liu, Tao Peng, Jules A. Hoffmann, Carine Meignin, Laurent Daeffler, Jean-Luc Imler
Journal: Immunity (2018)
Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium
Authors: GeorgHorstick, OliverBerg, AxelHeimann, OttoGötze, MichaelLoos, GerdHafner, BenjaminBierbach, SteffenPetersen, SucharitBhakdi, HaraldDarius, MarinaHorstick, JürgenMeyer, OliverKempski
Journal: Circulation (2001)

Background— Complement activation during reperfusion of ischemic myocardium augments myocardial injury, and complement inhibition with C1-esterase inhibitor (C1-INH) at the time of reperfusion exerts marked cardioprotective effects in experimental studies. Application of C1-INH in newborns, however, was recently reported to have dangerous and even lethal side effects. This study addresses the essential role of dosage in studies using C1-INH. Methods and Results— Cardioprotection by C1-INH was examined in a pig model with 60 minutes of coronary occlusion followed by 120 minutes of reperfusion. C1-INH was administered intravenously 5 to 10 minutes before coronary reperfusion without heparin at a dose of 40, 100, and 200 IU/kg body wt. Compared with the NaCl controls, C1-INH 40 IU/kg reduced myocardial injury (44.1±13.8% versus 76.7±4.6% necrosis of area at risk, P≤0.05) and significantly suppressed local C3a and C5a generation. Myocardial protection was accompanied by reduced plasma concentrations of creati...
Staphylococcal α-Toxin Provokes Coronary Vasoconstriction and Loss in Myocardial Contractility in Perfused Rat Hearts
Authors: UlfSibelius, UlrichGrandel, MichaelBuerke, DorisMueller, LadislauKiss, Hans-JoachimKraemer, RuedigerBraun-Dullaeus, WernerHaberbosch, WernerSeeger, FriedrichGrimminger
Journal: Circulation (2000)

Background—Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal α-toxin, in isolated perfused rat hearts. Methods and Results—α-Toxin 0.25 to 1 μg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dtmax), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A2 and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban full...
Oxidative Stress–Dependent Sphingosine Kinase-1 Inhibition Mediates Monoamine Oxidase A–Associated Cardiac Cell Apoptosis
Authors: DimitriPchejetski, OxanaKunduzova, AudreyDayon, DenisCalise, Marie-HélèneSeguelas, NathalieLeducq, IsabelleSeif, AngeloParini, OlivierCuvillier
Journal: Circulation Research (2007)

The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species–dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A– and reactive oxygen species–dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A–dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C2-ceramide or H2O2. In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H2O2-induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed signif...
Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle
Authors: NorioFukuda, HidetoshiKajiwara, Shin’ichiIshiwata, SatoshiKurihara
Journal: Circulation Research (2000)

Abstract—The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 μm decreased the muscle width by ≈11% and shifted the midpoint of the pCa-tension relationship (pCa50) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca2+-activated tension and concomitantly diminished the SL-dependent shift of pCa50 in a concentration-dependent manner. In contrast, pimobendan, a Ca2+ sensitizer, which promotes Ca2+ binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa50, suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1.9 μm, osmotic compression, produced by 5% wt/vol dextran (molecular weight ≈464 000), reduced the muscle width by ≈13% and shifted pCa50 leftward to a similar degree as that observed when increasing SL to 2.3 μm. This favors the idea that a decrease in th...
Direct Conversion of Adult Skin Fibroblasts to Endothelial Cells by Defined Factors
Authors: Jung-KyuHan, Sung-HwanChang, Hyun-JuCho, Saet-ByeolChoi, Hyo-SukAhn, JaewonLee, HeewonJeong, Seock-WonYoun, Ho-JaeLee, Yoo-WookKwon, Hyun-JaiCho, Byung-HeeOh, PeterOettgen, Young-BaePark, Hyo-SooKim
Journal: Circulation (2014)

Background—Cell-based therapies to augment endothelial cells (ECs) hold great therapeutic promise. Here, we report a novel approach to generate functional ECs directly from adult fibroblasts. Methods and Results—Eleven candidate genes that are key regulators of endothelial development were selected. Green fluorescent protein (GFP)–negative skin fibroblasts were prepared from Tie2-GFP mice and infected with lentiviruses allowing simultaneous overexpression of all 11 factors. Tie2-GFP+ cells (0.9%), representing Tie2 gene activation, were detected by flow cytometry. Serial stepwise screening revealed 5 key factors (Foxo1, Er71, Klf2, Tal1, and Lmo2) that were required for efficient reprogramming of skin fibroblasts into Tie2-GFP+ cells (4%). This reprogramming strategy did not involve pluripotency induction because neither Oct4 nor Nanog was expressed after 5 key factor transduction. Tie2-GFP+ cells were isolated using fluorescence-activated cell sorting and designated as induced ECs (iECs). iECs exhibited ...
Abstract 949: Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal breast cancer
Authors: Amy R. Dwyer, Deepali Sachdev, Carol A. Lange
Journal: Cancer Research (2018)

Abstract Luminal breast cancers account for ~75% of all cases and while adjuvant hormone therapy targeting ERα has significantly improved overall survival for patients with ER+ tumors, acquired resistance remains a major clinical problem. Tamoxifen-resistant (TamR) breast cancer models show loss of IGF1R concomitant with increased insulin-induced growth, underpinned by insulin receptor (InsR) compensation for IGF1R loss. PR (gene name PGR) is an estrogen-regulated target gene whose expression is used as a clinical marker of ER activity. However, its de novo relevance to breast cancer is unclear. We have shown previously that post-translational modifications create unique PR species whose altered behavior drives an endocrine-resistant gene signature, in part by crosstalk with the IGFR pathway. We propose that phospho-PR target gene selectivity is mediated by cooperation between PR-B and InsR/IGF1R pathway components. Herein we show that phospho-PR-expressing T47D cells lose expression of IGF1R compared to control cells expressing WT PR-B. Furthermore, expression of the adapter protein IRS-1 requires PRB expression and these IRS-1+ cells were more sensitive to insulin in anchorage-dependent growth assays. Phospho-PR T47D cells exhibit increased ALDH+ and CD24-/CD44+ tumorsphere formation compared to wt PRB-expressing cells. Inhibitors targeting IRS-1 and InsR were used to test their requirement for tumorsphere growth and, surprisingly, IRS-1 perturbation reduced phospho-PRB but not wt PRB tumorsphere growth. Interestingly, IRS-1 replaces IGF1R in phospho-PRB-containing transcriptional complexes that are recruited to the CTSD promoter, which we previously identified as a phospho-PR target gene. Finally, breast cancer cells expressing phospho-PR species exhibited tamoxifen-resistant growth. Collectively our data suggest that phospho-PRB cooperates with IRS-1 downstream of the Ins/IGF1R system to promote outgrowth of endocrine-resistant cells that include ALDH+ stem-like cells capable of forming secondary tumorspheres in vitro. Targeting phospho-PR species in addition to the signaling components of PR-complexes may provide a means to block emergence of endocrine-resistant cancer cells during breast cancer progression. Citation Format: Amy R. Dwyer, Deepali Sachdev, Carol A. Lange. Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal 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 949.
Estrogen Receptor-β Activation Results in S-Nitrosylation of Proteins Involved in Cardioprotection
Authors: JeffreyLin, CharlesSteenbergen, ElizabethMurphy, JunhuiSun
Journal: Circulation (2009)

Background— It has been shown that the activation of estrogen receptor-β (ER-β) plays an important cardioprotective role against ischemia/reperfusion injury. However, the mechanism for this protection is not clear. We hypothesize that estrogen protects by ER-β activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins. Methods and Results— We treated ovariectomized C57BL/6J mice with the ER-β selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitrile (DPN), 17β-estradiol (E2), or vehicle using Alzet minipumps for 2 weeks. Isolated hearts were Langendorff perfused and subjected to ischemia and reperfusion. Compared with vehicle-treated hearts, DPN- and E2-treated hearts had significantly better postischemic functional recovery and decreased infarct size. To test the specificity of DPN, we treated ER-β–knockout mice with DPN. However, no cardioprotective effect of DPN was found in ER-β–knockout mice, indicating that the DPN-induced cardioprotection occurs through the activation of ER-β...
Abstract 11969: Effects of Definition of Defibrillation Success on Predictability of Ventricular Fibrillation Waveform Analysis
Authors: Yongqin Li, Yushun Gong, Mi He, Weilun Quan
Journal: Circulation (2015)

Introduction: Quantitative analysis of ventricular fibrillation (VF) waveform has the potential to optimize the timing of defibrillation by predicting defibrillation outcome. However, there is no consensus on the definition of defibrillation success in out-of-hospital settings. In the present study, we used a registry data of out-of-hospital cardiac arrest (OHCA) to investigate the effects of different definitions of defibrillation success on the predictability of amplitude spectrum area (AMSA). Methods: A total of 581 shocks from 264 OHCA patients with VF as the first recorded rhythm were included in this study.We determined the presence of VF, asystole or organized rhythm 120 seconds after shock delivery as the final outcome. In order to identify how different definitions of defibrillation success affect the predictive value of AMSA, we used 3 different definitions that were previously described in the literatures. (1) Termination of VF: A successful shock is defined as no presence of VF for 5 seconds or longer. (2) Return of organized electrical activity (ROEA): A successful shock is defined by an organized rhythm observed for at least 5 seconds after delivery of the shock. (3) Return of a potentially perfusing rhythm: An organized rhythm is restored with a heart rate greater than 40 beats/min, commencing within 60 seconds after shock delivery. Results: A total of 153 cases (26.3%) had an final outcome of organized rhythm. The defibrillation success rates were 72.1%, 49.2% and 27.0% when the 3 different definitions were used. The area under the receiver-operating-characteristic curve was 0.563 for termination of VF, 0.706 for organized rhythm, and 0.814 for return of potentially perfusing rhythm (p&lt;0.001). Conclusion: AMSA’s ability to predict shock success varied strongly depending on which definition of shock success was used. Termination of VF may be a good measure of defibrillation efficacy for new onset of VF, while return of a potentially perfusing rhythm is clinically more relevant as a definition for defibrillation success in OHCA. AMSA had the highest predictive value when used with the outcome of potentially perfusing rhythm. This supports the assumption that AMSA is, at least to some extent, a measure of myocardial viability.
Cardioprotection Afforded by Inducible Nitric Oxide Synthase Gene Therapy Is Mediated by Cyclooxygenase-2 via a Nuclear Factor-κB–Dependent Pathway
Authors: QianhongLi, YiruGuo, WeiTan, QinghuiOu, Wen-JianWu, DianaSturza, BuddhadebDawn, GregHunt, ChuanjueCui, RobertoBolli
Journal: Circulation (2007)

Background— Gene therapy with inducible nitric oxide synthase (iNOS) markedly reduces myocardial infarct size; this effect is associated with cyclooxygenase-2 (COX-2) upregulation and is ablated by COX-2 inhibitors. However, pharmacological inhibitors are limited by relative lack of specificity; furthermore, the mechanism whereby iNOS gene therapy upregulates COX-2 remains unknown. Accordingly, we used genetically engineered mice to test the hypothesis that the cardioprotection afforded by iNOS gene transfer is mediated by COX-2 upregulation via a nuclear factor (NF)-κB–dependent pathway. Methods and Results— Mice received an intramyocardial injection of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 3 days later, myocardial infarction was produced by a 30-minute coronary occlusion followed by 4 hours of reperfusion. Among Av3/LacZ-treated mice, infarct size was similar in COX-2−/− and wild-type groups. iNOS gene transfer (confirmed by iNOS immunoblotting and activity assays) markedly reduced infarct siz...
Fate of Orally Administered 3H-Digitoxin in Man with Special Reference to the Absorption
Authors: Björnbeermann, Kjellhellström, Andersrosén
Journal: Circulation (1971)

3H-digitoxin and polyethylene glycol (nonabsorbable marker) were given orally to five subjects provided with a gastrointestinal tube. Of the radioactivity administered, approximately 15, 30, and 70% had been absorbed when the test solution was passing the stomach, the duodenum, and the upper jejunum, respectively. The absorption was rapid, and the plasma contained detectable amounts of radioactivity after 5 minutes. There was no evidence of a disposition of 3H-digitoxin in intestinal aspirates. On a sixth subject labeled digitoxin was instilled in the mid-jejunum. The concentration of label in the plasma and the pattern of elimination of radioactivity in the urine and the feces in this subject indicated that the absorption of digitoxin was effective also in the more distal part of the gut. The combined results from the present study indicate that the absorption of orally administered digitoxin is complete. The biliary excretion of label 4 to 24 hours after the start of the experiments was calculated from ...
Abstract 3245: The interplay between patient´s features and mutational processes in tobacco related cancers
Authors: João Paulo da Silveira Nogueira Lima, Rodrigo Couto Duarte Drummond, Monize Nakamoto Provisor Santos, Renan Valieris, Rafael Andres Rosales Mitrowsky, Vladmir Cordeiro Lima, Diana Noronha Nunes, Emmanuel Dias-Neto, Israel Tojal da Silva
Journal: Cancer Research (2018)

Abstract Background: There is a complex interplay between smoking and patient demographics in the emergence and development of cancer. We vetted the possible relationship between gender, race and age with mutational processes operating on aerodigestive tract cancers, known to be highly associated to tobacco. Methods: We used an empirical Bayesian approach to identify genomic patterns that lead to mutational processes in head and neck, esophageal, and lung cancers from TCGA database followed by confirmation in independent cohorts (cBioPortal). Results: After confronting clinical information and smoking-habits to molecular findings in those cancers, we identified imprints of different mutational processes in a disease-, gender- and race-specific fashion. Black and female patients - despite their lower tobacco consumption in comparison to whites or males - had tumors with the highest enrichment for tobacco-induced DNA damage. The relevance of mutational signatures related to aging varied across race and gender and were independent from chronological age. The activity of smoking signature was different according to disease histotype, and stage. tumors of never-smoker lung cancer patients showed tobacco-specific mutational signatures, which could suggest the influence of second-hand smoking. Patients with tumors enriched for the smoking mutational signature presented longer survival, whereas those with ageing-enriched signature had poorer prognosis. Conclusions: Mutational processes may unravel connections between patient features and tumorigenesis, particular to race, gender, and tumor type. Therefore, it is paramount to assess those details with greater granularity in every effort of personalized medicine either in preventive or therapeutic approaches. Citation Format: João Paulo da Silveira Nogueira Lima, Rodrigo Couto Duarte Drummond, Monize Nakamoto Provisor Santos, Renan Valieris, Rafael Andres Rosales Mitrowsky, Vladmir Cordeiro Lima, Diana Noronha Nunes, Emmanuel Dias-Neto, Israel Tojal da Silva. The interplay between patient´s features and mutational processes in tobacco related 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 3245.
A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell–derived kidney model for drug discovery
Authors: Cecilia Boreström, Anna Jonebring, Jing Guo, Henrik Palmgren, Linda Cederblad, Anna Forslöw, Anna Svensson, Magnus Söderberg, Anna Reznichenko, Jenny Nyström, Jaakko Patrakka, Ryan Hicks, Marcello Maresca, Barbara Valastro, Anna Collén
Journal: Kidney International (2018)

Development of physiologically relevant cellular models with strong translatability to human pathophysiology is critical for identification and validation of novel therapeutic targets. Herein we describe a detailed protocol for generation of an advanced 3-dimensional kidney cellular model using induced pluripotent stem cells, where differentiation and maturation of kidney progenitors and podocytes can be monitored in live cells due to CRISPR/Cas9-mediated fluorescent tagging of kidney lineage markers (SIX2 and NPHS1). Utilizing these cell lines, we have refined the previously published procedures to generate a new, higher throughput protocol suitable for drug discovery. Using paraffin-embedded sectioning and whole-mount immunostaining, we demonstrated that organoids grown in suspension culture express key markers of kidney biology (WT1, ECAD, LTL, nephrin) and vasculature (CD31) within renal cortical structures with microvilli, tight junctions and podocyte foot processes visualized by electron microscopy. Additionally, the organoids resemble the adult kidney transcriptomics profile, thereby strengthening the translatability of our in vitro model. Thus, development of human nephron-like structures in vitro fills a major gap in our ability to assess the effect of potential treatment on key kidney structures, opening up a wide range of possibilities to improve clinical translation.