tbuckley/cabot-search huggingface dataset:
Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction
Authors: Ting-Ting Tang, Yuan-Yuan Li, Jing-Jing Li, Ke Wang, Yue Han, Wen-Yong Dong, Zheng-Feng Zhu, Ni Xia, Shao-Fang Nie, Min Zhang, Zhi-Peng Zeng, Bing-Jie Lv, Jiao Jiao, Heng Liu, Zong-Shu Xian, Xiang-Ping Yang, Yu Hu, Yu-Hua Liao, Qing Wang, Xin Tu, Ziad Mallat, Yu Huang, Guo-Ping Shi, Xiang Cheng
Journal: Theranostics (2018)

Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.
Development of a Drug Screening Platform Based on Engineered Heart Tissue
Authors: ArneHansen, AlexandraEder, MarleneBönstrup, MarianneFlato, MarcoMewe, SebastianSchaaf, BülentAksehirlioglu, AlexanderSchwörer, JuneUebeler, ThomasEschenhagen
Journal: Circulation Research (2010)

Rationale: Tissue engineering may provide advanced in vitro models for drug testing and, in combination with recent induced pluripotent stem cell technology, disease modeling, but available techniques are unsuitable for higher throughput. Objective: Here, we present a new miniaturized and automated method based on engineered heart tissue (EHT). Methods and Results: Neonatal rat heart cells are mixed with fibrinogen/Matrigel plus thrombin and pipetted into rectangular casting molds in which two flexible silicone posts are positioned from above. Contractile activity is monitored video-optically by a camera and evaluated by a custom-made software program. Fibrin-based mini-EHTs (FBMEs) (150 μL, 600 000 cells) were transferred from molds to a standard 24-well plate two hours after casting. Over time FBMEs condensed from a 12×3×3 mm gel to a muscle strip of 8 mm length and, depending on conditions, 0.2 to 1.3 mm diameter. After 8 to 10 days, FBMEs started to rhythmically deflect the posts. Post properties and ...
Apoptosis in Ischemic and Reperfused Rat Myocardium
Authors: HenryFliss, DeborahGattinger
Journal: Circulation Research (1996)

Apoptosis has been observed previously in hearts subjected to either continuous ischemia or ischemia followed by reperfusion. The purpose of this study was to compare the timing and extent of apoptosis in both continuously ischemic and reperfused myocardium. We show that rats subjected to continuous coronary artery occlusion display characteristic signs of apoptosis solely in the ischemic myocardium after only 2.25 hours of ischemia, as illustrated by positive in situ end labeling (ISEL) of apoptotic cardiomyocyte nuclei in tissue sections and/or the presence of DNA “ladders” in agarose gels. In contrast, reperfusion after a 45-minute occlusion accelerated the process, with apoptosis becoming evident solely in the reperfused myocardium after only 1 hour of reperfusion. ISEL and DNA ladder intensity increased with duration of ischemia or reperfusion. The volume of myocardium in which ISEL was observed was smaller in the reperfused hearts, and the ISEL-stained nuclei represented 23% and 33% of the total nuc...
Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis
Authors: Daniel H. Solomon, M. Elaine Husni, Katherine E. Wolski, Lisa M. Wisniewski, Jeffrey S. Borer, David Y. Graham, Peter Libby, A. Michael Lincoff, Thomas F. Lüscher, Venu Menon, Neville D. Yeomans, Qiuqing Wang, Weihang Bao, Manuela F. Berger, Steven E. Nissen
Journal: Arthritis & Rheumatology (2017)

Objective To determine the relative risks of cardiovascular ( CV ), gastrointestinal ( GI ), and renal adverse events during long‐term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis ( OA ) and patients with rheumatoid arthritis ( RA ). Methods A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double‐blind randomized controlled trial. Interventions included celecoxib at a dosage of 100–200 mg twice daily, ibuprofen at a dosage of 600–800 mg 3 times daily, or naproxen at a dosage of 375–500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. Results In the subgroup of patients with OA , the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [ HR ] 0.84, 95% confidence interval [95% CI ] 0.72–0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HR s of 1.06 (95% CI 0.69–1.63) and 1.22 (95% CI 0.78–1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51–0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55–0.98). Duplicate comparisons in patients with RA revealed HR s of 0.48 (95% CI 0.22–1.07) and 0.54 (95% CI 0.24–1.24), respectively. In patients with OA , a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40–0.82). In patients with RA , celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment ( HR 0.47, 95% CI 0.25–0.88). Conclusion Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV , GI , and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA .
Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer: a nationwide, observational follow up study in Sweden
Authors: Subhayan Chattopadhyay, Guoqiao Zheng, Amit Sud, Hongyao Yu, Kristina Sundquist, Jan Sundquist, Asta Försti, Akseli Hemminki, Richard Houlston, Kari Hemminki
Journal: The Lancet Haematology (2018)
Arterial Hemodynamics in Patients After Kawasaki Disease
Authors: HideakiSenzaki, Chen-HuanChen, HirotakaIshido, SatoshiMasutani, TamotsuMatsunaga, MioTaketazu, ToshikiKobayashi, NozomuSasaki, ShuneiKyo, YujiYokote
Journal: Circulation (2005)

Background— Histopathological findings in the acute stage of Kawasaki disease (KD) indicate widespread vascular inflammation that involves not only coronary arteries but also systemic arteries. This may cause changes in systemic arterial wall properties after KD, which could have adverse effects on arterial hemodynamics (an important predictor of cardiovascular morbidity and mortality). Methods and Results— Systemic arterial hemodynamics were investigated by measuring aortic input impedance during cardiac catheterization in 42 KD patients who had developed coronary artery lesions (CALs) in the acute stage of KD. The KD patients were subdivided into 2 groups according to the angiographic findings (group 1A, 26 patients with persistent CALs; group 1B, 16 patients with regressed CALs), and results were compared with those of 36 referents (group 2). Compared with referents, characteristic impedance was significantly higher for KD patients (137.0±5.1, 125.7±8.2, and 97.9±4.1 dyne · s · cm−5 · m2 for group 1A, ...
Abstract LB-084: Dasatinib reduces tumor growth in xenograft models derived from human lung tumors with YES1 overexpression
Authors: Irati Garmendia, Cristina Bértolo, Irene Ferrer, María J Pajares, Daniel Ajona, Luis Paz-Ares, Ruben Pio, Luis M Montuenga, Jackeline Agorreta
Journal: Cancer Research (2018)

Abstract Introduction Lung cancer accounts for 13.2% of all new cancer cases and is the leading cause of cancer-related death worldwide. For a reduction of mortality rates, new personalized therapies are needed. The great challenge is to identify the alterations responsible for the tumor malignant phenotype which should be targeted by specific therapeutic strategies. The aim of our study is to evaluate the use of YES1 kinase amplification and overexpression as a companion biomarker to predict sensitivity to dasatinib using patient-derived xenograft models. Previous results Our previous experiments showed that downregulation of YES1 expression by specific siRNAs impairs cell proliferation and survival in lung cancer cell lines with amplification and high expression of YES1 (YES1High). Inhibition of YES1 in cell lines with normal copy number and low expression (YES1Low) had no effect on cell proliferation. Moreover, YES1 downregulation induced apoptosis and inhibited invasion only in YES1High cells, and YES1 overexpression promoted proliferation in lung cancer cell lines. Methods Eight patient-derived xenograft mouse models were used: two YES1High adenocarcinomas (ADC), two YES1Low ADC, two YES1High squamous cell carcinomas (SCC) and two YES1Low SCC. Small fragments of xenografted tumors (2-3 mm in diameter) were subcutaneously implanted into the right flank of 7-8-week-old BALB/c-Rag2−/−-IL2γc−/− immunodeficient mice. Mice were treated with dasatinib (60 mg/kg) or citric acid daily by oral gavage. Tumor volume was measured twice a week. Tumor volumes were calculated by the formula (LxW2)/2. Results In those tumors harboring YES1 amplification (YES1High), dasatinib significantly reduced tumor growth. This treatment induced tumor response in both ADC and SCC PDX models. On the contrary, in tumors with low expression of YES1, dasatinib did not affect tumor growth in ADC or SCC PDX models. Conclusions Dasatinib treatment significantly reduces tumor growth in YES1High PDX models but not in YES1Low models, providing support to our hypothesis that YES1 expression may be a useful companion biomarker for dasatinib as NSCLC treatment. Citation Format: Irati Garmendia, Cristina Bértolo, Irene Ferrer, María J Pajares, Daniel Ajona, Luis Paz-Ares, Ruben Pio, Luis M Montuenga, Jackeline Agorreta. Dasatinib reduces tumor growth in xenograft models derived from human lung tumors with YES1 overexpression [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 LB-084.
Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO
Authors: TienushRassaf, PetraKleinbongard, MichaelPreik, AndréDejam, PutrikaGharini, ThomasLauer, JuliaErckenbrecht, AlexejDuschin, RainerSchulz, GerdHeusch, MartinFeelisch, MalteKelm
Journal: Circulation Research (2002)

Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S-nitrosothiols (RSNOs), with no apparent saturation limit up to 200 μmol/L. The presence of red blood cells reduced the formation of plasma RSNOs. Intravenous infusion of 30 μmol/min NO in healthy volunteers increased plasma levels of RSNOs and induced systemic hemodynamic effects at the level of both conduit and resistance vessels, as reflected by dilator responses in the brachial artery and forearm microvasculature. Intravenous application of S-nitrosoglutathione, a potential carrier of bioactive...
Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation
Authors: PierreJaïs, BrunoCauchemez, LaurentMacle, EmileDaoud, PaulKhairy, RajeshSubbiah, MélèzeHocini, FabriceExtramiana, FrédericSacher, PierreBordachar, GeorgeKlein, RukshenWeerasooriya, JacquesClémenty, MichelHaïssaguerre
Journal: Circulation (2008)

Background—The mainstay of treatment for atrial fibrillation (AF) remains pharmacological; however, catheter ablation has increasingly been used over the last decade. The relative merits of each strategy have not been extensively studied. Methods and Results—We conducted a randomized multicenter comparison of these 2 treatment strategies in patients with paroxysmal AF resistant to at least 1 antiarrhythmic drug. The primary end point was absence of recurrent AF between months 3 and 12, absence of recurrent AF after up to 3 ablation procedures, or changes in antiarrhythmic drugs during the first 3 months. Ablation consisted of pulmonary vein isolation in all cases, whereas additional extrapulmonary vein lesions were at the discretion of the physician. Crossover was permitted at 3 months in case of failure. Echocardiographic data, symptom score, exercise capacity, quality of life, and AF burden were evaluated at 3, 6, and 12 months by the supervising committee. Of 149 eligible patients, 112 (18 women [16%];...
Abstract A61: Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine
Authors: Yoshiko Nanki, Akira Hirasawa, Hiroyuki Nomura, Aki Okubo, Manabu Itoh, Tomoko Akahane, Tatsuyuki Chiyoda, Fumio Kataoka, Eiichiro Tominaga, Daisuke Aoki
Journal: Clinical Cancer Research (2018)

Abstract Objective: Ovarian cancer is a poor-prognosis gynecologic disease with over 220,000 diagnoses each year worldwide and a 5-year survival rate less than 40%. In this study, we present a method for isolation and characterization of ovarian cancer cells from patient-derived ascites and tissue samples by using three-dimensional (3D) cell culture. Materials and Methods: Ascites and tissue samples were obtained from primary ovarian, peritoneal, and fallopian tube cancer patients intraoperatively. Samples were isolated and cultured within 6 hours after collection. After isolation, cells were resuspended in Matrigel and were placed at the center of each well. Optimized medium is added to each well. NanoCulture Plate LH96 (Low-Binding, MH pattern, 96-wells, Medical and Biological Laboratories Co., Ltd., Japan) were used for 3D cell culture. Plates were incubated at 37°C. The cultures were examined for metabolically active cells by ATP assay and medium changed on days 0, 1, 4, 7, 10, and 14. Results: We successfully obtained ascites-derived primary cell cultures within 1-7 days from 100% (3/31) of the ascites samples and 62% (5/8) from tissue-derived primary cell cultures. Spheroids-like structures were formed in 30% (1/3) of ascites samples and 50% (4/8) of tissue samples. The tumorigenicity and invasiveness of the cells were demonstrated using new 3D spheroid model cultured in vitro by NanoCulture Plate LH96. Conclusion: Primary ascites and tissue culture of ovarian cancer cells can successfully be cultured by 3D cell culture plates. We may apply this method for drug sensitivity testing; therefore, 3D cell culture has a potential to evaluate the sensitivity of candidate chemotherapeutic drug for individual patients. Citation Format: Yoshiko Nanki, Akira Hirasawa, Hiroyuki Nomura, Aki Okubo, Manabu Itoh, Tomoko Akahane, Tatsuyuki Chiyoda, Fumio Kataoka, Eiichiro Tominaga, Daisuke Aoki. Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine. [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 A61.
Abstract 3337: Nuclear S1P binds PASB domain of HIFα to facilitate HIFα-HIF1β heterodimer formation in hypoxic TNBC cells
Authors: Nitai C. Hait, Aparna Maiti
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancers (TNBCs) have increased expression of hypoxia-inducible factor 1α (HIF1α) and HIF-direct genes that associated with decreased overall survival in patients. Previously we have shown that nuclear sphingosine-1-phosphate (S1P), a lipophilic pro-cancer signal mediator, a product of the catalytic reaction by sphingosine kinase 2 (SphK2), directly binds to and inhibits histone deacetylases-1 and -2 (HDAC1 and 2), thus, altered epigenetic landscape in breast cancer cells. SphK2/S1P signaling is essential for metastatic TNBC cell growth and survival. We hypothesize that SphK2/S1P epigenetically regulates HIFα functions in TNBC cells; TNBC subset with elevated SphK2 and HIF1α would be a marker for SphK2-mediated HIFα targeted therapy. METABRIC cohort gene expression analysis revealed that the mRNA expression of HIF1α mRNA and downstream angiogenesis gene, vascular endothelial growth factor B (VEGFB) are associated with overall poor survival for TNBC patients compared to non-TNBC patients. Here, we demonstrate that a subset of TNBC patient tissue samples nuclei has elevated HIF1α and SphK2 protein expressions. SphK2/S1P markedly enhances hypoxia-induced HIFα proximal promoter histone acetylation. SphK2/S1P is found in the nuclear protein complexes with HIFα. Moreover, S1P is docked well at the PASB domain of HIFα and facilitate HIFα-HIF1β heterodimer formation in hypoxia. SphK2/S1P markedly augmented HIF1α direct target gene HIF2α and VEGFA promoter occupancy in hypoxia. Down-regulation of SphK2 with siRNA markedly attenuated transcription of HIFα-direct target genes associated with cancer stem cells, angiogenesis, and metastasis. In agreement with an oncogenic role of SphK2, selective inhibition of SphK2 markedly reduced nuclear histone acetylation, HIF1α expression, and in vivo human TNBC tumor growth in mice. Our data strongly suggested that TNBC subset with elevated SphK2 and HIF1α would be a good candidate for SphK2 targeted therapy. Supported by Health Research, Inc. (HRI) Grant 71-4084-01 (NCH). Citation Format: Nitai C. Hait, Aparna Maiti. Nuclear S1P binds PASB domain of HIFα to facilitate HIFα-HIF1β heterodimer formation in hypoxic TNBC 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 3337.
Abstract 1205: Long-term survival of children with acute lymphoblastic leukemia, according to treatment regimen, in a regional French population
Authors: Sophie Gauthier, Morgane Mounier, Stéphanie Girard, Claire Briandet, Paule Marie Carli, Marc Maynadie
Journal: Cancer Research (2018)

Abstract Acute Lymphoblastic Leukemia (ALL) is the main neoplastic disease in children. Treatment is based on chemotherapy associated or not to bone marrow transplantation. The 5-year survival rate in European children is reported as 86% but long term survival data are not available. We investigated the 20 year Overall Survival (OS) and Net survival (NS) of the patients diagnosed in the population of the Côte d'Or area in France. 162 cases were diagnosed in the population of the Côte d'Or area between 1970 and 2015. Cases diagnosed between 1970 and 1979 (n=29) were not formally registered in the registry database but data were available through the unique regional, reference hematology laboratory. All cases were followed until 01 01 2017. The treatment regimens that were used were as follows in chronological order (from the earliest to the most recent); LAL 76 and 80; the FRALLE 83, 87 and 89 until 1993; the FRALLE 93 from 1993 to 2001 and then the FRALLE 2000. The 20-y OS and NS of ALL was respectively 66% and 67%. It was 59% in boys but 75% in girls (p=0.04). No statistical difference was found according to age. According to lineage subtype, the 20-y NS was 82% in B-ALL, 65% in T-ALL and 34% in ALL, not otherwise specified (p&amp;lt;0.001). According to treatment regimen, the 20-y-NS was 51% before the use of the FRALLE 93, compared to 71% for cases treated by the FRALLE 93 regimen and 95% for those treated with the FRALLE 2000 regimen (p&amp;lt;0.001). The survival was 95% irrespective of the time of diagnosis following introduction of the FRALLE 2000 regimen. Data on long term survival of ALL in children are scarce. Our results show 1) a very high 20 year survival rate indicating the efficacy and safety of the treatment regimens used, 2) the utility of randomized clinical trials to define new standards of care. Citation Format: Sophie Gauthier, Morgane Mounier, Stéphanie Girard, Claire Briandet, Paule Marie Carli, Marc Maynadie. Long-term survival of children with acute lymphoblastic leukemia, according to treatment regimen, in a regional French population [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 1205.
Mechanisms of NO/cGMP-Dependent Vasorelaxation
Authors: MatthiasSausbier, RudolfSchubert, ViktorVoigt, ChristophHirneiss, AlexanderPfeifer, MichaelKorth, ThomasKleppisch, PeterRuth, FranzHofmann
Journal: Circulation Research (2000)

Abstract—Both cGMP-dependent and -independent mechanisms have been implicated in the regulation of vascular tone by NO. We analyzed acetylcholine (ACh)- and NO-induced relaxation in pressurized small arteries and aortic rings from wild-type (wt) and cGMP kinase I–deficient (cGKI–/–) mice. Low concentrations of NO and ACh decreased the spontaneous myogenic tone in wt but not in cGKI–/– arteries. However, contractions of cGKI–/– arteries and aortic rings were reduced by high concentrations (10 μmol/L) of 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO). Iberiotoxin, a specific blocker of Ca2+-activated K+ (BKCa) channels, only partially prevented the relaxation induced by DEA-NO or ACh in pressurized vessels and aortic rings. DEA-NO increased the activity of BKCa channels only in vascular smooth muscle cells isolated from wt cGKI+/+ mice. These results suggest that low physiological concentrations of NO decrease vascular tone through activation of cGKI, whereas high concentrations of DEA-NO relax vascular ...