tbuckley/cabot-search huggingface dataset:
Assessment of Myocardial Viability in Patients With Chronic Coronary Artery Disease
Authors: PasqualePerrone-Filardi, LeonardoPace, MariellaPrastaro, FiorenzoSquame, SandroBetocchi, AndreaSoricelli, FedericoPiscione, CiroIndolfi, TeresaCrisci, MarcoSalvatore, MassimoChiariello
Journal: Circulation (1996)

Background To date, late redistribution after resting 201Tl injection has not been evaluated. In addition, the concordance between resting 201Tl imaging and dobutamine echocardiography in identifying viable myocardium has not been assessed. Methods and Results Forty patients with coronary artery disease underwent rest–4-hour–24-hour 201Tl tomography and dobutamine echocardiography (5 to 10 μg·kg−1·min−1). Late redistribution occurred in 46 (21%) of 219 persistent defects at 4 hours. Systolic function and contractile reserve were similar among persistent defects at 4 hours with and without late redistribution. Contractile reserve was more frequent in segments with normal 201Tl uptake (59%), completely reversible defects (53%), or mild to moderate defects at 4 hours (56%) compared with severe defects (14%; P<.02 versus all). Of 105 hypokinetic segments, 99 (94%) were viable by 201Tl, and 88 (84%) showed contractile reserve. In contrast, of 155 akinetic segments, 119 (77%) were viable by 201Tl, but only 34 (...
Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis
Authors: Yannick Allanore, Oliver Distler, Alexandre Jagerschmidt, Stephane Illiano, Laetitia Ledein, Eric Boitier, Inoncent Agueusop, Christopher P. Denton, Dinesh Khanna
Journal: Arthritis & Rheumatology (2017)

Objective Preclinical studies suggest a role for lysophosphatidic acid ( LPA ) in the pathogenesis of systemic sclerosis ( SS c). We undertook this study to assess SAR 100842, a potent selective oral antagonist of the LPA 1 receptor, for safety, biomarkers, and clinical efficacy in patients with diffuse cutaneous SS c (dc SS c). Methods An 8‐week double‐blind, randomized, placebo‐controlled study followed by a 16‐week open‐label extension with SAR 100842 was performed in patients with early dc SS c who had a baseline modified Rodnan skin thickness score ( MRSS ) of at least 15. The primary end point was safety during the double‐blind phase of the trial. Exploratory end points included the identification of an LPA ‐induced gene signature in patients’ skin. Results Seventeen of 32 patients were randomly assigned to receive placebo and 15 to receive SAR 100842; 30 patients participated in the open‐label extension study. The most frequent adverse events reported for SAR 100842 during the blinded phase were headache, diarrhea, nausea, and falling, and the safety profile was acceptable during the open‐label extension. At week 8, the reduction in MRSS was numerically greater in the SAR 100842 group than in the placebo group (mean ± SD change −3.57 ± 4.18 versus −2.76 ± 4.85; treatment effect −1.2 [95% confidence interval −4.37, 2.02]; P = 0.46). A greater reduction of LPA ‐related genes was observed in skin samples from the SAR 100842 group at week 8, indicating LPA 1 target engagement. Conclusion SAR 100842, a selective orally available LPA 1 receptor antagonist, was well tolerated in patients with dc SS c. The MRSS improved during the study although the difference was not significant, and additional gene signature analysis suggested target engagement. These results need to be confirmed in a larger controlled trial.
Abstract 1163: Chemoprevention of testosterone-induced benign prostatic hyperplasia by hexane fraction from seeds of <i>Annona muricata</i> (soursop) in rats
Authors: Oluwatosin A. Adaramoye, Taiwo D. Oladipo, Olubukola O. Akanni, Solomon O. Owumi, Olusoji J. Abiola
Journal: Cancer Research (2018)

Abstract Alternative medicine is an extensively recognized therapeutic approach for the management of several diseases. Annona muricata commonly called sour sop is traditionally used to manage an array of human diseases, especially cancer. In this study, we hypothesized that hexane fraction from seeds of Annona muricata (HFAM) will ameliorate testosterone propionate (TP)-induced benign prostatic hyperplasia (BPH) in rat model. Castration was performed via the scrotal route under ketamine anesthesia and BPH was induced through daily intraperitoneal injection of TP (3 mg/kg) for 4 weeks after castration. Rats were assigned into six groups of six animals each viz: non-castrated control, castrated control, castrated rats that received TP (BPH group), BPH + HFAM, BPH + HFAM + finasteride, BPH + finasteride. Results showed that BPH rats had 3.1 and 2.4 folds increase in prostatic and organo-somatic weight, respectively. Furthermore, BPH increased the activities of total acid and alkaline phosphatases by 62% and 53%, respectively, and levels of lipid peroxidation products by 48% in the prostate of rats. Also, BPH caused significant increase in the levels of inflammatory markers (Myeloperoxidase and total nitric oxide) in rats. In contrast, there were no significant differences in the activities of prostatic antioxidant enzymes in BPH group relative to others. In BPH group, immuno-histochemistry revealed strong expression of prostatic inducible nitric oxide synthase, Bcl2, beta-catenin, androgen and estrogen receptors proteins, while mild expression of p53 and Bax were observed. Interestingly, treatment of BPH rats with HFAM or HFAM + finasteride significantly attenuated inflammatory indices and induced apoptotic parameters. Overall, hexane fraction from seeds of Annona muricata may be used as a therapeutic agent for BPH via anti-inflammatory effect. Citation Format: Oluwatosin A. Adaramoye, Taiwo D. Oladipo, Olubukola O. Akanni, Solomon O. Owumi, Olusoji J. Abiola. Chemoprevention of testosterone-induced benign prostatic hyperplasia by hexane fraction from seeds of Annona muricata (soursop) in rats [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 1163.
Abstract 5873: BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors
Authors: Clara Lemos, Volker K. Schulze, Benjamin Bader, Clara D. Christ, Hans Briem, Oliver Politz, Florian Prinz, Simon Holton, Tobias Heinrich, Julien Lefranc, Philip Lienau, Arne Scholz, Franz von Nussbaum, Carl Friedrich Nising, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth
Journal: Cancer Research (2018)

Abstract The AMP-activated protein kinase (AMPK) is a sensor of the energy status in the cells, playing a key role in controlling their metabolism. For many years, AMPK was mainly perceived as a tumor suppressor in agreement with being a component of the LKB1 tumor suppressor cascade, which inhibits mTORC1. However, in the last few years, some studies suggested that AMPK might actually exert a pro-tumorigenic role in certain contexts. For instance, Liu and colleagues demonstrated that dysregulated MYC expression renders tumor cells sensitive to AMPK depletion (Liu et al, 2012. Nature). The authors showed that, due to their increased anabolism, MYC-dependent cells rely on AMPK to restore ATP levels and to prevent an energy crisis that results in apoptosis and cell death. Here we report the discovery of a new lead structure for the inhibition of AMPK by biochemical high throughput screening. The optimization of this lead structure towards potency and selectivity led to the probe compound BAY-3827 and the use of this tool compound to evaluate the therapeutic potential of AMPK inhibition in MYC-dependent tumors. To demonstrate a cellular effect of BAY-3827 an HRTF® assay (Homogeneous Time Resolved Fluorescence, cisbio) for phospho-Acetyl-CoA carboxylase (p-ACC, Ser79), a direct substrate of AMPK, was used. ACC phosphorylation was strongly inhibited by BAY-3827 in COLO 320DM and IMR-32 cells. However, despite its high potency, BAY-3827 failed to inhibit the proliferation of cells with dysregulated c-MYC or N-MYC. In conclusion, we have identified a potent and selective AMPK inhibitor. Despite demonstrated inhibition of AMPK kinase activity, BAY-3827 treatment did not translate into antiproliferative activity in MYC-dependent cells. While we could not confirm our initial hypothesis, one might speculate that inhibition of AMPK might be of therapeutic utility in other biological contexts. Therefore, the availability of potent and selective inhibitors, as described here, will contribute to further insight into the potential of AMPK inhibition as a therapeutic target in cancer. Citation Format: Clara Lemos, Volker K. Schulze, Benjamin Bader, Clara D. Christ, Hans Briem, Oliver Politz, Florian Prinz, Simon Holton, Tobias Heinrich, Julien Lefranc, Philip Lienau, Arne Scholz, Franz von Nussbaum, Carl Friedrich Nising, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth. BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors [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 5873.
Abstract 899: Phosphorylated mTOR by signaling through EphB3 confers resistance to a selective FGFR inhibitor in SNU-16 gastric cancer cells
Authors: Suk-young Lee, YooJin Na, YoonA Jung, JungLim Kim, Sang Cheul Oh, Dae-Hee Lee
Journal: Cancer Research (2018)

Abstract Because about 10% of gastric cancers show amplification of FGFR2, inhibition of FGFR2 activation has been regarded as one of therapeutic targets. AZD4547, a selective inhibitor of the FGFR1-3 tyrosine kinases, was developed to inhibit FGFR signaling; however, its efficacy is limited by emergency of the acquired resistance. We tried to clarify a resistance mechanism against the FGFR inhibitor. The cell line resistant against AZD4547 was established using SNU-16 (SNU16R), an FGFR2-amplified gastric cancer cell line, by culturing with increasing concentration of AZD4547. The expression levels of FGFR or phosphorylated FGFR (pFGFR), EphB3 and downstream signaling molecules, proteins involved in epithelial-mesenchymal transition (EMT) and apoptosis, were determined by Western blot. Cell viability was measured with EZ-Cytox kit reagent (DoGen, Seoul, Korea). Relative level of tyrosine phosphorylation of receptor tyrosine kinases (RTKs) was evaluated with Proteome ProfilerTM array by human phosphor-RTK kit (R&amp;D Systems). Apoptosis was determined by Annexin V-FITC apoptosis detection kit (BioBud, Seoul, Korea). Cell cycle assay was performed using Beckman Coulter flow cytometer and WinMDI for determination of cell numbers in G1, S, G2/M phases. Here we show the following: 1) establishment of a gastric cancer cell line (SNU16) resistant to AZD4547 (SNU16R); 2) expression of EphB3 receptor in SNU16R and induction of apoptosis and cell cycle arrest as well as inhibition of cell proliferation and suppressed expression of EMT markers under the treatment EphB3 inhibitor in SNU16R; 3) demonstration of mTOR as a downstream signaling cascade molecule of EphB3 by showing increased expression of phosphorylated (p-) mTOR and its downstream molecules in SNU16R and suppressed expression of p-mTOR by the EphB3 inhibitor. Cell cycle arrest, inhibition of cell proliferation and suppressed expression of p-mTOR under treatment with everolimus were also shown. We concluded that phosphorylation of mTOR through activation of EphB3 receptor is one of the mechanisms that confer resistance to AZD 4547, a selective FGFR inhibitor, in gastric cancer cells. Citation Format: Suk-young Lee, YooJin Na, YoonA Jung, JungLim Kim, Sang Cheul Oh, Dae-Hee Lee. Phosphorylated mTOR by signaling through EphB3 confers resistance to a selective FGFR inhibitor in SNU-16 gastric cancer 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 899.
The metabolite D-tryptophan from probiotic bacteria ameliorates allergic airway disease and influences the gut microbiome
Authors: S. Bartel, G. Jatzlauk, I Kepert, J. Fonseca, C. Müller, K. Milger, K. Hochwind, M. Kostric, O. Eickelberg, M. Schloter, A. Hartmann, P. Schmitt-Kopplin, S. Krauss-Etschmann
Journal: Allergy (2017)
Abstract 127: Exosomes derived from head and neck cancer enhance the cytotoxicities of NK cells by NAP1-IRF-3 pathway
Authors: Wantao Chen, Yingnan Wang, Jianjun Zhang
Journal: Cancer Research (2018)

Abstract Objective: To examine the effect of tumor-derived exosomes (TEXs) from oral cancer on natural killer (NK) cells and to explore the underlying mechanism. Materials and Methods: TEXs were isolated from the medium supernatant of oral cancer (OC) cells using ultrafiltration and affinity chromatography and were identified using electronic microscopy, nanoparticle tracking analysis and immunoblotting. The effects of TEXs on NK cells were analyzed using laser scanning confocal microscopy and several functional assays of NK cells. To explore the mechanism, antibody array, protein mass spectrometry and RNA interference were adopted. Results: The particles isolated from the OC cells were identified as exosomes with satisfactory morphology, concentration and purity. The TEXs were internalized by the NK cells and then promoted the biologic functions of these cells, including proliferation, cytotoxicity and the release of perforin and granzyme M. Furthermore, we found that the TEXs increased the expression of interferon regulatory factor 3 (IRF-3) and phosphorylated IRF-3 by antibody array, which drove the expression of the type I interferon (IFN) gene and the chemokine (C-X-C motif) ligand (CXCL) genes, thereby promoting the function of NK cells. We also found that NF-κB-activating kinase-associated protein 1 (NAP1), an upstream activator of IRF-3, was enriched in TEXs, and treatment with TEXs increased NAP1 in NK cells. Importantly, NAP1-depleted TEXs obtained from OC cells dramatically weakened the influence of the TEXs on NK cells. Conclusion: Our findings reveal a previously unrecognized function of exosome derived from oral cancer cells in enhancing the cytotoxicity of NK cells by NAP1- IRF-3 pathway. This work was supported by the National Program on Key Research Project of China (2016YFC0902700). Citation Format: Wantao Chen, Yingnan Wang, Jianjun Zhang. Exosomes derived from head and neck cancer enhance the cytotoxicities of NK cells by NAP1-IRF-3 pathway [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 127.
Abstract 13025: Deficiency of Interleukin-1 Receptor Antagonist Promotes Angiotensin II-induced Aortic Inflammation and Aneurysm
Authors: KojiAkita, KikuoIsoda, SarasaIsobe, TomiharuNiida, HiroyukiDaida
Journal: Circulation (2014)

Introduction: Angiotensin II (AngII) increases arterial pressure and induces inflammation. Although interleukin-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines, the role of IL-1Ra in AngII-induced aortic inflammation and aneurysm remains unknown. Methods and Results: To determine the contrition of IL-1Ra to AngII-induced aortic inflammation, male wild-type (WT) (n=18) and IL-1Ra-deficient (IL-1Ra-/-) (n=18) mice were infused with AngII (3000ng/kg per minute) using subcutaneous osmotic pumps for 28 days. 7 days after infusion, real-time PCR of abdominal aorta in IL-1Ra-/- mice revealed significantly increased mRNA levels of IL-6 (2.1-fold, p<0.01), TNF-α (4.1-fold, p<0.01), and MMP-9 (20.3-fold, p<0.05) compared with WT mice. 14 days after infusion, both systolic blood pressure (178±21 vs 135±21 mmHg, p<0.01)and abdominal aortic width (1.02±0.12 vs 0.82±0.05 mm, p<0.01) in IL-1Ra-/- mice significantly increased compared with WT mice. Moreover, AngII infusion into IL-...
Disordered Cellular Migration and Angiogenesis in cd39-Null Mice
Authors: ChristianGoepfert, ChristianSundberg, JeanSévigny, KeiichiEnjyoji, TomokazuHoshi, EvaCsizmadia, SimonRobson
Journal: Circulation (2001)

Background— Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 is the major ectonucleotidase of endothelial cells and monocytes and catalyzes phosphohydrolysis of extracellular nucleoside diphosphates (NDP) and triphosphates (NTP, eg, ATP and UTP). Deletion of cd39 causes perturbations in the hydrolysis of NTP and NDP in the vasculature. Activation of P2 receptors appears to influence endothelial cell chemotactic and mitogenic responses in vitro. Therefore, aberrant regulation of nucleotide P2 receptors may influence angiogenesis in cd39-null mice. Methods and Results— In control mice, implanted Matrigel plugs containing growth factors were rapidly populated by monocyte/macrophages, endothelial cells, and pericytes, with the development of new vessels over days. In cd39-null mice, migrating cells were completely confined to the tissue-Matrigel interface in a clearly stratified manner. Absolute failure of new vessel ingrowth was consistently observed in the mutant mice. Linked to these findings, ...
Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study
Authors: Séverine Sabia, Aurore Fayosse, Julien Dumurgier, Aline Dugravot, Tasnime Akbaraly, Annie Britton, Mika Kivimäki, Archana Singh-Manoux
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine the association between alcohol consumption and risk of dementia. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Civil service departments in London (Whitehall II study). <h3>Participants</h3> 9087 participants aged 35-55 years at study inception (1985/88). <h3>Main outcome measures</h3> Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. Measures of alcohol consumption were the mean from three assessments between 1985/88 and 1991/93 (midlife), categorised as abstinence, 1-14 units/week, and &gt;14 units/week; 17 year trajectories of alcohol consumption based on five assessments of alcohol consumption between 1985/88 and 2002/04; CAGE questionnaire for alcohol dependence assessed in 1991/93; and hospital admission for alcohol related chronic diseases between 1991 and 2017. <h3>Results</h3> 397 cases of dementia were recorded over a mean follow-up of 23 years. Abstinence in midlife was associated with a higher risk of dementia (hazard ratio 1.47, 95% confidence interval 1.15 to 1.89) compared with consumption of 1-14 units/week. Among those drinking &gt;14 units/week, a 7 unit increase in alcohol consumption was associated with a 17% (95% confidence interval 4% to 32%) increase in risk of dementia. CAGE score &gt;2 (hazard ratio 2.19, 1.29 to 3.71) and alcohol related hospital admission (4.28, 2.72 to 6.73) were also associated with an increased risk of dementia. Alcohol consumption trajectories from midlife to early old age showed long term abstinence (1.74, 1.31 to 2.30), decrease in consumption (1.55, 1.08 to 2.22), and long term consumption &gt;14 units/week (1.40, 1.02 to 1.93) to be associated with a higher risk of dementia compared with long term consumption of 1-14 units/week. Analysis using multistate models suggested that the excess risk of dementia associated with abstinence in midlife was partly explained by cardiometabolic disease over the follow-up as the hazard ratio of dementia in abstainers without cardiometabolic disease was 1.33 (0.88 to 2.02) compared with 1.47 (1.15 to 1.89) in the entire population. <h3>Conclusion</h3> The risk of dementia was increased in people who abstained from alcohol in midlife or consumed &gt;14 units/week. In several countries, guidelines define thresholds for harmful alcohol consumption much higher than 14 units/week. The present findings encourage the downward revision of such guidelines to promote cognitive health at older ages.
Ultrasound for Lower Extremity Deep Venous Thrombosis
Authors: Laurence Needleman, John J. Cronan, Michael P. Lilly, Geno J. Merli, Srikar Adhikari, Barbara S. Hertzberg, M. Robert DeJong, Michael B. Streiff, Mark H. Meissner
Journal: Circulation (2018)

Venous ultrasound is the standard imaging test for patients suspected of having acute deep venous thrombosis (DVT). There is variability and disagreement among authoritative groups regarding the necessary components of the test. Some protocols include scanning the entire lower extremity, whereas others recommend scans limited to the thigh and knee supplemented with serial testing. Some protocols use gray-scale ultrasound alone, whereas others include Doppler interrogation. Point-of-care ultrasound is recommended in some settings, and there is heterogeneity of these protocols as well. Heterogeneity of recommendations can lead to errors including incorrect application of guidelines, confusion among requesting physicians, and incorrect follow-up. In October 2016, the Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts to evaluate the current evidence to develop recommendations regarding ultrasound protocols for DVT and the terminology used to communicate results to clinicians. Recommendations were made after open discussion and by unanimous consensus.The panel recommends a comprehensive duplex ultrasound protocol from thigh to ankle with Doppler at selected sites rather than a limited or complete compression-only examination. This protocol is currently performed in many facilities and is achievable with standard ultrasound equipment and personnel. The use of these recommendations will increase the diagnosis of calf DVT and provide better data to explain the presenting symptoms. The panel recommends a single point-of-care protocol that minimizes underdiagnoses of proximal DVT.The panel recommends the term chronic postthrombotic change to describe the residual material that persists after the acute presentation of DVT to avoid potential overtreatment of prior thrombus.Adoption of a single standardized comprehensive duplex ultrasound and a single point-of-care examination will enhance patient safety and clinicians' confidence.
Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator
Authors: MadlenRother, StefanieKrohn, GabrielaKania, DavyVanhoutte, AndreasEisenreich, XiaominWang, DirkWestermann, KostasSavvatis, NadineDannemann, CarstenSkurk, DeniseHilfiker-Kleiner, ToniCathomen, HenryFechner, UrsulaRauch, Heinz-PeterSchultheiss, StephaneHeymans, UrsEriksson, CarmenScheibenbogen, WolfgangPoller
Journal: Circulation (2010)

Background—CCN1 is an evolutionary ancient matricellular protein that modulates biological processes associated with tissue repair. Induction at sites of injury was observed in conditions ranging from skin wounds to cardiac diseases, including ischemic and inflammatory cardiomyopathy. Here, we provide evidence of a novel function of CCN1 as a modulator of immune cell migration. Methods and Results—To understand the role of CCN1 in cardiomyopathies and to evaluate its therapeutic potential, we overexpressed CCN1 using an adenoviral hepatotropic vector in murine experimental autoimmune myocarditis, a model of human inflammatory cardiomyopathy. CCN1 gene transfer significantly reduced cardiac disease score and immune cell infiltration. In vivo tracking of hemagglutinin epitope–tagged CCN1 revealed binding to spleen macrophages but not to cardiomyocytes. Unexpectedly, CCN1 therapy left cardiac chemokine and cytokine expression unchanged but instead strongly inhibited the migration of spleen macrophages and ly...