tbuckley/cabot-search huggingface dataset:
Hepatic Zonation Now on Hormones!
Authors: Sungjin Ko, Satdarshan P. Monga
Journal: Hepatology (2018)

Ko, Sungjin D.V.M., Ph.D.; Monga, Satdarshan P. M.D., F.A.A.S.L.D.Editor(s): Corey, Kathleen E.4; Malhi, Harmeet5 Author Information
Abstract 2883: Repurposing atovaquone, an antiprotozoal drug for management of breast cancer by inhibiting HER2/β-catenin signaling
Authors: Nehal Gupta, Sanjay Srivastava
Journal: Cancer Research (2018)

Abstract Breast cancer is the second highest cause of cancer-related mortality in women. HER2 is an oncogene overexpressed in about 30% of breast cancer patients and β-catenin, a proto-oncogene plays a pivotal role in breast cancer metastasis and drug resistance leading to poor prognosis. In the current study, we evaluated the anti-cancer effects of an anti-protozoal drug, atovaquone against several breast cancer cell lines such as MCF-7, 4T1, HCC1806, CI66, SKBR3 and T47D. Our results showed that atovaquone treatment induced apoptosis as evaluated by PI/Annexin assay and cleavage of caspase-3 and PARP, and inhibited the growth of all the breast cancer cell lines tested. Similar observations were made in patient-derived cancer cell lines. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1 and c-Myc in these cell lines. Treatment of HCC1806 cells with 5 µM atovaquone resulted in significant reduction in mammosphere forming efficiency (MFE) of breast cancer cells. Mammosphere-forming cells are known to exhibit cancer stem cell (CSC)-like properties together with drug resistance. Efficacy of atovaquone was evaluated in the in-vivo tumor model by orthotopic implantation of two highly aggressive 4T1 and CI66, triple negative breast cancer cells in the mammary fats of female mice. Our results demonstrate that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60% respectively. Atovaquone treated tumors exhibited reduced HER2, β-catenin and increased apoptosis when analyzed by western blot. We also developed resistance in 4T1 breast cancer cells towards paclitaxel, a first line chemotherapeutic agent for treatment of metastatic breast cancer. 4T1 paclitaxel resistant cells were orthotopically implanted in female balb/c mice and mice were treated with atovaquone for 20 days. Our results showed that atovaquone was able to suppress the growth of paclitaxel resistant tumors by 42%. Conclusively, our results indicate that atovaquone effectively reduces the growth of primary breast tumors as well as paclitaxel resistant tumors by inhibiting HER2/β-catenin signaling. Most importantly, atovaquone is already in clinical use with an established safety record therefore, any positive findings from our studies will prompt further clinical investigation into repurposing atovaquone for the treatment of advanced breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH]. Citation Format: Nehal Gupta, Sanjay Srivastava. Repurposing atovaquone, an antiprotozoal drug for management of breast cancer by inhibiting HER2/β-catenin signaling [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 2883.
Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial
Authors: Martin J van den Bent, Martin Klein, Marion Smits, Jaap C Reijneveld, Pim J French, Paul Clement, Filip Y F de Vos, Antje Wick, Paul J Mulholland, Martin J B Taphoorn, Joanne Lewis, Michael Weller, Olivier L Chinot, Johan M Kros, Iris de Heer, Tina Verschuere, Corneel Coens, Vassilis Golfinopoulos, Thierry Gorlia, Ahmed Idbaih
Journal: The Lancet Oncology (2018)
Abstract 1101: Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer network in vitro and in vivo
Authors: Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara
Journal: Cancer Research (2018)

Abstract Background: Epithelial-mesenchymal transition (EMT) is a biologic process by which epithelial cancer cells acquire mesenchymal phenotype with malignant properties for invasion and metastasis, leading to poor prognosis. Inflammatory microenvironment has been shown to be responsible for the development and progression of colorectal cancer (CRC). However, the precise role of inflammatory microenvironment in the EMT-related tumor progression remains unclear because EMT network is regulated by complex crosstalk between tumor and normal cells. In this study, we developed a fluorescence-guided live-cell imaging system for the spatiotemporal visualization of EMT state, and assessed the in vitro and in vivo visualization of EMT state in human CRC cells under the inflammatory microenvironment. Methods: We used two human CRC cell lines, HCT116 and RKO. The promoter of mesenchymal marker vimentin was used for inducing the EMT-dependent red fluorescence protein (RFP) expression in human CRC cells. The RFP expression was quantitatively analyzed to evaluate its association with EMT-related markers and malignant phenotype. Inflammatory cytokines, IL-1β (1 ng/ml) and TNF-α (20 ng/ml), or co-culture with inflammatory mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide (LPS) (200 ng/mL) were used as an inflammatory microenvironment. Biodistribution of EMT cells was analyzed using in vivo experiments with primary and metastatic CRC xenograft tumors. Results: Inflammatory cytokines reversely induced the RFP expression in association with EMT-related malignant phenotype, such as morphologic change, EMT marker modulation, and invasion ability, in HCT116 and RKO cells. Co-culture with LPS-stimulated inflammatory macrophages also induced the RFP expression by secreting inflammatory cytokines. In vivo experiments revealed that EMT cells were detected within tumor tissues at colon, liver and peritoneum. Conclusions: Our results suggest that inflammatory microenvironment has a great potential to induce EMT program in CRC cells. This fluorescence-guided EMT imaging system is a useful tool for monitoring the EMT state in the inflammation microenvironment-CRC network in vitro and in vivo. Citation Format: Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara. Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer network in vitro and in vivo [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 1101.
Abstract 3110: Heterokaryon formation and nuclear fusion of hybridizing cancer cells visualized in real time by color-coded imaging
Authors: Atsushi Suetsugu, Takuro Matsumoto, Kousuke Hasegawa, Miki Nakamura, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman
Journal: Cancer Research (2018)

Abstract Background: Fusion of cancer cells has been studied for over half a century. However, the steps involved after initial fusion between cells, such as heterokaryon formation and nuclear fusion, have been difficult to observe in real time. In order to be able to visualize these steps, we have established cancer-cell sublines from the human HT-1080 fibrosarcoma, one expressing green fluorescent protein (GFP) linked to histone H2B in the nucleus and a red fluorescent protein (RFP) in the cytoplasm and the other subline expressing RFP in the nucleus (mCherry) linked to histone H2B and GFP in the cytoplasm. Materials and Methods: The two reciprocal color-coded sublines of HT-1080 cells were fused using the Sendai virus. The fused cells were cultured on plastic and observed using an Olympus FV1000 confocal microscope. Results: Multi-nucleate (heterokaryotic) cancer cells, in addition to hybrid cancer cells with a single fused nucleus undergoing mitosis, were observed by confocal microcopy. Red, green, orange and yellow nuclei were observed in cells. The orange and yellow nuclei indicate nuclear fusion. Red and green nuclei remained unfused. Conclusion: Cell fusion with subsequent heterokaryon formation followed by nuclear hybridization may be an important natural phenomenon between cancer cells that may make them more malignant. The ability to image the complex processes following cell fusion using reciprocal color-coded cancer cells will allow greater understanding of the genetic basis of malignancy. Citation Format: Atsushi Suetsugu, Takuro Matsumoto, Kousuke Hasegawa, Miki Nakamura, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman. Heterokaryon formation and nuclear fusion of hybridizing cancer cells visualized in real time by color-coded imaging [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 3110.
Abstract 10752: Effect of Guided High Mechanical Index Impulses and Intravenous Microbubbles on Infarct Size and Systolic Function Assessed by Cardiac Magnetic Resonance Imaging Following Acute Myocardial Infarction
Authors: FengXie, JuefeiWu, SamerSayyed, JiaLiu, JeffryPowers, WilliamShi, FrancoisVignon, JohnLof, Shelby LKutty, ThomasPorter
Journal: Circulation (2012)

Background. Guided high mechanical index (MI) impulses from a modified diagnostic ultrasound system during an intravenous microbubble (IV MB) contrast infusion have been shown to improve ST segment resolution and recanalization rates in atherosclerotic pig models with ST elevation acute myocardial infarction (STEMI). Cardiac magnetic resonance imaging (CMRI) with delayed gadolinium enhancement imaging (DE-MRI) allows for quantification of systolic function, infarct size, and microvascular flow in this setting. We hypothesized that this guided high MI impulses and IV MB, utilized with low dose tissue plasminogen activator (TPA), would result in quantitative improvements in these CMRI parameters. Methods. Twelve pigs with acute STEMI of the left anterior descending artery were treated with low dose TPA alone (0.5 mg/kg over 30 minutes; n=5) or a low dose TPA infusion (n=7) combined IV MB (MRX 801; NuVox) and guided high MI (1.0) impulses (20 usec pulse duration 1.6 MHz S5-1 transducer; Philips Medical), whi...
Abstract 1063: A clear cell renal cancer metastasis model identifies novel mediators of tumor aggressiveness and predictors of patient survival
Authors: Felix Geist, Teresa Dolt, Thomas Höfner, Corinna Klein, Vanessa Vogel, Albrecht Stenzinger, Tim Holland-Letz, Ornella Kossi, Wilko Weichert, Peter Schirmacher, Sascha Pahernik, Markus Hohenfellner, Andreas Trumpp, Martin Sprick
Journal: Cancer Research (2018)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma with a 5-year survival rate of only 10.5%, and chemotherapy and radiotherapy regimen have shown limited efficacy. On the molecular level, significant inter- and intra-tumor heterogeneity hamper identification of drug targets, biomarkers and unraveling of disease mechanisms. We developed a novel patient-derived model system of ccRCC that recapitulates the heterogeneity of the originating cancer enabling us to study ccRCC on a functional level. In five rounds and in three biological replicates of an in vivo selection, we transplanted the metastases of orthotopically transplanted tumor cells into the renal capsules of NOD scid gamma (NSG) mice. The tumor was enriched for cells with higher growth and metastatic potential compared to the initial heterogeneous population. Comparative gene-expression analysis revealed candidate genes associated with enhanced malignant growth and metastasis. Absolute shrinkage and selection operator (LASSO) regression identified a gene signature that can robustly predict patient survival. The prognostic power of our signature was additionally verified in independent patient cohorts suggesting that this approach leverages efficient stratification of patients into distinctive risk groups. One of the hallmark genes in this signature is known to alter cellular signaling properties. Therefore, we hypothesized that this gene contributes to tumor growth and metastasis and thus to aggressiveness of ccRCC. In fact, in knockdown and overexpression xenografts experiments we could confirm an essential role for tumor aggressiveness in vivo suggesting that the gene and associated downstream signaling pathways are attractive targets for treatment of clear cell renal cancer. Citation Format: Felix Geist, Teresa Dolt, Thomas Höfner, Corinna Klein, Vanessa Vogel, Albrecht Stenzinger, Tim Holland-Letz, Ornella Kossi, Wilko Weichert, Peter Schirmacher, Sascha Pahernik, Markus Hohenfellner, Andreas Trumpp, Martin Sprick. A clear cell renal cancer metastasis model identifies novel mediators of tumor aggressiveness and predictors of patient survival [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 1063.
Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
Authors: Pablo Villa-Pérez, Beatriz Merino, Cristina M. Fernández-Díaz, Pilar Cidad, Carmen D. Lobatón, Alfredo Moreno, Harrison T. Muturi, Hilda E. Ghadieh, Sonia M. Najjar, Malcolm A. Leissring, Irene Cózar-Castellano, Germán Perdomo
Journal: Metabolism (2018)

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood.This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance.We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action.L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded.IDE is not a rate-limiting regulator of plasma insulin levels in vivo.
Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism
Authors: TatsuhiroShibata, ShojiKawakami, TeruoNoguchi, TomotakaTanaka, YasuhideAsaumi, TomoakiKanaya, ToshiyukiNagai, KazuhiroNakao, MasashiFujino, KazuyukiNagatsuka, HatsueIshibashi-Ueda, KunihiroNishimura, YoshihiroMiyamoto, KengoKusano, ToshihisaAnzai, YoichiGoto, HisaoOgawa, SatoshiYasuda
Journal: Circulation (2015)

Background—Coronary artery embolism (CE) is recognized as an important nonatherosclerotic cause of acute myocardial infarction. Its prevalence, clinical features, and prognosis remain insufficiently characterized. Methods and Results—We screened 1776 consecutive patients who presented with de novo acute myocardial infarction between 2001 and 2013. CE was diagnosed based on criteria encompassing histological, angiographic, and other diagnostic imaging findings. The prevalence, clinical characteristics, treatment strategies, in-hospital outcomes, and long-term risk of CE recurrence or major adverse cardiac and cerebrovascular events (cardiac death, fatal arrhythmia, or recurrent thromboembolism) were evaluated. The prevalence of CE was 2.9% (n=52), including 8 (15%) patients with multivessel CE. Atrial fibrillation was the most common cause (n=38, 73%). Only 39% of patients with CE were treated with vitamin K antagonists, and the median international normalized ratio was 1.42 (range, 0.95–1.80). Eighteen of...
Abstract 19675: Management of Pump Thrombosis in Heartware Hvad Patients
Authors: Thomas Krabatsch, Friedrich Kaufmann, Christoph Hörmandinger, Markus Müller, Alexandra Kretzschmar, Panagiotis Pergantis, Volkmar Falk, Evgenij V Potapov
Journal: Circulation (2015)

Introduction: Implantable continuous-flow left ventricular assist device (LVAD) HeartWare HVAD has found broad acceptance, but a significant number of patients present with pump thrombosis (PT). We report our diagnostic and therapeutic strategy. Methods: We retrospectively analyzed pump thrombosis in 540 patients supported with the HeartWare HVAD in 8/2009-5/2015. Our anticoagulation protocol consisted of bridging with heparin until sufficient oral anticoagulation. Patients with clear evidence of pre- or post-device thrombus (n=5 and n=3) were excluded. Suspected PT was defined as marked increase of LVAD power consumption, significant increase of hemolysis (according to Intermacs definitions) and/or positive signals in acoustic analysis. Confirmed PT was defined as either demonstration of thrombotic material in the explanted LVAD or complete disappearance of hemolysis and normalization of device parameters after thrombolytic therapy. Results: As median support in this group was 248 (range 0-2106) days the cohort represents 617 patient-years. Eighty-three episodes of PT were detected in 66 patients with 10 of these episodes successfully treated by thrombolysis (15%). PT occurred within 2-1521 days after primary implantation, median 349 days. Cumulative rate of all types of PT per patient-year (EPPY) was 0.13, with 0.11 for proven and 0.02 for suspected PT. The decision to exchange the pump was triggered by marked hemolysis and/or high power consumption or failed thrombolysis, if initiated. Fifty-five operative pump exchanges, including 5 after unsuccessful thrombolysis were necessary in 48 patients 5 patients experienced two and 1 patient three exchanges. Fifty pump exchanges were performed via lateral mini-thoracotomy and five through a median re-sternotomy. Eight patients died before pump exchange. The hospital discharge rate was 62% after the first and 100% after the second and third pump exchange. Conclusions: Minority of pump thrombosis after HeartWare implantation could be cured medically. As most thrombosed devices can be exchanged through a lateral mini-thoracotomy with low postoperative mortality, the pump exchange should not be delayed and then even repeated thrombotic events can be handled successfully.
Abstract 17353: B Cell Depletion Promotes Aortic Infiltration of Tolerogenic Immune Cells and is Protective of Experimental Aortic Aneurysm
Authors: Basil Schaheen, Emily A Downs, Gang Su, Yunge Zhao, Prasad Srikakulapu, Coleen A McNamara, Cherié Butts, Gilbert R Upchurch Jr., Akshaya K Meher, Gorav Ailawadi
Journal: Circulation (2015)

Anti-CD20 antibody-mediated B cell depletion therapy is widely used for the treatment of B cell malignancies and rheumatoid arthritis. Given the observation that B cells are abundant in abdominal aortic aneurysms (AA), we hypothesize that B cell depletion would be protective of experimental AA formation. C57BL/6j and IL-10 knock-out (KO) mice (male, 8-10 weeks old) were injected intraperitoneal (IP) or intravenous (IV) with mouse monoclonal anti-CD20 IgG2a (or IgG2a control) antibodies at day 7 before and day 7 following induction of AA using the elastase AA perfusion model. AA size was measured at day 14 following perfusion. Depletion of B cell (B1, B2 and IL-10 producing B cells) was confirmed using flow cytometry or immunohistochemistry. IgG and IgM levels were quantified using ELISA. One-way ANOVA was used for data analysis. B1 cells were prominent in peritoneal cavity, whereas B2 cells were spleen and blood. 85-95% of B1 and B2 cells were depleted at day 7 following both IP and IV treatments. Interestingly, both the treatments strikingly suppressed AA growth (control, 96±8%; IP, 62±5%; and IV, 55±4%, p&lt;0.01, n=8-10). Plasma IgM levels were significantly lower (p&lt;0.01), whereas, IgG levels were similar in the B cell depleted mice compared to control mice. Immunohistology showed IL-10 producing B cells were preserved in spleen of B cell depleted mice. B cell depletion in IL-10 KO mice partially suppressed AA formation (control, 111±6%; anti-CD20, 92±8%; n=4-5) suggesting AA growth was partly dependent on IL-10 producing B cells. Flow cytometry revealed presence of CD19+ with B220+ or CD20+, CD138+ (plasma cells), CD1d+ and IgM+IgD+ cells in AA of control mice, which were absent in B cell depleted mice. Despite the preservation of elastin layers, B220+ cells were found the in the AA of B cell depleted mice, which were CD20- and IDO+ (Indole 2,3-dioxygenase), suggesting they are T cell tolerogenic plasmacytoid dendritic cells (pDC). Correlated with this, the CD4+FoxP3+ regulatory T cell population was higher in the aorta of B cell depleted mice. The present results suggest B cell depletion protects mice from experimental AA formation partly via preserving IL-10 producing B cells and promoting the presence of tolerogenic pDCs in the aorta.
NADH Oxidase Activation Is Involved in Arsenite-Induced Oxidative DNA Damage in Human Vascular Smooth Muscle Cells
Authors: ShugeneLynn, Jia-RanGurr, Hsien-TsungLai, Kun-YanJan
Journal: Circulation Research (2000)

Abstract—Arsenic is atherogenic, carcinogenic, and genotoxic. Because atherosclerotic plaque has been considered a benign smooth muscle cell tumor, we have studied the effects of arsenite on DNA integrity of human vascular smooth muscle cells. By using single-cell alkaline electrophoresis, apparent DNA strand breaks were detected in a 4-hour treatment with arsenite at a concentration above 1 μmol/L. DNA strand breaks of arsenite-treated cells were increased by Escherichia coli formamidopyrimidine–DNA glycosylase and decreased by diphenylene iodinium, superoxide dismutase, catalase, pyruvate, DMSO, or d-mannitol. Extract from arsenite-treated cells showed increased capacity for producing superoxide when NADH was included in the reaction mixture; however, addition of arsenite to extract from untreated cells did not increase superoxide production. The superoxide-producing ability of arsenite-treated cells was also suppressed by diphenylene iodinium, 4,5-dihydroxy-1,2-benzenedisulfonic acid disodium salt (Tir...