tbuckley/cabot-search huggingface dataset:
Abstract 4131: Plasticity of transcriptional and epigenetic cellular states in neuroblastoma is driven by core lineage transcription factors
Authors: Johan V. Nes, Tim V. Groningen, Jan Koster, Linda Valentijn, Danny Zwijnenburg, Ellen M. Westerhout, Mohamed Hamdi, Rogier Versteeg
Journal: Cancer Research (2018)

Abstract Background: Core Regulatory Circuitries (CRCs) of lineage transcription factors associate with super-enhancers and are drivers of cellular identity. We recently showed that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal (MES) cells and committed adrenergic (ADRN) tumor cells resemble cells from developmental stages of the adrenergic lineage. Results: We identified the unique super-enhancer (SE) landscapes of MES and ADRN-type cells. SEs associated with lineage transcription factors that identified the Core Regulatory Circuitries (CRC) for each cell type. MES cells were resistant to chemotherapy. Accordingly, MES cells were strongly enriched in post-treatment samples, suggesting that MES cells could play a role in resistance and relapse development. MES and ADRN cells of isogenic origin spontaneously interconverted, showing the transcriptional plasticity of CRCs. We studied the mechanism of MES and ADRN transdifferentiation. The MES TFs PRRX1 and NOTCH were expressed as single genes in ADRN cells. Each of the genes induced a step-wise reprogramming of the ADRN transcriptome towards a MES state. The transcriptional switch was accompanied by genome-wide remodeling of the epigenome to a MES enhancer state. MES TFs repressed super-enhancers of ADRN core TFs, leading to transcriptional downregulation of the ADRN CRC. Deregulated enhancers associated with Polycomb repression. The transdifferentiation was initially reversible, but became gradually stabilized. The transgenes activated an endogenous feed-forward loop including ligands, receptors and co-factors from the NOTCH signaling route. Ultimately, this endogenous NOTCH-cascade maintained a transgene-independent MES state. Super-enhancers in stable MES cell lines associated with NOTCH receptors and co-factors, consistent with NOTCH driving MES lineage identity. Both NOTCH-induced MES cells and ADRN cells were tumorigenic in vivo. Conclusions: Our results demonstrate that single TFs from the MES CRC impose transdifferentiation via remodeling of the epigenetic and transcriptional landscape of ADRN cells, mimicking spontaneous interconversion. Plasticity of CRCs and lineage identity may have profound implications for treatment strategies in neuroblastoma. Citation Format: Johan V. Nes, Tim V. Groningen, Jan Koster, Linda Valentijn, Danny Zwijnenburg, Ellen M. Westerhout, Mohamed Hamdi, Rogier Versteeg. Plasticity of transcriptional and epigenetic cellular states in neuroblastoma is driven by core lineage transcription factors [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 4131.
Abstract 1456: Integrin beta4-induced mitophagy promotes the lactate production of cancer-associated fibroblasts in breast cancer
Authors: Jin Sol Sung, Suki Kang, Joo Hyun Lee, Seong Gyeong Mun, Baek Gil Kim, Nam Hoon Cho
Journal: Cancer Research (2018)

Abstract Integrin beta4 neoexpression is induced in cancer-associated fibroblasts (CAFs) by some triple negative breast cancer cells (MDA-MB-231 and BT-20) through a contact-dependent manner. Integrin beta4 expression is well known to contribute to the migration and survival of cancer cells. However, there is very little known about the role of integrin beta4 expression in CAFs, especially in the aspect of tumor progression. In our study, we found that the exogenous expression of integrin beta4 increased the lactate production of CAFs. The observation made us to hypothesize that integrin beta4 neoexpression is associated with the mitophagy, a cause for aerobic glycolysis, in CAFs. To confirm the assumption, the expression alteration of mitophagy-related genes was first screened in the CAF transfected with integrin beta4 overexpression plasmid. BCL2 interacting protein 3 like (BNIP3L) and microtubule associated protein 1 light chain 3 alpha-II (LC3-II) were significantly upregulated in the integrin beta4 overexpressing CAFs, which was reversed both in the knockdown of integrin beta4 expression and the treatment with an integrin beta4 inhibitor. Autophagosome maturation and lysosomal fusion were also increased in the integrin beta4 overexpressing CAFs compared to the control. Phosphorylation level of c-Jun was upregulated by integrin beta4 overexpression in CAFs and was able to bind to the putative promoter regions of BNIP3L and LC3-II. Taken together, these results demonstrate that integrin beta4 neoexpression induces upregulation of BNIP3L and LC3-II ultimately leading to mitophagy in CAFs, contributing to cancer metabolism via mitophagy-induced lactate production, namely reverse Warburg effect. Citation Format: Jin Sol Sung, Suki Kang, Joo Hyun Lee, Seong Gyeong Mun, Baek Gil Kim, Nam Hoon Cho. Integrin beta4-induced mitophagy promotes the lactate production of cancer-associated fibroblasts in 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 1456.
Nox1 Is Involved in Angiotensin II–Mediated Hypertension
Authors: KuniharuMatsuno, HiroyukiYamada, KazumiIwata, DenanJin, MasatoKatsuyama, MasatoMatsuki, ShinjiTakai, KiyofumiYamanishi, MizuoMiyazaki, HiroakiMatsubara, ChihiroYabe-Nishimura
Journal: Circulation (2005)

Background— Increased production of reactive oxygen species (ROSs) by angiotensin II (Ang II) is involved in the initiation and progression of cardiovascular diseases. NADPH oxidase is a major source of superoxide generated in vascular tissues. Although Nox1 has been identified in vascular smooth muscle cells as a new homolog of gp91phox (Nox2), a catalytic subunit of NADPH oxidase, the pathophysiological function of Nox1-derived ROSs has not been fully elucidated. To clarify the role of Nox1 in Ang II–mediated hypertension, we generated Nox1-deficient (−/Y) mice. Methods and Results— No difference in the baseline blood pressure was observed between Nox1+/Y and Nox1−/Y. Infusion of Ang II induced a significant increase in mean blood pressure, accompanied by augmented expression of Nox1 mRNA and superoxide production in the aorta of Nox1+/Y, whereas the elevation in blood pressure and production of superoxide were significantly blunted in Nox1−/Y. Conversely, the infusion of pressor as well as subpressor d...
Inhibitory Effects of Antioxidants on Neonatal Rat Cardiac Myocyte Hypertrophy Induced by Tumor Necrosis Factor-α and Angiotensin II
Authors: KazufumiNakamura, KazuoFushimi, HirosukeKouchi, KoichiroMihara, MasahiroMiyazaki, TohruOhe, MasayoshiNamba
Journal: Circulation (1998)

Background—Tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF-α and Ang II might cause myocyte hypertrophy via the generation of ROIs. Methods and Results—To test the hypothesis, we tested whether TNF-α and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2′,7′-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-α and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-α (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [3H]leucine uptake, and BHA (10 μmol/L) significantly inhibited both effects. Other antioxidants, such...
Abstract 15196: Statin Use and Titration Patterns in the First Year Following a Cardiovascular Event in Commercially-Insured Populations
Authors: Anne C Beaubrun, Keri L Monda, Deborah Kim, Katherine Mues, Brian D Bradbury, Robert S Rosenson, Paul Muntner, Charles A Herzog
Journal: Circulation (2016)

Introduction: Guidelines recommend statin treatment for patients with established cardiovascular disease (CVD). We determined the real-word use and titration of statins after an atherosclerotic CVD event from two commercial claims databases. Methods: The first occurrence of MI, unstable angina, ischemic stroke, or TIA in 2012 was identified for each patient using ICD-9 CM diagnosis codes from the MarketScan and Optum databases. During the ensuing 1 year, we evaluated statin use and titration in the first and second 6-month follow-up periods. Prevalent statin users were defined as those on a statin at the time of the CVD event. Results: The 183,752 MarketScan patients were slightly younger (mean age 67.3 years) and 54.6% were male vs. the 63,199 Optum patients (mean age 72.4 years) where 51.4% were male. Among the MarketScan patients, 36.4% used a statin in both the first and second 6-month periods following hospital discharge, 13.2% used a statin only in the first period, 1.6% used a statin only in the se...
Abstract 349: Tracking Human Pluripotent Stem Cell-Derived Cardiomyocytes in Post-Myocardial Infarction Heart with Photoacoustic Imaging
Authors: Xulei Qin, Haodong Chen, Kai Li, Huaxiao Yang, Haodi Wu, Xin Zhao, Heike Daldrup-Link, Joseph C Wu
Journal: Circulation Research (2017)

Background: Molecular imaging has helped unravel potential benefits and barriers of stem cell therapy, yet in vivo tracking of cell injection and engraftment with high 3D spatial resolution remains a challenge. This study aims to testify the feasibility of photoacoustic imaging (PAI) as an efficient method to monitor transplanted therapeutic cells in post-myocardial infarction (MI) hearts. Methods: Cell penetrating peptide-conjugated photoacoustic nanoparticles (PANPs) were synthesized and applied directly to cultured human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) at the concentration of 4nM for 6h. Post exogenous labeling, cells were injected into mouse MI hearts (n=5) guided by PAI and then monitored by PAI in vivo . These engraftments were further confirmed by immunostaining. Results: Flow cytometry and confocal imaging indicated that PANP labeling significantly increased the labeling efficiency of hPSC-CMs from 38% to 90% compared to endocytosis labeling. Moreover, calcium imaging and contractile analysis indicated that PANP labeling had no cardiotoxicity to both electrical and mechanical functions of hPSC-CMs. In addition, quantitative polymerase chain reaction (qPCR) showed no adverse effects of PANP labeling on the genes related to cardiomyocyte structures and functions. Finally, animal experiments demonstrated the feasibility of PAI for both injection guidance and followed tracking of hPSC-CMs in vivo . The real-time acquired PAI images showed a high spatial resolution (~100 μm) for mice hearts and a high intensity for the labeled cells. Conclusion: We utilized PAI for the first time to monitor cardiac regenerative therapy in a preclinical study. PAI demonstrated its superior potential to track cell therapy in vivo due to its high spatial resolution, low cost, and non-radioactivity. It will be a useful tool for the investigation of cardiac regenerative therapy.
Overinterpretation and misreporting of prognostic factor and biomarker studies in medical oncology.
Authors: Emmanuelle Kempf, Jennifer de Beyer, Raphael Porcher, Long Nguyen, Karel Moons, Douglas Altman, Johannes Reitsma, Sally Hopewell, Willi Sauerbrei, Gary Collins
Journal: Journal of Clinical Oncology (2017)

e14023 Background: To generate empirical evidence, classify and estimate the frequency of distorted presentation and overinterpretation of results in prognostic factor (PF) studies in oncology. Methods: We selected 17 oncology journals with an impact factor of 7 or more. PubMed was searched to identify primary clinical studies evaluating one or more PFs published in 2015. Each article was independently evaluated by 2 reviewers using a data extraction form that was extensively pilot-tested. We classified aspects of overinterpretation as misleading reporting, interpretation and extrapolation. Results: Our search identified 10 844 articles, 98 met eligibility criteria. The PF was assessed prospectively in 8 of 56 observational studies, and in 16 of 42 clinical trials. The median number of PFs per study was 2 (Q1-Q3, 1-5). Overall survival was used as the outcome in 77 studies. The median number of statistical analyses reported with regards to the PF effect assessment was 42.5 per study (Q1-Q3, 15.5-86.5). Thirty-three reports reported using 2 or more different multivariable models to assess the PF effect and 21 did not adjust. Misleading reporting included selective and incomplete reporting of the PF effect (n = 26 and n = 8, respectively). The conclusions focused solely on significant results in 80 reports, and in those where there was at least one NS result, 80% of studies focused their conclusions solely on the significant results. Misleading interpretation included not reporting the PF effect within a multivariable model (n = 23 and n = 54 in full-texts and abstracts, respectively). One out of 5 conclusions used linguistic spin with strong statements in both full-text and abstract. Linguistic spin of NS results was found in 28 Results sections in the full-text and in 18 abstract conclusions. The conclusions were inconsistent with the study findings in one out of five articles (both in the full-text and abstract). Discrepancies between the conclusions presented in the full-text and in the abstract were found in 18 reports. Conclusions: Our study provides insight into the level of reporting and overinterpretation of findings that were frequently inconsistent with the results in oncology journals with high impact factors.
In vitro/vivo assessment of praziquantel nanocrystals: Formulation, characterization, and pharmacokinetics in beagle dogs
Authors: Ruyi Yang, Tao Zhang, Jiang Yu, Yan Liu, Yingli Wang, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2018)

To investigate the impact of particle size on in vitro/vivo performance of praziquantel (PZQ), nanocrystals (NCs) and microcrystals (MCs) of PZQ were prepared using the methods of wet milling and jet milling, respectively. PZQ NCs and MCs were characterized with dynamic light scattering, laser particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray powder diffraction and fourier transform infrared spectroscopy. The average diameters of PZQ NCs and MCs were 364.4 nm and 3.7 µm, respectively. No change in crystalline form was observed. Dissolution tests were performed in two different media, where the cumulative dissolution and dissolution rate of NCs were significantly improved in comparison with those of MCs and KANGQING® in non-sink condition. Similarly, oral bioavailability of PZQ NCs in beagle dogs was 1.68 (P < 0.05) and 1.83 fold (P < 0.01) higher than that of MCs and KANGQING®. Considering the advantages of in vitro/vivo performance and facile preparation, PZQ NCs may have a great application in the treatment of schistosomiasis.
Abstract 342: Strigolactone analogues show potential as new combination therapy agents against pancreatic cancer
Authors: Matthew D. Park, Jefferson M. Haake, Erika Parasido, Christopher Albanese, Ronit I. Yarden
Journal: Cancer Research (2018)

Abstract There is an increasing appreciation for combination therapy of antineoplastic drugs that target key pathways often through a synergistic effect, reducing the chance for tumor growth, self-renewal of cancer stem cell (CSC), spread of metastasis and drug resistance. The combination of DNA repair impairment and DNA damage was shown to be a successful approach. Previously, we had shown that strigolactone (SLs; synthetic analogues, SLAs), a novel class of phytohormones, causes DNA double strand breaks (DSBs) and inhibits breast and osteosarcoma cancer cells and CSC viability. Here, we tested whether SLAs inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) cells and stem cells and whether SLAs sensitize the effects of Gemcitabine (Gemzar), the most commonly prescribed drug for PDAC patients. We show that SLAs induce DSBs in different PDAC cells and the combination of SLAs with Gemcitabine significantly increases apoptosis when compared to PDAC cells treated with Gemcitabine alone. This additive effect is independent of BRCA2 expression, which suggests that SLAs are effective at impairing multiple repair mechanisms and is suitable in combination with multiple DNA damaging agents. Interestingly, we show that SLAs sensitize patient-derived Gemcitabine non-responsive, PDAC Conditionally-Reprogrammed Cells (CRCs) to Gemcitabine, reducing their overall viability by more than 30%. Accordingly, the SLA- Gemcitabine combination has a significant impact on tumorsphere (CSCs) growth outcome. These findings demonstrate the potential for a novel drug combination of SLAs and Gemcitabine and underscore the potential of SLAs for multiple highly valuable translational applications regarding alternative therapies to combat cancer. Citation Format: Matthew D. Park, Jefferson M. Haake, Erika Parasido, Christopher Albanese, Ronit I. Yarden. Strigolactone analogues show potential as new combination therapy agents against pancreatic 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 342.
Abstract 13102: Microrna-150 Modulates Ischemia-induced Neovascularization in Atherosclerotic Conditions
Authors: Michel Desjarlais, Dussault Sylvie, Wahiba Dhahri, Raphael Mathieu, Alain Rivard
Journal: Circulation (2016)

Background: Hypercholesterolemia is an atherosclerotic condition that is associated with impaired neovascularization in response to ischemia. This study sought to define the role of microRNAs (miRNAs) in that pathophysiology. Methods and results: Next generation sequencing and qRT-PCR analyses identified miR-150 as a pro-angiogenic miRNA which expression is significantly reduced in the ischemic muscles of hypercholesterolemic ApoE-deficient (ApoE -/- ) mice, and in HUVECs exposed to oxLDL. Forced expression of miR-150 using a miR mimic could rescue oxLDL-mediated impairment of endothelial cell migration and tubule formation in vitro. In a mouse model of hindlimb ischemia, intramuscular injection of miR-150 mimic restored blood flow recuperation, vascular densities in ischemic muscles, and functional mobility in ApoE -/- mice. Treatment of ApoE -/- mice with miR-150 also increased the number and the activities of pro-angiogenic cells (PACs). miR-150 targets SRC kinase signaling inhibitor 1 (SRCIN1), an important regulator of Src activity. Here we found that hypercholesterolemia and oxLDL exposure are associated with increased SRCIN1 expression and decreased Src activity. However, treatment with miR-150 mimic reduces SRCIN1 expression and restores Src and downstream eNOS and Akt activities both in vitro and in vivo. We also demonstrate that the angiogenic effects of miR-150 are abolished when endothelial cells are treated with an inhibitor of Src. Conclusions: Hypercholesterolemia is associated with reduced expression of miR-150, impaired Src signaling and inefficient neovascularisation in response to ischemia. Forced expression of miR-150 using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in atherosclerotic conditions.
Tricuspid Atresia With Atrial Septal Defect, Ventricular Septal Defect, and Right Ventricular Hypoplasia Demonstrated by Multidetector Computed Tomography
Authors: TeruhitoMochizuki, TakashiOhtani, HiroshiHigashino, YoshifumiSugawara, TakaharuTsuda, MichihitoSekiya, MasaoMiyagawa, KenjiOhmoto, JunpeiIkezoe
Journal: Circulation (2000)
Abstract 16125: Persistent Atrial Fibrillation is Associated with Selective Reduction in Rotenone-Sensitive NADH Oxidoreductase Activity in Human Atria
Authors: Larisa Emelyanova, Mahek Mirza, Arshad Jahangir
Journal: Circulation (2012)

Introduction: Atrial fibrillation (AF) causes electrical and structural alterations that promote the substrate for AF recurrence and progression. Although remodeling of the atria has been well char...
Abstract 5494: Targeting deregulated expression and function of Mitofusin 1 in glioblastoma
Authors: Maheedhara Reddy Guda, Swapna Asuthkar, Collin M. Labak, Chase P. Smith, Andrew J. Tsung, Kiran Velpula
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most common form of adult primary malignant brain tumor with a poor prognosis. Despite advances in standard treatments, such as surgery, radiation, and adjuvant chemotherapy, outcome remains poor. To further develop effective therapeutic approaches, it is essential to garner a better understanding of GBM progression. Substantial research has shown that GBM's progression is associated with metabolic remodeling, that includes the use of aerobic glycolysis as the main source of energy. Here, we report the novel role of Mitofusin 1 (MFN1), a key regulator of mitochondrial outer membrane fusion in glycolysis. We first established that MFN1 is highly expressed in GBM when compared to its isoform MFN2 using TCGA (The Cancer Genome Atlas) and OncomineTM glioma datasets. Silencing MFN1 using MFN1-shRNA in GBM10 cells showed decreased expression levels of PDK1 and HIF1-alpha as observed in western blotting and RT-PCR analysis. Interestingly, c-myc expression was significantly reduced in the shMFN1 treated GBM 10 cell. In addition, RNASeq analysis conducted on shPDK1 treated GBM-10 cells revealed reduced MFN1 levels. Further silencing of MFN1 showed increased OCR and decreased ECAR using seahorse XFp bio analyzer. Collectively, our preliminary data points to MFN1 as a candidate metabolic oncogene in GBM, and targeting MFN1 will be a novel GBM treatment. Citation Format: Maheedhara Reddy Guda, Swapna Asuthkar, Collin M. Labak, Chase P. Smith, Andrew J. Tsung, Kiran Velpula. Targeting deregulated expression and function of Mitofusin 1 in glioblastoma [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 5494.
Plasma Lipoprotein(a) Is Not a Predictor for Restenosis After Elective High-Pressure Coronary Stenting
Authors: FlavioRibichini, GiuseppeSteffenino, AntonioDellavalle, AntonelloVado, ValeriaFerrero, TerenzioCamilla, SilviaGiubergia, EugenioUslenghi
Journal: Circulation (1998)

Background—Lipoprotein(a) is a risk factor for coronary artery disease. Although it has been implicated in restenosis after balloon angioplasty, its role in restenosis within coronary stents is unknown. The aim of the study was to assess the role of plasma lipoprotein(a) as a predictor for restenosis after elective coronary stenting. Methods and Results—Elective, high-pressure stenting of de novo lesions in native coronary arteries with Palmaz-Schatz stents was performed in 325 consecutive patients. Clinical, angiographic, and biochemical data were analyzed prospectively. Angiographic follow-up was performed at 6 months. Lipoprotein(a) levels were compared in patients with and without restenosis. Angiographic follow-up was obtained in 312 patients (96%); recurrence was observed in 67 patients (21.5%). No clinical or biochemical variable was associated with restenosis. Lipoprotein(a) level was 37.81±49.01 mg/dL (median, 22 mg/dL; range, 3 to 262 mg/dL) in restenotic patients and 36.95±40.65 mg/dL (median, ...