tbuckley/cabot-search huggingface dataset:
Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice
Authors: Meng Zhao, Chengming Fan, Patrick J Ernst, Yawen Tang, Hanxi Zhu, Saidulu Mattapally, Yasin Oduk, Anton V Borovjagin, Lufang Zhou, Jianyi Zhang, Wuqiang Zhu
Journal: Cardiovascular Research (2018)

The effectiveness of cell-based treatments for regenerative myocardial therapy is limited by low rates of cell engraftment. Y-27632 inhibits Rho-associated protein kinase (ROCK), which regulates the cytoskeletal changes associated with cell adhesion, and has been used to protect cultured cells during their passaging. Here, we investigated whether preconditioning of cardiomyocytes, derived from human-induced pluripotent stem cells (hiPSC-CM), with Y-27632 improves their survival and engraftment in a murine model of acute myocardial infarction (MI).After MI induction, mice were subjected to intramyocardial injections of phosphate-buffered saline, hiPSC-CM cultured under standard conditions (hiPSC-CM-RI), or Y-27632-preconditioned hiPSC-CM (hiPSC-CM+RI). The resulting engraftment rate calculated 4 weeks after implantation was significantly higher and the abundance of apoptotic transplanted cells was significantly lower in hiPSC-CM+RI recipients than in hiPSC-CM-RI animals. In cultured hiPSC-CM, Y-27632-preconditioning reversibly reduced contractile activity and the expression of troponin genes, while increasing their attachment to an underlying mouse cardiomyocyte (HL1) monolayer. Y-27632 preconditioning also increased the expression of N-cadherin and integrin ß1, the two cell junction proteins. hiPSC-CM+RI were also larger in cell area with greater cytoskeletal alignment and a more rod-like shape than hiPSC-CM-RI, both after transplantation (in vivo) and in culture. The effects of Y-27632 preconditioning on contractile activity and morphology of hiPSC-CMs in culture, as well as on their engraftment rate and apoptotic death in MI mouse grafts, could be recapitulated by hiPSC-CM treatment with the L-type calcium-channel blocker verapamil.Preconditioning with the ROCK inhibitor Y-27632 increased the engraftment of transplanted hiPSC-CM in a murine MI model, while reversibly impairing hiPSC-CM contractility and promoting adhesion.
BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis
Authors: JenniferHeinke, LeonieWehofsits, QianZhou, ChristophZoeller, Kim-MiriamBaar, ThomasHelbing, AnnaLaib, HellmutAugustin, ChristophBode, CamPatterson, MartinMoser
Journal: Circulation Research (2008)

Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP endothelial cell precursor–derived regulator) is a differentially expressed protein in embryonic endothelial precursor cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on endothelial cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extracellular matrix protein expressed by endothelial cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on endot...
Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Authors: Costanza Paoletti, Gaia Schiavon, Emily M. Dolce, Elizabeth P. Darga, T. Hedley Carr, Joseph Geradts, Matthias Hoch, Teresa Klinowska, Justin Lindemann, Gayle Marshall, Shethah Morgan, Parul Patel, Vicky Rowlands, Nitharsan Sathiyayogan, Kimberly Aung, Erika Hamilton, Manish Patel, Anne Armstrong, Komal Jhaveri, Seock-Ah Im, Nadia Iqbal, Fouziah Butt, Caroline Dive, Elizabeth A. Harrington, J. Carl Barrett, Richard Baird, Daniel F. Hayes
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to &amp;lt;5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with &amp;lt;5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm+ ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm+ ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
A young man with severe hypertension
Authors: Jin Ern Tan, Danielle Wu, Michael Stowasser
Journal: BMJ (2018)

A 31 year old man with a background of sleep apnoea was referred to the endocrine clinic for his newly diagnosed hypertension. He had a documented blood pressure of 170/128 mm Hg. On repeat measurements, he was found to have persistent hypertension (164/110 mm Hg and 173/110 mm Hg on separate measurements). He complained of lethargy for the past six months and reported intermittent headaches. He was an ex-smoker with a 20 pack-year history and had had follow-up appointments with his general practitioner for his sleep apnoea. He was started on prazosin 4 mg twice daily by his GP for the hypertension.

On examination, his heart rate was 106 beats per minute. There was no evidence of cushingoid features, hyperpigmentation, renal bruits, carotid bruits, or fine tremors. Apart from his elevated blood pressure and his raised body mass index of 34, he had an unremarkable physical examination.

His full blood count, urea, and electrolyte levels were normal. In view of his young age, history of sleep apnoea, and severe hypertension, further investigations were carried out (table 1)

View this table:

Table 1 
Investigations and results



Renal artery Doppler showed no evidence of renal artery stenosis.



### 1. What is the most likely diagnosis?

The most likely diagnosis is primary aldosteronism. Suspect this diagnosis in patients with:

#### Discussion

Primary …
A Case of Glioblastoma With Calcified Region Imaged With 18F-NaF PET/CT
Authors: Mariko Ishimura, Yuka Yamamoto, Katsuya Mitamura, Takashi Norikane, Yoshihiro Nishiyama
Journal: Clinical Nuclear Medicine (2018)

Abstract 18 F-NaF is a bone-seeking positron-emitting tracer with high sensitivity and specificity for detection of osseous lesions. We report a case of primary glial tumor that showed extraosseous uptake on 18 F-NaF PET/CT. CT revealed a mass in the right parietal lobe with calcification. 18 F-NaF PET/CT showed abnormal tracer uptake in the brain tumor, which was subsequently confirmed to be a glioblastoma by histologic examination.
Recent trends in life expectancy across high income countries: retrospective observational study
Authors: Jessica Y Ho, Arun S Hendi
Journal: BMJ (2018)

To assess whether declines in life expectancy occurred across high income countries during 2014-16, to identify the causes of death contributing to these declines, and to examine the extent to which these declines were driven by shared or differing factors across countries.Demographic analysis using aggregated data.Vital statistics systems of 18 member countries of the Organisation for Economic Co-operation and Development.18 countries with high quality all cause and cause specific mortality data available in 2014-16.Life expectancy at birth, 0-65 years, and 65 or more years and cause of death contributions to changes in life expectancy at birth.The majority of high income countries in the study experienced declines in life expectancy during 2014-15; of the 18 countries, 12 experienced declines in life expectancy among women and 11 experienced declines in life expectancy among men. The average decline was 0.21 years for women and 0.18 years for men. In most countries experiencing declines in life expectancy, these declines were predominantly driven by trends in older age (≥65 years) mortality and in deaths related to respiratory disease, cardiovascular disease, nervous system disease, and mental disorders. In the United States, declines in life expectancy were more concentrated at younger ages (0-65 years), and drug overdose and other external causes of death played important roles in driving these declines.Most of the countries that experienced declines in life expectancy during 2014-15 experienced robust gains in life expectancy during 2015-16 that more than compensated for the declines. However, the United Kingdom and the United States appear to be experiencing stagnating or continued declines in life expectancy, raising questions about future trends in these countries.
Direct Intracoronary Evidence of Collateral Steal in Humans
Authors: ChristianSeiler, MartinFleisch, BernhardMeier
Journal: Circulation (1997)

Background Coronary steal is defined as a fall in blood flow toward a certain vascular region in favor of another area during arteriolar vasodilatation, ie, a coronary flow velocity reserve (CFVR) <1. The purpose of this study was to determine the frequency of steal in patients with a wide range of collateral supply to a vascular area of interest and to assess whether steal is associated with the amount of collateral flow. Methods and Results One hundred patients 57±9 years old with a coronary artery stenosis to be dilated were examined with intracoronary (IC) Doppler guidewires. IC adenosine–induced CFVR<1 obtained distal to the stenosis was defined as steal. An index for collateral flow was determined by positioning the Doppler guidewire in the collateral-dependent vessel distal to the stenosis and measuring the flow velocity time integral during (Vioccl, cm) and after (Vio-occl) balloon occlusion. Vioccl/Vio-occl was determined without and with intravenous adenosine (140 μg · kg−1 · min−1). Coronary st...
Administration of a Decoy Against the Activator Protein-1 Binding Site Suppresses Neointimal Thickening in Rabbit Balloon-Injured Arteries
Authors: MasazumiKume, KimihiroKomori, TakuyaMatsumoto, ToshihiroOnohara, KensukeTakeuchi, YoshikazuYonemitsu, KeizoSugimachi
Journal: Circulation (2002)

Background— Transcription factor activator protein-1 (AP-1) is activated and upregulated in injured arterial smooth muscle cells in vivo, yet the exact role of the AP-1–related pathway in vascular disease in vivo has remained unclear. We examined the role of the transfer of synthetic double-stranded cis-element decoy oligodeoxynucleotides (ODNs) in balloon-injured rabbit carotid arteries and the effects of these ODNs on neointimal thickening. Methods and Results— Transfection of fluorescein isothiocyanate–labeled ODNs using the hemagglutinating virus of Japan liposome method resulted in widespread distribution of fluorescent nuclear signals over the entire medial layer in injured arteries. Gel mobility shift assay revealed that AP-1 DNA binding was activated and that the AP-1 decoy reduced AP-1 DNA binding activity as a result of specific binding affinity to AP-1 in vivo. In morphometric analyses, AP-1 decoy led to a significant reduction in the neointimal area and a significant reduction in cell number a...
Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-ζ Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy
Authors: HirokiTakahashi, YasuchikaTakeishi, TimSeidler, TakanoriArimoto, HideyukiAkiyama, YasukazuHozumi, YoKoyama, TetsuroShishido, YuichiTsunoda, TakeshiNiizeki, NaokiNozaki, Jun-ichiAbe, GerdHasenfuss, KaoruGoto, IsaoKubota
Journal: Circulation (2005)

Background— Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1–induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results— Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1–induced translocation of PKC-e was blocked by Ad-DGKζ (P<0.01). Ad-DGKζ also inhibited ET-1–induced activation of...
Abstract 2245: Deconvolution of diverse immune cell populations within tumors using ACE Transcriptome
Authors: Eric Levy, Sean M. Boyle, Pamela Milani, Shujun Luo, John West, Richard Chen
Journal: Cancer Research (2018)

Abstract Comprehensive tumor immuno-genomic characterization is becoming an important tool for identifying new biomarkers correlated with patient response to immunotherapy. Both the abundance and composition of tumor-infiltrating lymphocytes have been associated with tumor progression and patient outcome. Prior studies have shown that an enrichment of cytotoxic immune cells, and depletion of immunosuppressive cells, can indicate better clinical outcome. While common lab approaches are used to profile tumor samples for the presence and enumeration of immune cell types, these approaches can be limited by the number of markers and throughput. Thus, there is interest in using an accurate computational method leveraging NGS data to more comprehensively profile the distribution of immune cells in the tumor microenvironment. Through the use of marker genes that are expressed in a cell type specific manner, it is possible to computationally predict the fractions of multiple cell types in a mixed sample. This approach relies on an input of reference gene expression signatures, which are used to estimate the proportions of the cell types represented in the reference. The generation and validation of these reference signatures are critical for ensuring the accuracy of the results on a given platform. We have used the ACE Cancer Transcriptome, from the ACE ImmunoID platform, to produce high-quality gene expression profiles of purified immune cells representing many lineages, including B cells, monocytes, NK cells, and T cells. These profiles were used to create reference signatures of immune cell type specific genes, enabling quantification of their cellular abundances. In addition, we test the accuracy of the deconvolution approach on mixtures of immune cells. Finally, we validate the approach on tumor samples with immune cells quantified by widely accepted orthogonal methods. Through these results, we show that deconvolution of TILs through our ACE Cancer Transcriptome can be a robust platform for elucidating the composition of immune cells in a tumor sample. Citation Format: Eric Levy, Sean M. Boyle, Pamela Milani, Shujun Luo, John West, Richard Chen. Deconvolution of diverse immune cell populations within tumors using ACE Transcriptome [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 2245.
Abstract 3458: Neurotensin increases breast cancer proliferation through activation of AMPK
Authors: Jeremy Johnson, Jing Li, B. Mark Evers
Journal: Cancer Research (2018)

Abstract Introduction. Neurotensin (NT), a thirteen amino acid peptide predominantly localized to enteroendocrine cells of the small intestine, is released after fat ingestion. While its major role involves regulating lipid metabolism and storage, NT, acting through its high-affinity receptor (NTR1), stimulates the growth and progression of a variety of NTR1-positive cancers. Proneurotensin—a stable precursor produced in equimolar amounts as NT—has been associated with breast cancer development in women, and prior work has implicated the NT/NTR1 axis in breast cancer progression; however, very little is known about the underlying NT signaling pathways that stimulate breast cancer growth. The purpose of this study is to elucidate mechanisms by which NT leads to increased proliferation and aggression of breast cancer—with particular emphasis placed on the role of AMP-activated protein kinase (AMPK). Methods. MCF-7 (estrogen-dependent) and MDA-MB-231 (triple negative) are breast cancer cell lines that express NTR1. (i) Proliferation assays were performed by treating both cell lines with NT (0 or 100 nM) in serum-free media for 24, 48, and 72 h and then counting the viable cells. (ii) Next, to assess signaling pathways mediating the effects of NT, both cell lines were treated with NT (0 or 100 nM) in serum-free media for 15 min, 30 min, 1 h, 6 h, 12 h, and 24 h; immunoblotting was performed for phosphorylated and total forms of AMPK and its downstream effector acetyl CoA carboxylase (ACC). Results. (i) Increased proliferation of MCF-7 cells treated with NT (100 nM) was observed after serum-starvation for 48 h. While MDA-MB-231 cells treated with NT demonstrated improved survival after serum-starvation for 48 h, the effects were not significantly different. (ii) NT induced activation of AMPK and ACC in MCF-7 cells after treatment for 6 and 12 h, but these effects were not observed in MDA-MB-231 cells. Conclusions. Our findings suggest a possible linkage between NT and increased proliferation of estrogen-dependent breast cancer cells through activation of AMPK and its downstream effector proteins. These effects were minimal in NTR1-expressing triple negative breast cancer cells, suggesting that the molecular classification of the tumor plays an important role in NT signaling and downstream effects. Further delineation of the differential effects of NT in specific breast cancer phenotypes has the potential to identify novel therapeutic targets in the treatment of this disease. Citation Format: Jeremy Johnson, Jing Li, B. Mark Evers. Neurotensin increases breast cancer proliferation through activation of AMPK [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 3458.
Abstract 20213: Smooth Muscle Cells-Specific Deletion of NADPH Oxidase 1 Subunit NOXA1 Attenuates KLF4-Dependent VSMC Phenotypic Modulation in Atherosclerosis
Authors: Aleksandr E Vendrov, Julia R Gips, Jason Shiau, Nageswara R Madamanchi, Marschall S Runge
Journal: Circulation (2017)

Excessive reactive oxygen species (ROS) generation is implicated in development of vascular pathology and atherosclerosis, in part, by modulating the phenotype of vascular smooth muscle cells (VSMC...
Abnormal Postexercise Cardiovascular Recovery and Its Determinants in Patients After Right Ventricular Outflow Tract Reconstruction
Authors: HideoOhuchi, HiroyukiOhashi, JiksooPark, JohjiHayashi, AyaMiyazaki, ShigeyukiEchigo
Journal: Circulation (2002)

Background— Abnormal responses of heart rate (HR) and oxygen uptake (Vo2) during exercise characterize patients after right ventricular outflow tract reconstruction (RVOTR) for congenital heart defects. However, little is known about the postexercise dynamics. Methods and Results— We evaluated postexercise cardiovascular dynamics in 52 patients after closure of an atrioventricular septal defect (group A), 79 patients after RVOTR (group B), and 44 control subjects. HR variability, arterial baroreflex sensitivity (BRS), plasma norepinephrine, and hemodynamics were measured. Although there was no difference between group A and control subjects, declines in HR and Vo2 after light and peak exercise and in systolic blood pressure (SBP) after peak exercise were delayed in group B. Age, low-frequency component of HR variability, and plasma norepinephrine were independent determinants of early HR decline. Peak SBP and Vo2 had a great impact on the corresponding recoveries. When the peak values were excluded, bo...
Abstract 604: Metabolomics in predicting breast cancer treatment responses
Authors: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Jennifer Hu
Journal: Cancer Research (2018)

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in American women. Postoperative adjuvant radiotherapy (RT) significantly improve local-regional recurrence and survival. Therefore, there has been increasing usage of adjuvant RT in early-stage breast cancer patients. Although well tolerated by some patients, 48% patients in our study experience RT-induced early adverse skin reactions (EASRs) that negatively impact quality of life. Therefore, we evaluated urine metabolomics in predicting RT-induced EASRs and precision intervention. Based on the pilot data of 478 metabolites in 60 patients, we used the MetaboAnalyst 3.0 (www.metaboanalyst.ca) to conduct metabolomic data analysis, visualization and interpretation. Using KEGG pathway analysis, we have identified 7 pathways that are significantly associated with RT-induced EASRs (i.e., False Discovery Rate (FDR) p less than 0.05). The alanine, aspartate and glutamate metabolism pathway has the most significant FDR p-value and the highest impact value of 0.60 in predicting RT-induced EASRs. In summary, to the best of our knowledge, this is the first study in breast cancer patients associating glutamate metabolism pathway to RT-induced EASRs. Our research will have significant clinical impact because: (i) many tumor cells depend on glutamine-glutamate as energy source for growth and survival, (ii) breast cancer cells secrete high levels of glutamate often metastasize to bone with severe pain issue, (iii) glutaminase inhibitors enhance chemotherapy in triple negative breast cancer, (iv) two thirds of cancer patients receive RT, and (v) glutamate metabolism is associated with RT-induced EASRs. With increasing recent interest in targeting tumor metabolism, we anticipate that glutaminase inhibitors will also have application in preventing RT-induced EASRs in addition to their anticancer activities in triggering metabolic crisis in tumor cells and enhancing chemotherapy. Citation Format: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Jennifer Hu. Metabolomics in predicting breast cancer treatment responses [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 604.