tbuckley/cabot-search huggingface dataset:
Development of recombinant human soluble angiotensin converting enzyme 2 (rhACE2) for cancer therapy
Authors: Hans Loibner, Evelyne Janzek, Bernhard Peball, Manfred Schuster
Journal: Cancer Research (2008)

4075  The membrane-anchored glycoprotein ACE2 is a key enzyme of the Renin Angiotensin System (RAS) and is expressed in most organs. ACE2 degrades the octapeptide Angiotensin II (Ang II) to yield Angiotensin (1-7) (Ang(1-7)). Ang II, a key effector peptide of the RAS, acting via AT1-receptor and AT2-receptor is a major regulator of blood pressure and cardiovascular homeostasis, is pro-inflammatory and a potent mitogen. In contrast, Ang(1-7) via its receptor Mas has vasodilator, anti-inflammatory and anti-proliferative properties, thereby opposing the functions of Ang II. Thus, ACE2 acts in a counter-regulatory manner to the Ang II-forming ACE by shifting the balance between Ang II and Ang(1-7), and serving as a functional clearance mechanism for Ang II. In cancer, Ang II may play a role in supporting tumor cell proliferation, angiogenesis, inflammation and thus formation of metastases. For example, in ovarian cancer AT1-receptor expression is associated with tumour angiogenesis and correlated with poor patient outcome. Importantly, Ang(1-7) has been shown to inhibit proliferation of tumor cell lines in vitro and also is effective to retard tumor growth in athymic mouse models.  In consideration of these findings, a novel approach for the treatment of various cancers may be based on the utilization of the counter-balancing functions of ACE2 to degrade elevated tumor-promoting Ang II levels to generate Ang(1-7) with tumor growth-inhibiting, anti-angiogenic and anti-inflammatory properties. In this context, we are developing a recombinant soluble form of ACE2 (rhACE2) for systemic therapy. The ectodomain of ACE2 was expressed in Chinese Hamster Ovary (CHO) cells in a fully glycosylated manner leading to a stable and highly active enzyme. An industrial production process under cGMP has been established and substantial amounts of rhACE2 produced. The enzyme efficiently degrades Ang II to Ang(1-7) in vitro and in vivo in mice, piglets and Rhesus monkeys. The terminal half-life of enzymatically active protein in Rhesus monkeys is 10,5 hours. No side effects of repeated i.v. treatment has been detected and importantly the enzyme does not lower blood pressure in normotensive animals.  The effects of rhACE2 on tumor cell growth were assessed in vitro in the presence of its substrate Ang II: MCF-7 human breast cancer cells and Calu-3 human lung cancer cells were cultivated under standard conditions in triplicates at 37°C and 5% CO2 with 100 nM Ang II plus 20ug/ml rhACE2 (controls: medium, Ang II without rhACE2, rhACE2 without Ang II). Metabolically active cells were determined using the WST-1 reagent and measurement of optical density at OD 450/620nm: rhACE2 in the presence of its substrate Ang II after 72 hours significantly inhibited the growth both of Calu-3 and MCF-7 cells, presumably via in-situ formation of Ang(1-7). Further studies have now been initiated to explore the antitumor properties of rhACE2 in vitro and in vivo.
第3千年期のための産業衛生における生殖研究の検討議題 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Lawson C C, Daston G P, Grajewski B, Marcus M, Mcdiarmid M, Murono E, Perreault S D, Schrader S M, Shelby M
Journal: Environmental Health Perspectives (2003)
Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury
Authors: Mike K. Terkelsen, Sofie M. Bendixen, Daniel Hansen, Emma A.H. Scott, Andreas F. Moeller, Ronni Nielsen, Susanne Mandrup, Anders Schlosser, Thomas L. Andersen, Grith L. Sorensen, Aleksander Krag, Kedar N. Natarajan, Sönke Detlefsen, Henrik Dimke, Kim Ravnskjaer
Journal: Hepatology (2020)

Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition, impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single-cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis.We applied single-cell transcriptomics to map the heterogeneity of sinusoid-associated cells in healthy and injured livers and reconstructed the single-lineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted gene correlation network analysis of the HSC trajectory led to the identification of core genes whose expression proved highly predictive of advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH). Among the core members of the injury-repressed gene module, we identified plasmalemma vesicle-associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease.Our study offers a single-cell resolved account of drug-induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advanced fibrosis in human NASH.
Quantitative Analysis for Carotid Intra-plaque Neovascularization Using Contrast-enhanced Ultrasound is Useful for Risk Stratification in Patients with Coronary Artery Disease | Article Information | J-GLOBAL
Authors: Nakamura Jun, Nakamura Takamitsu, Deyama Juntaro, Fujioka Daisuke, Kawabata Kenichi, Obata Junei, Watanabe Kazuhiro, Watanabe Yousuke, Kugiyama Kiyotaka
Journal: Circulation (2015)
Abstract I10: Immune cell signaling in human and mouse pancreas cancer
Authors: Aida Habtezion
Journal: Cancer Research (2019)

Abstract Acute pancreatitis (AP) is the most common gastrointestinal disorder leading to hospital admission in the United States. Patients who present with recurrent acute pancreatitis are at a very high risk of developing chronic pancreatitis (CP). Patients with CP experience intractable, difficult to treat abdominal pain and the disease is associated with pancreatic acinar cell loss and fibrosis, and can result in exocrine and endocrine insufficiency. CP is also a risk factor for developing pancreatic ductal adenocarcinoma (PDAC). In AP, initial injury signals likely start at the acinar cell level, where injured acinii produce proinflammatory cytokines and chemokines leading to the recruitment of inflammatory leukocytes into the pancreas. One of the initially recruited leukocytes includes neutrophils, which play pathogenic role locally within the pancreas and in distant organs such as the lung. Soon after, inflammatory monocytes follow into the pancreas and differentiate into macrophages with pro-inflammatory properties and exacerbate the pancreatic injury. Earlier and recent studies show that T cells and macrophages are the predominant immune cell infiltrates in CP. Macrophages in CP are found in close proximity to key pro-fibrogenic pancreatic stellate cells. Experimental studies suggest an interaction between the stellate cells and macrophages to promote fibrosis in CP. In contrast to AP, macrophages in CP display alternate activation consistent with immunosuppressive environment associated with CP. Immune cells also play a critical and differential role of anti- and pro-tumor functions in PDAC. For example, immune signals such as IL-22/IL-22R axis are involved in AP, CP, and PDAC but play differential role between the diseases. To get insight into the inflammatory processes involved, we use multiplex based assays to profile immune cells isolated from the pancreas as well as in situ to determine functional and geographic localization. Citation Format: Aida Habtezion. Immune cell signaling in human and mouse pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I10.
Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF‐2
Authors: Edward R. Horton, Queralt Vallmajo‐Martin, Ivan Martin, Jess G. Snedeker, Martin Ehrbar, Ulrich Blache
Journal: Advanced Healthcare Materials (2020)

Abstract In native tissues, the interaction between cells and the surrounding extracellular matrix (ECM) is reciprocal, as cells not only receive signals from the ECM but also actively remodel it through secretion of cell‐derived ECM. However, very little is known about the reciprocal interaction between cells and their secreted ECM within synthetic biomaterials that mimic the ECM for use in engineering of tissues for regenerative medicine or as tissue models. Here, poly(ethylene glycol) (PEG) hydrogels with fully defined biomaterial properties are used to investigate the emerging role of cell‐derived ECM on culture outcomes. It is shown that human mesenchymal stromal cells (MSCs) secrete ECM proteins into the pericellular space early after encapsulation and that, even in the absence of material‐presented cell adhesion motifs, cell‐derived fibronectin enables cell spreading. Then, it is investigated how different culture conditions influence MSC ECM expression in hydrogels. Most strikingly, it is found by RNA sequencing that the fibroblast growth factor 2 (FGF‐2) changes ECM gene expression and, in particular, decreases the expression of structural ECM components including fibrillar collagens. In summary, this work shows that cell‐derived ECM is a guiding cue in 3D hydrogels and that FGF‐2 is a potentially important ECM regulator within bioengineered cell and tissue systems.
Abstract 16473: Role of Low-Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus
Authors: Hua-Chen Chan, Hsiu-Chuan Chan, Chan-Jung Liang, Hsiang-chun Lee, Hung Su, An-sheng Lee, Jentaie Shiea, Wen-Chan Tsai, Tsan-Teng Ou, Cheng-Chin Wu, Chih-Sheng Chu, Richard A. Dixon, Liang-Yin Ke, Jeng-Hsien Yen, Chu-Huang Chen
Journal: Circulation (2019)

Introduction: Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. We investigated the role of L...
Abstract P159: In-hospital Mortality Of Transcatheter Versus Surgical Aortic Valve Replacement: A Nationwide Analysis
Authors: Rodrigo Aguilar, Waiel Abusnina, Kanaan Mansoor, carlos Rueda
Journal: Circulation (2020)

Background: Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis Commercial use or TAVR has expanded widely, nonetheless, is still considered a developing procedure and is not used widely in the country. Methods, techniques, training and valves are continuously evolving. Methods: Nationwide inpatient sample (NIS) data from 2005 to 2012 was queried. Patients who had aortic stenosis and underwent consequent either TAVR or SAVR were selected. Cases who received both techniques were excluded. We further stratified the groups according to the propensity match score and used TAVR as a reference. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina). All p-values were based on 2-tailed tests and were considered statistically significant when p &lt; 0.05. Results: Among 48,022 patients admitted for aortic valve replacement between 2005 and 2012, 96.67% (n=46,424) underwent SAVR and 3.33% (n=1,598) underwent TAVR. Mortality prior to propensity match was higher in TAVR (4.51% vs3.21%, p = 0.004). ). The all-cause mortality remained higher in TAVR (4.62% vs 3.57%, p = 0.15), after adjusting for age, sex, race, insurance payer, diabetes, hypertension, hyperlipidemia, smoking status, heart failure, coronary artery disease (CAD) and prior myocardial infarction. Length of stay was shorter in TAVR (8.38 days vs 11.52 days). Conclusion: Data analysis results demonstrated that patients with higher mortality have occurred when performing TAVR as compared to SAVR, however recent reports support improving techniques, faster recovery, shorter length of stay. Furthermore, usually TAVR candidates usually have more comorbidities and lower performance status, hence the expected mortality is higher. Further studies are suggested to further stratify mortality across the years.
Abstract MP42: Do Adult Ambulatory BP Cut-points Predict Target Organ Damage Better Than Pediatric ABP Percentiles?
Authors: Elaine M Urbina, Michael A Ferguson, Marc B Lande, Kevin Meyers, Bernard Rosner, Joshua A Samuels, Joseph T Flynn
Journal: Circulation (2020)

Ambulatory hypertension (HT) is more strongly related to cardiac target organ damage (TOD) than clinic BP. Therefore, correct classification of ambulatory blood pressure (ABP) phenotype is needed to determine which patients to refer for imaging. Pediatric ABPM interpretation is based on percentiles of ABP while adult ABPM interpretation is based on static cut-points. We sought to determine which ABP classification system was the best predictor of TOD in adolescents. We measured adiposity, LV mass index (LVMI), systolic and diastolic function (strain, E/e’ ratio) in 315 adolescents (15.9 + 1.4 years, 64% white, 59% male). BP phenotype was determined by mean of 6 casual aneroid SBPs, and 24-hour SBP on ABP (Spacelabs Inc., Snoqualmie, WA) 1) by age, sex and height specific pediatric cut-points and 2) by adult ABPM cut-points (day &lt;130, night &lt; 110, 24-hour &lt; 125 mmHg). We evaluated concordance in classification and prevalence of TOD with Chi square and kappa statistic for agreement. For daytime SBP, 5% of all subjects (16 of 315) reclassified from normotensive (NT) to masked hypertension (MH) and 8% (24 of 315) reclassified from white coat (WC) to HT. Results were similar for night and 24-hour ABP. Fewer NT and WC subjects had any form of TOD by adult vs pediatric cut-point (NT 32 vs 36%, WC 8 vs 13%; chi square &lt; 0.0001, kappa 0.73). The only significant differences in cardiac TOD by ABP phenotype were found using adult ABP cut-points (LVMI higher and strain lower HT vs NT, diastolic E/e’ higher HT and MH vs NT all p &lt;=0.05). We conclude that classification of ABP by adult cut-points is superior in identifying adolescents at risk for cardiac TOD. These findings may inform future pediatric ABP guidelines.
Abstract 14752: Canagliflozin Reduces Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Chronic Kidney Disease Regardless of Baseline HbA1c, Including Those With HbA1c <7%: Results From the CREDENCE Trial
Authors: Christopher P. Cannon, Vlado Perkovic, Rajiv Agarwal, James Baldassarre, George L. Bakris, Barry M. Brenner, David Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J. Lambers Heerspink, Meg Jardine, Adeera Levin, Jing-Wei Li, Bruce Neal, Carol Pollock, David Wheeler, Hong Zhang, Bernard Zinman, Kenneth W. Mahaffey
Journal: Circulation (2019)

Background: SGLT2 inhibitors have to date been recommended as add-on therapy for patients whose HbA1c is not at goal, typically >7%, based on the initial clinical trials. We sought to determine if ...
Abstract #1246: Preclinical efficacy and pharmacodynamics of SCH 900105 (AV-299), an anti-HGF antibody
Authors: Kristan Meetze, Kelly Connolly, Andrea Boudrow, Hamid Tissire, Russell Karp, Jeno Gyuris, May Han
Journal: Cancer Research (2009)

Hepatocyte growth factor (HGF) is the soluble ligand for the c-Met receptor tyrosine kinase. The study of human and animal tumor models has provided compelling evidence that signaling through the HGF/c-Met pathway mediates a plethora of cellular activities that are involved in cancer cell dysregulation, tumorigenesis, and metastasis including proliferation, survival, angiogenesis, migration, and invasion. Tumor cell HGF/c-Met autocrine and paracrine loops have been reported in a number of human cancers including breast, lung, bladder, gastric, head and neck, glioma, multiple myeloma, leukemias, and certain sarcomas. SCH 900105, also known as AV-299, is a humanized IgG1 antibody with high affinity to HGF and neutralizes its biological functions with sub-nM potency. In vivo efficacy of SCH 900105 was explored in both autocrine and paracrine xenograft models. In these studies, SCH 900105 treatment resulted in significant tumor regression at doses as low as 0.1 mg/kg in one model. SCH 900105 treatment also demonstrated dose-dependent efficacy in paracrine models of the HGF-dependent xenograft lines in SCID mice engineered to produce human HGF. In these models, SCH 900105 treatment resulted in dose-dependent increases in complexed SCH 900105/HGF in serum. Treatment also led to significant decreases in tumor phospho-c-Met levels, phospho-Akt, increased cleaved caspase-3, as well as decrease in Ki67 staining. To explore the effects of dosing schedule on tumor growth inhibition, xenograft studies were performed with various dosing frequencies. All schedules resulted in initial tumor regression; however, SCH 900105 was most efficacious in causing tumor regression and delaying ultimate tumor escape when administered twice weekly compared to weekly or bi-weekly treatment. Several combination studies were also performed with other target therapeutics, chemotherapies and anti-angiogenic agents in subcutaneous and orthotopic models.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1246.
No Difference in Incidence of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection Treated With Entecavir vs Tenofovir
Authors: Hyunwoo Oh, Eileen L. Yoon, Dae Won Jun, Sang Bong Ahn, Hyo-Young Lee, Jae Yoon Jeong, Hyoung Su Kim, Soung Won Jeong, Sung Eun Kim, Jae-Jun Shim, Joo Hyun Sohn, Yong Kyun Cho
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract P449: Associations of Unhealthy Food and Physical Activity Environments With Adverse Cardiac Function: The Coronary Artery Risk Development in Young Adults (Cardia) Study
Authors: Ravi B Patel, Laura A Colangelo, Penny Gordon-Larsen, Clyde W Yancy, Donald M Lloyd-Jones, Kiarri N Kershaw, Sadiya S Khan
Journal: Circulation (2020)

Background: Substantial disparities in risk of heart failure (HF) exist by race, which may be driven by certain social or environmental factors. The relationship between the neighborhood built environment, including food and physical activity facilities, and risk of HF is unclear. The associations of the built environment and subclinical cardiac dysfunction may offer insight into mechanisms that lead to increased HF risk. Methods: In the CARDIA study, we evaluated the associations between measures of the neighborhood built environment and echocardiographic indices of cardiac function at the Year 25 exam (Y25). Built measures were assessed within a 3-km Euclidean distance from participant residence and included: 1) proportion of fast food restaurants or convenience stores relative to total food outlets and 2) number of public or commercial physical activity facilities. Results: Among 2,363 participants (44% male, 51% black) with available data from Y25, higher proportions of fast food restaurants and convenience stores were independently associated with lower left ventricular (LV) diastolic function (lower e’ tissue velocities and higher E/e’) ( Table ). Lower number of public and commercial physical activity facilities were independently associated with lower LV systolic function (LV longitudinal strain) and diastolic function. Conclusions: Food environments with higher proportions of fast food and convenience stores are associated with lower diastolic function, and environments with less physical activity facilities are associated with worse systolic and diastolic function. These findings suggest relationships between the built environment and subclinical HF.
Capsaicin inhibits the growth of breast cancer cells and decreases expression of EGFR and Her2/Neu.
Authors: James O'Kelly, Daning Lu, Amanda Leiter, H. Phillip Koeffler
Journal: Cancer Research (2007)

5540  Capsaicin is an active ingredient of chili peppers. We recently showed that capsaicin inhibited the growth of prostate cancer cells in vitro and in vivo. Here, we extended these studies and demonstrate that capsaicin has profound antiproliferative effects against breast cancer cells. Capsaicin inhibited the growth of estrogen receptor (ER)-positive (MCF-7, T47D, BT-474) and ER-negative (SK-BR-3, MDA-MB-231) breast cancer cell lines (ED50, 1x10-5 M - 5x10-5 M), due to an increase in apoptosis (from 5% in control cultures to 20% after 48 h treatment) as determined by annexin V staining. Expression of proteins involved in multiple signaling pathways that are important for breast cancer progression, were down-regulated by capsaicin. Specifically, expression of Akt, Her/Neu, and EGFR was decreased by incubation with capsaicin for 48 h in a dose-dependent manner (10-6 M to 2 x 10-4 M). Additionally, levels of these proteins were reduced to undetectable levels by 10-4 M capsaicin within 12 h of treatment. Decreases in expression of these proteins were not accompanied by decreases in their respective mRNA levels. In further experiments, reduced expression of EGFR caused by capsaicin in BT-474 cells led to diminished response to EGF. Phosphorylation of Erk in response to EGF was suppressed, and cells were less able to migrate towards the growth factor in Boyden chamber assays. Furthermore, capsaicin, when given orally, slowed by about 50% the growth of EGFR-positive MDA-MB-231 breast cancer cells grown as xenografts in nude mice. In summary, our data indicate that capsaicin is a novel regulator of EGFR and Her2 expression, and may provide therapeutic benefits for the management of ER+ and ER- breast cancers.
Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study
Authors: Sari Mäkimattila, Valma Harjutsalo, Carol Forsblom, Per-Henrik Groop
Journal: Diabetes Care (2020)

The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland.The study included 4,758 individuals with T1D from the Finnish Diabetic Nephropathy (FinnDiane) Study and 12,710 nondiabetic control individuals. The autoimmune diseases (ADs) were identified by linking the data with the Finnish nationwide health registries from 1970 to 2015.The median age of the FinnDiane individuals at the end of follow-up in 2015 was 51.4 (interquartile range 42.6-60.1) years, and the median duration of diabetes was 35.5 (26.5-44.0) years. Of individuals with T1D, 22.8% had at least one additional AD, which included 31.6% of women and 14.9% of men. The odds ratios for hypothyroidism, hyperthyroidism, celiac disease, Addison disease, and atrophic gastritis were 3.43 (95% CI 3.09-3.81), 2.98 (2.27-3.90), 4.64 (3.71-5.81), 24.13 (5.60-104.03), and 5.08 (3.15-8.18), respectively, in the individuals with T1D compared with the control individuals. The corresponding ORs for women compared with men were 2.96 (2.53-3.47), 2.83 (1.87-4.28), 1.52 (1.15-2.02), 2.22 (0.83-5.91), and 1.36 (0.77-2.39), respectively, in individuals with T1D. Late onset of T1D and aging increased the risk of hypothyroidism, whereas young age at onset of T1D increased the risk of celiac disease.This is one of the largest studies quantifying the risk of coexisting AD in adult individuals with T1D in the country with the highest incidence of T1D in the world. The results highlight the importance of continuous screening for other ADs in individuals with T1D.