tbuckley/cabot-search huggingface dataset:
Role of Histamine Produced by Bone Marrow–Derived Vascular Cells in Pathogenesis of Atherosclerosis
Authors: YasuyukiSasaguri, Ke-YongWang, AkihideTanimoto, MasatoTsutsui, HikaruUeno, YoshitakaMurata, YukariKohno, SohsukeYamada, HiroshiOhtsu
Journal: Circulation Research (2005)

To clarify the role of histamine-producing cells and its origin in atherosclerosis, we investigated histidine decarboxylase (HDC; histamine-producing enzyme) expression in murine arteries with vascular injuries after the animal had received transplanted bone marrow (BM) from green fluorescent protein (GFP)–transgenic mice. The neointima in the ligated carotid arteries contained BM-derived HDC+ cells that expressed macrophage (Mac-3) or smooth muscle cell antigen (α-SMA). In contrast, the HDC+ BM-derived cells, which were positive for Mac-3, were mainly located in the adventitia in the cuff replacement model. In apolipoprotein E-knockout mice on a high cholesterol diet, BM-derived cells expressing Mac-3 in the atheromatous plaques were also positive for HDC. In comparison with wild-type mice, HDC−/− mice showed reduced neointimal thickening and a decreased intima-to-media ratio after ligation and cuff replacement. These results indicate that histamine produced from BM-derived progenitor cells, which could ...
Regression of Myocardial Hypertrophy After Aortic Valve Replacement
Authors: GeorgePetrov, VeraRegitz-Zagrosek, ElkeLehmkuhl, ThomasKrabatsch, AnneDunkel, MichaelDandel, ElkeDworatzek, ShokoufehMahmoodzadeh, CarolaSchubert, EvaBecher, HannahHampl, RolandHetzer
Journal: Circulation (2010)

Background—In patients with aortic stenosis, pressure overload induces cardiac hypertrophy and fibrosis. Female sex and estrogens influence cardiac remodeling and fibrosis in animal models and in men. Sex differences and their molecular mechanisms in hypertrophy regression after aortic valve replacement have not yet been studied. Methods and Results—We prospectively obtained preoperative and early postoperative echocardiography in 92 patients, 53 women and 39 men, undergoing aortic valve replacement for isolated aortic stenosis. We analyzed in a subgroup of 10 patients matrix gene expression in left ventricular (LV) biopsies. In addition, we determined the effect of 17β-estradiol on collagen synthesis in isolated rat cardiac fibroblasts. Preoperatively, women and men had similar ejection fraction. Similar percentages of women and men had increased LV diameters (37% and 38%). Women more frequently exhibited LV hypertrophy than men (women: 86%; men: 56%; P<0.01). Postoperatively, increased LV diameters pers...
Differential Leukotriene Constrictor Responses in Human Atherosclerotic Coronary Arteries
Authors: SeanAllen, MichaelDashwood, KarenMorrison, MagdiYacoub
Journal: Circulation (1998)

Background—Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries. Methods and Results—The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. S...
Abstract 493: Circulating biliary tract microRNA signature discriminates cholangiocarcinoma from pancreatic cancer
Authors: Jisce R. Puik, Laura L. Meijer, Tessa Y. Le Large, Michal Heger, Frederike Dijk, Niccola Funel, Ingrid Garajová, Elisa Giovannetti, Geert Kazemier
Journal: Cancer Research (2018)

Abstract Accurate diagnosis of lesions in the pancreatic head is a challenge with substantial clinical consequences in daily practice. Located in the pancreatic head, both distal cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal malignancies with limited but distinct therapeutic options. Given these different therapeutic considerations, discovery of novel biomarkers that can ensure differential diagnostic specificity is an unmet clinical need. This study aims to identify a circulating microRNA (miRNA) signature to accurately diagnose and discriminate distal CCA from PDAC. In the initial discovery phase, microarray profiling of a panel of 752 miRNAs was performed on seven distal CCA and seven age- and sex-matched healthy control plasma samples. Raw data were normalized to the global mean. Based on probability value and fold change, candidate miRNAs were selected for further validation. In the validation phase, selected candidate miRNAs were analyzed in an independent cohort of distal CCA (n = 22) and healthy controls (n = 32) using RT-qPCR. To further assess the origin of lesions, candidate miRNA expression profiles were analyzed in malignant disease (n = 90) compared to benign disease (n = 15), and distal CCA (n = 22) compared to PDAC (n = 30). Following an empirically based selection of potential reference genes, raw data were normalized to a combination of two normalizing reference miRNAs. In the discovery phase, microarray analysis revealed nineteen miRNAs that were significantly deregulated in patients with distal CCA compared to healthy controls. Thirteen miRNAs were selected for further validation. In the validation phase, using logistic regression analysis, a three-miRNA panel was identified as the most robust diagnostic signature to discriminate malignant from benign disease (AUC = 0.881). Remarkably, two miRNAs of this panel were validated as specific classifier for distal CCA, with an AUC of 0.814 in differentiating distal CCA from PDAC. In addition, a combination of miR-93 and miR-101 was used as bona fide normalizing reference gene for these analyses. In conclusion, a combined panel of plasma miRNAs shows promising diagnostic capability to serve as unique minimally invasive distal CCA biomarker and has the potential to help clinical decision making for patients affected by pancreatobiliary disease in the pancreatic head. Citation Format: Jisce R. Puik, Laura L. Meijer, Tessa Y. Le Large, Michal Heger, Frederike Dijk, Niccola Funel, Ingrid Garajová, Elisa Giovannetti, Geert Kazemier. Circulating biliary tract microRNA signature discriminates cholangiocarcinoma from 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 493.
Circulating Cell-Free miR-375 as Surrogate Marker of Tumor Burden in Merkel Cell Carcinoma
Authors: Kaiji Fan, Cathrin Ritter, Paul Nghiem, Astrid Blom, Monique E. Verhaegen, Andrzej Dlugosz, Niels Ødum, Anders Woetmann, Richard W. Tothill, Rodney J. Hicks, Michael Sand, David Schrama, Dirk Schadendorf, Selma Ugurel, Jürgen C. Becker
Journal: Clinical Cancer Research (2018)

Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose.Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375-specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts.miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P < 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P = 0.037) but not in tumor-free (P = 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC = 0.954 and 0.800) as well as in the prospective cohorts (AUC = 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions.Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.
Abstract 2461: Prognostic impact of telomeric repeat containing RNA expression on long-term oncologic outcomes in colorectal cancer
Authors: SungUk Bae, Woon Kyung Jeong, Seong Kyu Bae, Jae-Ho Lee
Journal: Cancer Research (2018)

Abstract Purpose: Telomere shortening is associated with colorectal carcinogenesis and transcription from subtelomeres produces telomeric repeat containing RNA (TERRA), a natural inhibitor of telomerase activity (TA). Previous studies on TERRA expression demonstrated downregulation in advanced stages of human tumors. Materials and Methods: We evaluated the 2p TERRA expression and telomere length using quantitative real-time PCR in 60 patients who underwent surgical resection for colorectal cancer between June 2008 and November 2010. Results: Patients were grouped according to 2p TERRA expression, with 27 (45%) and 33 (55%) in the low and high TERRA expression groups, respectively. The median follow-up period was 80 months (range 2-103). 2p TERRA expression was marginally significantly associated with preoperative CEA (P = 0.082) and significantly associated with telomere length (P &amp;lt; 0.05). Five-year overall survival rates in the high 2p TERRA expression group and the low expression group were 73.6% and 78.2%, respectively (p = 0.322), and five-year disease-free survival rates in the high 2p TERRA expression group and the low expression group were 66.1% and 75.1%, respectively (p = 0.317). Conclusions: 2p TERRA expression was marginally significantly associated with preoperative CEA and significantly associated with telomere length; however, it was not prognostic on long-term oncologic outcomes in colorectal cancer. Citation Format: SungUk Bae, Woon Kyung Jeong, Seong Kyu Bae, Jae-Ho Lee. Prognostic impact of telomeric repeat containing RNA expression on long-term oncologic outcomes in colorectal 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 2461.
Abstract 3508: Separate and combined effects of caloric restriction mimetics and autophagy inhibition on KRAS-driven pancreatic adenocarcinoma
Authors: Xuewen Chen, Ciara H. O'Flanagan, Michael Coleman, Channing J. Der, Stephen D. Hursting
Journal: Cancer Research (2018)

Abstract Calorie restriction (CR) is one of the most effective dietary interventions for reducing cancer risk and progression. However, maintaining a dramatically reduced calorie intake over an extended time period is very challenging for most individuals. Thus a major effort is under way to identify mechanism-based pharmacologic approaches that mimic the anticancer effects of CR without the requirement of reduced calorie intake. We have established that CR exerts antitumor effects at least in part through altered metabolism, reduced circulating growth factors (such as insulin and IGF-1) and reduced signaling downstream of the insulin receptor and IGF-1R along the phosphoinositide 3-kinase/mTOR axis. We have previously shown CR reduced growth of KRAS-driven tumors in vivo, and the antitumorigenic effect was enhanced when combined with autophagy inhibition. Here we evaluated the effects of in vitro CR via glucose and serum modulation, as well as separate and combined effects of CR mimetics and autophagy inhibition on the KRAS-driven murine pancreatic adenocarcinoma (PDAC) cell line, FC1242. Glucose modulation alone via glucose restriction, metformin or AICAR treatment showed no effect on clonogenic growth of FC1242. In contrast, both cell viability and clonogenicity were significantly reduced by serum starvation, rapamycin treatment, IGF-1R/insulin receptor inhibition by BMS-754807, and sirtuin inhibition with nicotinamide, suggesting these cells are dependent on mTOR/IGF-1 signaling. The growth-suppressive effects of these CR mimetics were enhanced when combined with autophagy inhibition via chloroquine or verteporfin. Together, the study indicated the targeting of mTOR or IGF-1 signaling may most closely mimic the growth-suppressive effects of CR, and that co-treatment of these CR mimetics with autophagy inhibition may be an effective strategy for PDAC anticancer therapy. Citation Format: Xuewen Chen, Ciara H. O'Flanagan, Michael Coleman, Channing J. Der, Stephen D. Hursting. Separate and combined effects of caloric restriction mimetics and autophagy inhibition on KRAS-driven pancreatic adenocarcinoma [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 3508.
Abstract 2890: Trifluridine efficacy in cancer stem cell
Authors: Kenta Tsunekuni, Masamitsu Konno, Jun Koseki, Ayumu Asai, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2018)

Abstract Background: Cancer stem cells (CSC) have been involved in disease recurrence, metastasis, and therapeutic resistance, but effective anti-cancer agent for these cells is not still currently available. Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy etc. and improved overall survival. Here we showed the efficacy of FTD in CD44 and CD133 high expressing (CD44high/CD133high) cancer cells which has CSC like property. Method: CD44high /CD133high and CD44low /CD133low DLD-1 cells were separated by Fluorescence-Activated Cell Sorting (FACS) and subjected to sphere formation assay. Anti-proliferative and anti-sphere forming effects of FTD in CD44high /CD133high cells were measured. Then, 150 days FTD long exposed colorectal cell line's CSC markers CD44 and CD133 were measured by flow cytometry and its tumor initiating property in in vitro and in vivo were evaluated. Results: CD44 high /CD133 high DLD-1 cells formed much more sphere than CD44low /CD133low cells significantly. Compared to unsorted cells, CD44high /CD133high cells displayed 5-FU resistance (IC50 value of 5-FU for unsorted and CD44 high /CD133 high cells were 2.5 μM and 5.5 μM respectively) but not FTD resistance (IC50 value of FTD for unsorted and CD44 high /CD133 high cells were 8.9 μM and 10.7 μM, respectively) in in vitro proliferation assay. In addition, FTD treatment in a subtoxic concentration 1 μM for DLD-1 cells disrupted sphere formation. FTD-long exposed DLD-1 cell lines showed decreased CD44high /CD133high population compared to its parental cell line from 11.3% to 0.7%, and showed decreased sphere-forming efficacy. In addition, FTD-long exposed DLD-1 cell lines decreased tumor forming potential in in vivo. These results suggest that FTD is effective for CSC like cells and that long exposure to FTD might lead CSC depletion. Conclusion: FTD was proved to be effective for CSC like CD44high /CD133high cells. It suggests that FTD might be useful for CSC targeted chemotherapy in case of CD44 and CD133 are highly expressed subtype of tumors. Citation Format: Kenta Tsunekuni, Masamitsu Konno, Jun Koseki, Ayumu Asai, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Trifluridine efficacy in cancer stem cell [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 2890.
Abstract 5121: Obesity and prostate cancer progression: Role of the chemokine CXCL12
Authors: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the third leading cause of cancer in men in the United States. Many epidemiologic studies suggest that obesity increases PCa progression and mortality. However, the mechanistic relationship between PCa progression and obesity is very complex and not fully understood. In previous studies, we have shown that obesity enhances PCa growth and progression in the HiMyc mouse model of PCa by changing the surrounding tumor microenvironment, especially in white adipose tissue (WAT). WAT consists of many cells including mature adipocytes, adipose stromal cells (ASCs) and inflammatory cells, which secrete chemokines, cytokines and proinflammatory molecules. ASCs are an important component of the stromal vascular fraction (SVF) from WAT that secretes such factors. In this study, we evaluated the role of ASCs and ASC-derived CXCL12 in driving PCa progression in obesity. We observed upregulation of mRNA expression of CXCL12 in the SVF of the periprostatic WAT from obese HiMyc mice. In HMVP2 cells, a PCa cell line derived from HiMyc mice expressing high levels of CXCR4 and CXCR7, CXCL12 treatment increased activation of MAPKs (JNK and ERK), AKT, STAT3 and NFkB. In further studies, HMVP2 cells were treated with the CXCR4 antagonist, AMD3100, alone or together with CXCL12 and the CXCL12-induced signaling was abolished in AMD3100-treated cells. Similar results were observed in CXCR4 knockdown cells and CXCR7 knockdown cells. In addition, knockdown of CXCR4 and CXCR7 significantly decreased migration and invasion of the HMVP2 cells. Lastly, a tumor study was performed by injecting HMVP2 cells into the flank of FVB/N mice, which were fed either a control diet or obese diet. AMD3100 significantly inhibited the growth of HMVP2 tumors in both obese and control diet groups. AMD3100 also inhibited proliferation and epithelial-mesenchymal transition (EMT) in both obese and control diet groups. In conclusion, this study provides evidence that the CXCL12/CXCR4/CXCR7 signaling pathway is important for obesity-driven PCa progression in HiMyc mice. Furthermore, this pathway may represent a novel therapeutic target for inhibiting obesity-driven PCa growth and progression. Citation Format: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni. Obesity and prostate cancer progression: Role of the chemokine CXCL12 [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 5121.
Importance of Evaluating Cardiovascular Risk and Hepatic Fibrosis in Patients With Newly Diagnosed Nonalcoholic Fatty Liver Disease
Authors: Maria Cristina Moreno-del Castillo, Alain Sanchez-Rodriguez, Javier Jose Hernandez-Buen Abad, Jonathan Aguirre-Valadez, Isaac Ruiz, Ricardo Garcia-Buen Abad, Kassandra Oliva, Joey Piccolo, Esteban De Icaza-del Rio, Jose Ramon Mena-Ramirez, Maria Emilia Mendizabal-Rodriguez, Natalie Madeline Atkinson-Ginsburg, Jonathan Salazar-Segovia, Alberto Ríos-Zertuche Caceres, Ignacio Garcia-Juarez
Journal: Clinical Gastroenterology and Hepatology (2018)
Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis
Authors: Edward J. Gane, Catherine A. Stedman, Christian Schwabe, Leen Vijgen, Sushmita Chanda, Thomas N. Kakuda, John Fry, Lawrence M. Blatt, Matthew W. McClure
Journal: Hepatology (2018)

This open‐label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct‐acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6‐12‐week oral regimens of 400‐800 mg once daily (QD) AL‐335 + 50 mg QD/every other day odalasvir ± 75‐150 mg QD simeprevir were evaluated in treatment‐naïve, HCV genotype (GT)1/3‐infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV‐RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment‐emergent adverse events occurred, one of which (a Mobitz type 1 second‐degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1‐infected patients receiving 3‐DAA for 6‐8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1‐infected patients receiving 2‐DAA or GT3‐infected patients receiving 3‐DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance‐associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment‐naïve subjects without cirrhosis, AL‐335 + odalasvir + simeprevir for 6‐8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2‐DAA regimen in GT1‐infected subjects and the 3‐DAA regimen in GT3‐infected subjects.
Ultrasound Imaging–Guided Noninvasive Ultrasound Thrombolysis
Authors: UriRosenschein, VladimirFurman, EfimKerner, ItzchakFabian, JoelleBernheim, YoramEshel
Journal: Circulation (2000)

Background—Catheter-based therapeutic ultrasound thrombolysis was recently shown to be effective and safe. The purpose of this work was to study the safety and efficacy of external high-intensity focused ultrasound thrombolysis guided by ultrasound imaging in experimental settings. Methods and Results—A therapeutic transducer was constructed from an acoustic lens and integrated with an ultrasound imaging transducer. In vitro clots were inserted into bovine arterial segments and sonicated under real-time ultrasound imaging guidance in a water tank. With pulsed-wave (PW) ultrasound, the total sonication time correlated with thrombolysis efficiency (r2=0.7666). A thrombolysis efficiency of 91% was achieved with optimal PW parameters (1:25 duty cycle, 200-μs pulse length) at an intensity (Ispta) of >35±5 W/cm2. Ultrasound imaging during sonication showed the cavitation field as a spherical cloud of echo-dense material. Within <2 minutes, the vessel lumen evidenced neither residual clot nor damage to the arter...