tbuckley/cabot-search huggingface dataset:
Abstract 5151: Enhanced chemotactic response of MDA-MB-231 breast cancer cells towards stable gradients of EGF
Authors: Nina Baumann, Verena Kuttenberger, Christine Huemmer, Jan Schwarz, Elias Horn Horn, Roman Zantl
Journal: Cancer Research (2018)

Abstract Chemotactic cell migration is a basic mechanism underlying cancer cell invasion and hence metastasis. In this regard, growth factors such as epidermal growth factor (EGF) have been identified as guidance cues. Using ibidi's µ-Slide Chemotaxis we confirm the growth factor EGF as potent guidance cue for directional MDA-MB-231 migration in a physiological 3D environment. Moreover, we find enhanced sensitivity towards gradients of EGF in serum free media supplemented with defined protein composition (UltraCULTURETM). Combining defined, physiological migration conditions and enhanced sensitivity allowed us to quantify EGF dependent MDA-MB-231 chemotaxis in a detailed manor. MDA-MB-231 cells showed increased directional and kinetic response towards temporal and stable spatial gradients of EGF. While EGF guided directional migration was highly concentration dependent with a concentration optimum of 10 ng/mL, we found the chemokinetic effect induced by the presence of EGF being concentration independent. Those results suggest differential response of the migration and signal interpretation machinery of MDA-MB-231 cells. Both, blocking the ligand binding domain of the EGF-Receptor (EGFR) by a blocking antibody and inhibition of the kinase domain of EGFR by a small molecule inhibitor (AG1478) led to a reduction in EGF induced directional sensing and migration velocity. Additionally, low, non-effective single doses of antibody and small molecule inhibitor showed synergistically effective inhibition if combined. Those results support EGF being a potent guidance cue for MDA-MB-231 cell migration and help to understand the mechanisms behind chemotactic migration driven cancer metastasis. Citation Format: Nina Baumann, Verena Kuttenberger, Christine Huemmer, Jan Schwarz, Elias Horn Horn, Roman Zantl. Enhanced chemotactic response of MDA-MB-231 breast cancer cells towards stable gradients of EGF [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 5151.
Long-Term Additive Prognostic Value of Thallium-201 Myocardial Perfusion Imaging Over Clinical and Exercise Stress Test in Low to Intermediate Risk Patients
Authors: GéraldVanzetto, OlivierOrmezzano, DanielFagret, MichelComet, BernardDenis, JacquesMachecourt
Journal: Circulation (1999)

Background—The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. Methods and Results—One thousand one hundred thirty-seven patients (857 men, age 55±9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72±18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload ≤75 W) (2.36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic E...
Differentiating Primary From Secondary Hypertrophy Based on the Coronary Lumen Volume to Myocardial Mass Relationship
Authors: Ashraf Hamdan, Mithal Nassar, Daniel Monakier, Abid Assali, Gideon Shafir, Hana Vaknin-Assa, Israel Barbash, Orly Goitein, Ran Kornowski, Ehud Schwammenthal
Journal: JACC. Cardiovascular imaging (2018)
Abstract 1010: Establishing lobular-like and interlobular-like fibroblast cell lines from human breast reduction mammoplasties
Authors: Mikkel Morsing, Abbas Jafari, Moustapha Kassem, Ole William Petersen, Lone Rønnov-Jessen
Journal: Cancer Research (2018)

Abstract Introduction: The importance of epithelial-stromal interactions for tissue homeostasis and maintenance is well documented. We have recently provided evidence that two distinct fibroblast lineages in the human breast stroma, lobular and interlobular, respectively, can be prospectively isolated and stably propagated in serial-passage subculture. The aim of the present study was to generate immortalized and stable cell lines derived from lobular and interlobular fibroblasts with preserved lineage identity and functionality. The availability of such cell lines will allow for an as of yet unprecedented detailed characterization of mammary fibroblast lineages including their specific interactions with normal and malignant breast epithelium. Results: Lobular- and interlobular-derived fibroblast cell strains in passage 8 were immortalized by retroviral introduction of human telomerase reverse transcriptase (hTERT) followed by neomycin selection. At abstract submission deadline, lobular and interlobular hTERT expressing fibroblasts had reached passage 56 corresponding to 60 and 100 population doublings, respectively, while mock-transfected controls had seized proliferating in passage 21. Lineage restriction of immortalized cells was maintained as lobular fibroblasts express higher levels of CD105 than interlobular fibroblasts. Also, lobular fibroblasts are able to undergo adipogenic and osteogenic differentiation upon relevant induction in culture, but fail to generate bone in an in vivo ectopic bone formation model, thus functionally distinguishing lobular fibroblasts from bone marrow-derived mesenchymal/skeletal stem cells. Upon co-culture with primary breast luminal progenitors, lobular fibroblasts support epithelial growth and branching morphogenesis, including correct apical-basal polarization. Conclusion: Lobular and interlobular fibroblasts have been successfully immortalized while preserving both lineage restriction and functional characteristics of their primary counterparts. With 80% of breast cancers arising in lobular epithelium, these established fibroblast models may prove instrumental to unravel such focal susceptibility to breast cancer development. Citation Format: Mikkel Morsing, Abbas Jafari, Moustapha Kassem, Ole William Petersen, Lone Rønnov-Jessen. Establishing lobular-like and interlobular-like fibroblast cell lines from human breast reduction mammoplasties [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 1010.
Abstract 203: Regenerable altruism drives chemotolerance in clonal cancer cells
Authors: Kee Wah Lee, Muhammad Sufyan Masroni, Karen Meiling Tan, Mo-Huang Li, Lihan Zhou, Steven Tucker, Lynette Su Mien Ngo, Chan Fong Chang, Boon Huat Bay, Soo Yong Tan, Mikael Hartman, Huiwen Chua, Tze Ping Loh, Thomas Putti, Sai Mun Leong, Evelyn Siew-Chuan Koay
Journal: Cancer Research (2018)

Abstract Introduction: Cancer is thought to represent a breakdown of multicellular cooperation and reversion to Darwinian dynamics characterized principally by self-interested competition. However, there is increasing evidence that cancer cells can behave as communities, manifesting social behaviors that influence cancer progression. Methods: Circulating tumor cells enrichment, microRNA extraction, qRT-PCR, MTS assays, RNA in situ hybridization, immunohistochemical staining, SILAC-based mass spectrometry, flow cytometry, ChIP-sequencing, and western blotting. Results: We report here evidences of altruistic cooperation in clonal breast cancer cells. Heterogeneity in expression of a microRNA, miR-125b, leads to sectoring of clonal breast cancer cell populations into minority miR-125b-high and majority miR-125b-low subpopulations. Enhanced population-wide tolerance to taxane-based chemotherapy is mediated by the miR-125b-high minority, in part through increased secretion of extracellular public goods such as insulin-like growth factor binding protein 2 (IGFBP2) and chemokine (C-C motif) ligand 28 (CCL28). Cost-benefit analysis established this helping behavior to be altruistic, as survival benefits conferred to the miR-125b-low cells, via public goods sharing, occurred at a fitness cost to the miR-125b-high cells. Notwithstanding this fitness cost, miR-125b-high altruists regenerate readily from isolated populations of miR-125b-low defectors, via Kruppel-like factor 2-mediated epigenetic mechanism of histone deacetylation. As therapeutic proof-of-principle, we demonstrated that targeting extracellular IGFBP2 and CCL28, through ligand neutralization, markedly blunted the tolerance response of cancer cells towards taxane chemotherapy. Conclusions: Our results demonstrate how positive social engagement such as altruism may be employed by heterogeneous clonal cancer communities to drive chemotolerance, and understanding of such social behaviors could help formulate more effective treatment strategies. Citation Format: Kee Wah Lee, Muhammad Sufyan Masroni, Karen Meiling Tan, Mo-Huang Li, Lihan Zhou, Steven Tucker, Lynette Su Mien Ngo, Chan Fong Chang, Boon Huat Bay, Soo Yong Tan, Mikael Hartman, Huiwen Chua, Tze Ping Loh, Thomas Putti, Sai Mun Leong, Evelyn Siew-Chuan Koay. Regenerable altruism drives chemotolerance in clonal cancer cells [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 203.
Role for Sulfatides in Platelet Aggregation
Authors: MichaelMerten, PerumalThiagarajan
Journal: Circulation (2001)

Background— Sulfatides are sulfated glycosphingolipids present on the surface of oligodendrocytes, renal tubular cells, and certain tumor cells. They appear to be involved in nerve conduction and cell adhesion, but their precise physiological function is not known. Methods and Results— Here, we show a novel role for sulfatides as a major ligand for P-selectin in platelet adhesion and aggregation. Sulfatides are expressed on the platelet surface, and platelets expressing sulfatides adhere to P-selectin. Both sulfatide micelles and sulfatide-binding recombinant malaria circumsporozoite protein (MCSP) inhibit this adhesion. In parallel, platelets and CHO cells expressing P-selectin adhere to sulfatides, and anti-P-selectin antibodies inhibit this adhesion. Furthermore, both anti-P-selectin antibodies and sulfatide antagonist MCSP significantly reverse platelet aggregation induced by ADP, collagen, or thrombin receptor-activating peptide, suggesting that sulfatide-P-selectin interactions are necessary for the...
Abstract 5746: CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-<i>κ</i>B dependent Batf3 expression in DCs
Authors: Jun Yan, Qingnan Zhao, Konrad Gabrusiewicz, Ling-Yuan Kong, Longfei Huo, Xueqing Xia, Jun Wei, Jingda Xu, Eric Davis, Amy B. Heimberger, Shulin Li
Journal: Cancer Research (2018)

Abstract Brain cancer is the 10th leading cause of death in United States with increasing primary tumor morbidity and secondary brain metastasis morbidity. Glioblastoma (GBM) is most lethal brain tumor with less than 5% 5 years survival rate marked by significant resistance to majority of therapies targeting tumor cells or tumor microenvironment. Here we shown one approach to convert aggressive GBM cells to immunogenic tumor cells by knockout FGL2 in GBM cells to evoke efficient anti-tumor immunosurvilliance. FGL2 is an immunosuppressive molecule and its expression level is strongly correlated with glioma grade and poor diagnosis. FGL2 from GBM cells, but not from host cells, is essential for immune evasion dependent GBM progression using both preclinical GBM and brain metastatic tumor models. Knockout FGL2 in GBM cells completely abolish tumor progression of GBM models challenged with low or high number of tumor cells in immunocompetent mice and protect mice from tumor rechallenge in periphery. This eradication effect is impaired in immune deficient mice and CD8+ T cells depleted mice, but not in FGL2KO mice, showing the necessarily of immune system to eliminate FGL2KO tumor cells and the requirement of FGL2 in tumor cells to evade immunosurvilliance. To understand how the systemic CD8+ T cell-dependent anti-tumor response and memory was induced by FGL2KO GBM cells, we studied the impact of FGL2KO tumor cells on dendritic cells (DCs) which control immune response via its critical role in the generation of effective cytotoxic T lymphocyte (CTL) responses. Knockout FGL2 in GBM cells induced CD8a+/CD103+ DCs accumulation in brain in vivo; DCs proliferation and CD103+ DCs induction in vitro. In agreement with this discovery, knockout Batf3, a key transcription factor regulating CD8a+/CD103+ DCs, reverse the impact of FGL2KO in GBM cell in vivo. By molecule analysis, a novel signaling pathway was revealed that knockout FGL2 in GBM cells induce NF-κ B activation, and this activation induced Batf3 and associated CD103 expression in DCs. Therefore, target specific molecule in GBM cells, such as knockout FGL2, can convert aggressive GBM cells to immunogenic cells, pointing to new approach for immune therapy. Citation Format: Jun Yan, Qingnan Zhao, Konrad Gabrusiewicz, Ling-Yuan Kong, Longfei Huo, Xueqing Xia, Jun Wei, Jingda Xu, Eric Davis, Amy B. Heimberger, Shulin Li. CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-κB dependent Batf3 expression in DCs [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 5746.
Abstract 15470: The Impact of Angiotensin Converting Enzyme Inhibitor versus Angiotensin Receptor Blocker on Clinical Outcomes in Patients Undergoing Endovascular Intervention for Peripheral Artery Disease
Authors: Ji Young Park, Seung Woon Rha, Sung Kee Ryu, Jae Woong Choi, Byoung Geol Choi, Jae Kyeong Byun, Se Yeon Choi, Jun Hyuk Kang, Woo Hyeun Kim, Ja Yeon Choi, Eun Jin Park, Sung Hun Park, Sunki Lee, Hu Li, Jin Oh Na, Cheol Ung Choi, Jin Won Kim, Hong Euy Lim, Eung Ju Kim, Chang Gyu Park, Hong Seog Seo, Dong Joo Oh
Journal: Circulation (2016)

Backgrounds: Angiotensin-converting enzyme inhibitors (ACEI) have a well-established role in the treatment of patients (pts) with high risks of cardiovascular disease. The aim of this study is to e...
17β-Estradiol Inhibits Ca2+ Influx and Ca2+ Release Induced by Thromboxane A2 in Porcine Coronary Artery
Authors: Shu-ZhongHan, HideakiKaraki, YasuyoshiOuchi, MasahiraAkishita, HajimeOrimo
Journal: Circulation (1995)

Background We wished to investigate the possible mechanism of the protective effect of estrogen replacement on coronary atherosclerosis observed in postmenopausal women. Methods and Results Cytosolic Ca2+ concentration ([Ca2+]i) and contraction were measured simultaneously in fura 2–loaded porcine coronary arterial strips stimulated by the thromboxane A2 analogue U46619 and high-K+ depolarization in the presence and absence of 17β-estradiol. Pretreatment with 17β-estradiol (30 nmol/L to 30 μmol/L) inhibited the sustained elevation of [Ca2+]i and the sustained contraction induced by 300 nmol/L U46619. Higher concentrations of 17β-estradiol (1 to 100 μmol/L) also inhibited the U46619-induced transient increase in [Ca2+]i and contraction in the absence of extracellular Ca2+. In the strips precontracted by 90 mmol/L K+, 17β-estradiol (30 μmol/L) inhibited the increases in [Ca2+]i and contraction to resting levels. In contrast, 30 μmol/L 17β-estradiol only partially inhibited the U46619-induced sustained contr...
The dyspnoea–inactivity vicious circle in COPD: development and external validation of a conceptual model
Authors: Maria A. Ramon, Gerben Ter Riet, Anne-Elie Carsin, Elena Gimeno-Santos, Alvar Agustí, Josep M. Antó, David Donaire-Gonzalez, Jaume Ferrer, Esther Rodríguez, Robert Rodriguez-Roisin, Milo A. Puhan, Judith Garcia-Aymerich
Journal: European Respiratory Journal (2018)

The vicious circle of dyspnoea-inactivity has been proposed, but never validated empirically, to explain the clinical course of chronic obstructive pulmonary disease (COPD). We aimed to develop and validate externally a comprehensive vicious circle model.We utilised two methods. 1) Identification and validation of all published vicious circle models by a systematic literature search and fitting structural equation models to longitudinal data from the Spanish PAC-COPD (Phenotype and Course of COPD) cohort (n=210, mean age 68 years, mean forced expiratory volume in 1 s (FEV
Abstract 19796: Vascular eNOS S-Glutathionylation is Increased in Hypertension and Atherosclerosis with eNOS uncoupling: Data from Animal Models and Human Aortic Tissue of Patients Undergoing Surgical Revascularization
Authors: Saradhadevi Varadharaj, Levy Reyes, Juan Crestenello, Ahmed Kilic, Hassan Talukder, Chun-An Chen, Jay L Zweier
Journal: Circulation (2012)

Background: In vascular diseases, including hypertension (HTN) and atherosclerosis, endothelial dysfunction (ED) occurs secondary to altered function of endothelial NO synthase (eNOS); however, questions remain regarding the mechanism by which this occurs and how it can be reversed. We recently identified a novel redox regulated pathway through which eNOS is uncoupled due to S-glutathionylation. In vessels from spontaneous hypertensive rats (SHR) and in aortic tissue from patients undergoing coronary bypass (CABG) surgery, we measure eNOS S-glutathionylation and its effect on eNOS coupling. Methods: Studies were performed in aortic, femoral and carotid vessels from adult SHR rats and in aortic tissue from patients undergoing CABG or other vascular surgery. S-glutathionylation of eNOS was studied using anti-glutathione antibody, anti-eNOS antibody and an antibody specific for eNOS C689 S-glutathionylation. NO and superoxide (•O2--) was measured using fluorescent probes CuFL and DHE, respectively, in the absence or presence of the NOS inhibitor, L-NAME, NO scavenger, PTIO, or the SOD mimetic, MnTBAP. Results &amp; Conclusion: Immunohistology and immunoblotting revealed increased eNOS S-glutathionylation in vessels of SHR rats compared to matched WKY controls. The reducing agent DTT reversed this glutathionylation and reversed the impairment in endothelial-dependent relaxation measured from aortic rings. Mass spectroscopy on immunoprecipitated eNOS demonstrated modification at C689 in aorta of SHR but not WKY rats. Immunohistology with a specific eNOS C689 S-glutathionylation antibody confirmed endothelial C689 S-glutathionylation. Decreased NO and increased •O2-- was seen in these vessels. In patients undergoing CABG, high levels of C689 S-glutathionylation was seen abolished by DTT. Thus, eNOS S-glutathionylation is increased in an animal model of HTN with resultant ED and present in patients with coronary disease undergoing bypass surgery.
Serum Lipids and Lipoproteins in Men after Myocardial Infarction compared with Representative Population Sample
Authors: Andersgustafson, Dagelmfeldt, Larswilhelmsen, Göstatibblin
Journal: Circulation (1972)

A nonselected series of 229 postmyocardial infarction (MI) patients was studied for up to 2 years following hospitalization. Their lipoprotein patterns, serum cholesterol, and triglyceride values were compared to those of a random population sample of men at comparable ages. Hyperlipoproteinemia, cholesterol, and triglyceride elevations were more common in MI patients than in men in the random sample, occurring with greatest frequency in the younger patients. There was a trend toward higher mortality among patients with hyperlipoproteinemia. Types II A and B were very common in young patients. Serum cholesterol values were significantly higher in the youngest patients and serum triglycerides higher than in the controls in age groups ≦ 40, 46-50, and 51-55 years.
Abstract 167: Targeting the NF-kappaB pathway with bardoxolone methyl to inhibit ovarian cancer spheroid formation
Authors: Michelle K. Ozaki, Carrie D. House, Krystyna Mazan-Mamczarz, Madhu Lal-Nag, Craig Thomas, Christina M. Annunziata
Journal: Cancer Research (2018)

Abstract Over 70% of patients with advanced stage ovarian cancer relapse within 2 years, with long term overall survival being only 25%. Tumor-initiating cells (TICs) are thought to contribute to this high rate of recurrence as they can resist killing by platinum-based chemotherapy. In this study we sought to identify pathways unique to TICs and to disrupt these pathways in order to more effectively target this population of cells. We conducted an siRNA screen which identified NF-kappaB signaling as an important pathway in the maintenance of ovarian cancer cells grown in non-adherent spheroid cultures that mimic TICs. Downregulation of several known NF-kappaB target genes, including NXF1, RAC2, CDC42, BCL2L1 and SERPINB3, significantly decreased growth of TIC cultures but not the corresponding adherent cultures, thereby indicating that expression of these genes is necessary for growth in TIC cultures. These findings are consistent with previous studies which showed that higher NF-kappaB activity is linked with drug resistance in patients. In parallel, we conducted a drug screen to identify compounds that target TICs. One clear candidate was bardoxolone methyl, which has been shown to inhibit IKK, an upstream NF-kappaB signaling protein. We confirmed the results of the drug screen in a panel of ovarian cancer cell lines, showing that bardoxolone methyl decreased known TIC markers CD133 and ALDH by flow cytometry, and decreased NF-kappaB proteins by western blot. To further elucidate the mechanism of bardoxolone methyl on TICs we conducted an RNAi screen +/- bardoxolone methyl. Interestingly, the knockdown of genes including BRAF, MAP3K8, LMNA and SMAD6 acted in a synthetically lethal manner with bardoxolone methyl in the TICs. To begin translating to a clinically relevant model, we proceeded to test whether bardoxolone methyl could eliminate TICs that remained after treatment with platinum-based chemotherapy. We confirmed in vitro that bardoxolone methyl in combination with chemotherapy reduced TIC populations. Our ongoing studies will address whether this drug is effective in preventing relapse in vivo after chemotherapy treatment of ovarian cancer in mouse models. Citation Format: Michelle K. Ozaki, Carrie D. House, Krystyna Mazan-Mamczarz, Madhu Lal-Nag, Craig Thomas, Christina M. Annunziata. Targeting the NF-kappaB pathway with bardoxolone methyl to inhibit ovarian cancer spheroid formation [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 167.