tbuckley/cabot-search huggingface dataset:
Abstract 4025: An old foe with a new function: JAM-A regulates expression of EphB4 and inhibitor of apoptosis proteins in breast cancer
Authors: Sri HariKrishna Vellanki, Rodrigo G. Cruz, Cathy E. Richards, Kieran Brennan, Ann M. Hopkins
Journal: Cancer Research (2018)

Abstract Over-expression of Junctional Adhesion Molecule-A (JAM-A) in breast tumors has been linked with increased risk of metastasis. Since JAM-A is co-expressed with the receptor tyrosine kinase (RTK) HER2 and regulates HER2 protein expression, we hypothesized that JAM-A regulates the expression and function of other RTKs. Using a joint RT-PCR array/western blot approach in three breast cell lines with modified JAM-A expression, we identified EphB4 as a downstream target of JAM-A. Interestingly, EphB4 gene silencing also cross-regulated the protein expression of JAM-A. Immunofluorescence analysis revealed colocalisation of JAM-A and EphB4 at the cell membrane. Since JAM-A contains a PDZ-binding motif and EphB4 contains a PDZ domain, we speculated that this might underlie the basis of an interaction. Accordingly, overexpression of a JAM-A mutant lacking the PDZ domain failed to upregulate EphB4 expression to the same extent as wild type JAM-A. Next we investigated the signalling events downstream of JAM-A and EphB4 and found downregulation of the tight junction protein ZO-1 in breast cells silenced for JAM-A or EphB4. Using a bioinformatics approach, we identified the transcription factor c-FOS as a potential regulator of JAM-A and EphB4 expression. In JAM-A- or EphB4-silenced cells, c-FOS expression was not localized in the nucleus (relative to cells transfected with negative control siRNAs). Furthermore, ERK5 phosphorylation was inhibited in JAM-A- or EphB4-silenced cells, suggesting a mechanism for reduced c-FOS phosphorylation on Serine-32 and its consequent exclusion from the nucleus. In the context of a proposed block on c-FOS transcriptional activity, we examined the genes affected and show for the first time downregulation of inhibitor of apoptosis proteins (IAPs) in JAM-A- or EphB4-silenced cells. In conclusion, our data are consistent with a model whereby JAM-A regulates EphB4 expression in a PDZ-dependent manner and influences apoptosis via a pathway involving ERK5 and c-FOS. Our data suggest that the pharmacological antagonism of JAM-A in JAM-overexpressing breast cancers merits consideration by virtue of its predicted ability to downregulate EphB4 expression and remove a blockade on apoptosis. Citation Format: Sri HariKrishna Vellanki, Rodrigo G. Cruz, Cathy E. Richards, Kieran Brennan, Ann M. Hopkins. An old foe with a new function: JAM-A regulates expression of EphB4 and inhibitor of apoptosis proteins in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4025.
Abstract 3171: Vangl2 regulates cancer stem cell self-renewal and growth in rhabdomyosarcoma
Authors: Madeline Hayes, Karin McCarthy, Alexander Jin, Sowmya Iyer, Sara Garcia, Mariana L. Oliveira, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G Petur Nielsen, Jean-Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron Ignatius, David M. Langenau
Journal: Cancer Research (2018)

Abstract Growth and relapse are driven by cancer stem cells (CSCs) in a subset of tumors, yet mechanisms driving cancer cell fate choices, maintenance and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity pathway (Wnt/PCP), regulates CSCs self-renewal in human rhabdomyosarcoma (RMS) – a common pediatric cancer of muscle. Wnt/PCP signaling is essential during development and recent work has linked this pathway to cancer growth, invasion and metastasis. However, roles for Vangl2 in regulating tumor self-renewal have not been previously described. Here, we show that VANGL2 is expressed in a majority of human RMS, specifically within early mononuclear progenitor-like cells. VANGL2 depletion inhibited proliferation, reduced self-renewal, and induced differentiation of human RMS. VANGL2 was also required for continued tumor growth and maintenance following engraftment of human RMS using mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS) and limiting dilution cell transplantation approaches, we identified that Vangl2 expression enriches for CSCs in vivo and when transgenically expressed, at high levels elevates cancer stem cell number by 9-fold. Mechanistic studies revealed a role for RhoA downstream of Vangl2 in regulating maintenance of stem cell programs in human RMS. Our studies offer novel opportunities to isolate and characterize RMS cancer stem cells in vivo, and identify potential therapeutic targets for patient treatment. Citation Format: Madeline Hayes, Karin McCarthy, Alexander Jin, Sowmya Iyer, Sara Garcia, Mariana L. Oliveira, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G Petur Nielsen, Jean-Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron Ignatius, David M. Langenau. Vangl2 regulates cancer stem cell self-renewal and growth in rhabdomyosarcoma [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 3171.
Tumor Necrosis Factor-α Inhibits Insulin’s Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans
Authors: ChristianRask-Madsen, HelenaDomínguez, NikolajIhlemann, ThomasHermann, LarsKøber, ChristianTorp-Pedersen
Journal: Circulation (2003)

Background— Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-α inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Methods and Results— Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-α were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF-α (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-α inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (...
Inhibition of Intimal Hyperplasia After Balloon Injury by Antibodies to Intercellular Adhesion Molecule-1 and Lymphocyte Function–Associated Antigen-1
Authors: HideoYasukawa, TsutomuImaizumi, HidehiroMatsuoka, AkihikoNakashima, MinoruMorimatsu
Journal: Circulation (1997)

Background Although intercellular adhesion molecule-1 (ICAM-1) is known to be expressed in balloon-injured arteries, it remains unknown whether ICAM-1 plays a role in the progression of intimal hyperplasia (IH) induced by balloon injury. Methods and Results We examined the ICAM-1 expression in rat carotid arteries at 1, 2, 5, 7, 10, and 14 days after injury by immunohistochemistry. Medial smooth muscle cells (SMC) expressed ICAM-1 intensely at 1 to 2 days after injury. The regenerating endothelial cells expressed ICAM-1 more than did those of intact carotid arteries. To investigate the effects of monoclonal antibodies (MAbs) on IH, we examined the intima/medial ratio of arteries at 2 weeks after injury in five treatment groups: nonimmune IgG, anti-membrane glycoprotein MAb, anti–lymphocyte function–associated antigen-1 (LFA-1) MAb, anti–ICAM-1 MAb, and anti–ICAM/LFA-1 MAb. Treatments were administered intravenously into rats for 6 consecutive days after injury. MAb against LFA-1 alone or membrane glycopro...
Letter by Gasparini Regarding Article, “Syncope in High-Risk Cardiomyopathy Patients With Implantable Defibrillators: Frequency, Risk Factors, Mechanisms, and Association With Mortality: Results From the Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy (MADIT-RIT) Study”
Authors: MaurizioGasparini
Journal: Circulation (2014)
Indirect Assessment of Left Ventricular Performance in Acute Myocardial Infarction
Authors: Bernarddiamant, Thomaskillip, StuartSeides, RexStanbridge
Journal: Circulation (1970)

One hundred patients admitted to a cardiac care unit had indirect serial determinations of left ventricular systolic ejection times. Patients were divided into groups with transmural infarction, nontransmural infarction, and no infarction, according to clinical, biochemical, and electrocardiographic criteria. Total electromechanical systole and left ventricular ejection time were shortened in acute myocardial infarction, whereas the pre-ejection period and its components, the Q-S1 and isovolumic contraction time intervals, were prolonged. The most abnormal measurements were observed in patients with transmural infarction. Patients with nontransmural infarction demonstrated less severe abnormalities of the systolic ejection times, and the patients without infarction were the least affected. Some of the greatest deviations in the measured intervals were observed in the transmural infarction patients who died. Indirect measurement of left ventricular systolic ejection time is a valuable adjunct in the bedsid...
Nitric Oxide and C-Type Atrial Natriuretic Peptide Stimulate Primary Aortic Smooth Muscle Cell Migration via a cGMP-Dependent Mechanism
Authors: ClaireBrown, XiaoleiPan, AvivHassid
Journal: Circulation Research (1999)

Abstract—Migration of aortic smooth muscle cells is thought to be of essential importance in vascular restenosis, remodeling, and angiogenesis. Recent studies have shown that NO donors inhibit the migration of subcultured aortic smooth muscle cells. However, there is evidence that NO elicits opposite effects on cell proliferation in primary versus subcultured cells, indicating fundamental differences among different models of aortic smooth muscle cell cultures. The purpose of the current study was to investigate the effect of NO donors on migration of primary cultures of rat aortic smooth muscle cells and to compare and contrast their response with those in subcultured cells. A second purpose was to investigate some of the underlying mechanisms associated with NO-induced effects on cell migration. We report that 2 NO donors, S-nitroso-N-acetylpenicillamine (SNAP) and 2,2-(hydroxynitrosohydrazino)bis-ethanamine, stimulated the migration of primary cells in a wounded-culture model as well as in a transwell ...
Abstract 13539: Functional Evaluation in Aortic Stenosis: Determinant of Exercise Capacity
Authors: Francesco Bandera, Greta Generati, Marta Pellegrino, Valentina Labate, Francesco Carbone, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2015)

Background: Aortic stenosis (AS) is clinically characterized by dyspnea and intolerance to exercise. Clinical interpretation of such symptoms is often difficult due to the advanced age of AS patients. We aimed at identifying cardiac determinants of exercise intolerance in AS (Aortic Vmax &gt;3 m/s). Methods and results: We performed cardiopulmonary exercise test (CPET) simultaneously combined with exercise echocardiography in 43 patients with AS referred for functional assessment. Severe AS were evaluated because of symptoms not certainly related to valvular disease. Patients underwent a symptoms-limited maximal exercise, considering the 75% of predicted VO2 consumption as a marker of preserved functional capacity. Twenty-three patients had preserved functional capacity (group A), showing higher work, maximal VO2, O2 pulse and better VE/VCO2 and heart rate recovery. No differences were found in terms of rest systolic function and AS severity, while group A had higher peak heart rate (HR), higher peak cardiac power output (cardiac output x systolic pressure) and higher peak-rest transaortic mean gradient difference (ΔMG). At multivariate analysis, only ΔMG resulted independently associated with impaired functional capacity (p =0.048; CI 1.001-1.323). Conclusions: AS patients can present functional impairment which is related to cardiac response to exercise rather than to stenosis severity. These results suggest the role of inotropic and contractile reserve supporting the routinely evaluation of cardiac reserve as a determinant of symptoms development.
Abstract 1509: Cachexia: Leveraging transcriptomics to identify potential therapeutics
Authors: Matthew Ung, Kevin D. Fowler, Jason M. Funt, Renan Escalante-Chong, Gregory Koytiger, Sarah Kolitz, Rebecca L. Kusko, Benjamin Zeskind
Journal: Cancer Research (2018)

Abstract Cachexia is a common cause of morbidity across multiple cancer types, yet remains largely under-studied especially in the realm of transcriptomics. An essential component of cancer cachexia is the induced transition of adipocytes from white to brown, which increases energetic inefficiency and contributes to systemic loss of adipose tissue. This is likely caused by the tumor secreting thermo-stimulatory factors into the extracellular space. Here, we integrate publicly-available data to pinpoint actionable gene targets that enable cancer cells to induce fat “browning”. In particular, we identify genes differentially expressed between Lewis lung carcinoma subclones that can induce thermogenesis in primary adipocytes at high or low levels in vitro (GSE57797). We then evaluate whether the expression of these thermo-stimulatory genes predict patient survival in an independent gene expression dataset of primary tumors from advanced stage gastric cancer patients (GSE15459). Finally, we leverage drug gene expression data from CMAP and LINCS to identify molecules that reverse the thermo-stimulatory signature. Our analysis reveals that the thermo-stimulatory signature predicts prognosis in patients with advanced gastric cancer (p=0.005), with the low thermo-stimulatory group exhibiting improved prognosis. The thermo-stimulatory signature is most strongly reversed by expression signatures from inhibitors of MEK (MAP2K1), including pd-0325901, AZD-8330 (ARRY-704), CI-1040, trametinib, and selumetinib. Interestingly, we observe a time-dependent effect of these MEK inhibitors, with shorter durations of exposure consistently reversing thermo-stimulatory signatures more effectively than longer durations of exposure. Analysis of cachexia-related transcriptomic data reveals key marker genes and pathways which can be used to optimize MEK inhibitors for cachexia. Results from this study support the development of MEK inhibitors to treat cachexia, and suggest that careful optimization of pharmacokinetics will be important for success in the clinic. Citation Format: Matthew Ung, Kevin D. Fowler, Jason M. Funt, Renan Escalante-Chong, Gregory Koytiger, Sarah Kolitz, Rebecca L. Kusko, Benjamin Zeskind. Cachexia: Leveraging transcriptomics to identify potential therapeutics [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 1509.
Abstract A31: Mutant p53 increases integrin-ECM interactions in early HGSOC
Authors: Laura SM Lecker, Caterina Trevisan, Robin Delaine-Smith, Eleni Maniati, Oliver Pearce, Christoph Meinert, Marcin Iwanicki, Ronny Drapkin, Daniela Loessner, Frances Balkwill
Journal: Clinical Cancer Research (2018)

Abstract Until recently, it was thought that high-grade serous ovarian cancer (HGSOC) arises from the ovarian surface epithelium (OSE). Now, it has become clear that the epithelium of the fallopian tube fimbriae is the starting point of many HGSOCs. Serous tubal intraepithelial carcinomas (STICs) are suggested to be the earliest form of HGSOC and show mutations in the p53 gene. Part of the neoplastic transformation into invasive HGSOC may be the initial adhesion of STIC cells to the surface of the ovary as a first site of metastasis. To examine the role of mutant p53 immortalized fallopian tube secretory epithelial (FTSE) cells in the early onset of HGSOC, we used mechanically tunable hydrogels and developed a protocol to obtain decellularized human ovary scaffolds for 3D cell cultures. Stable expression of mutant p53 in FTSE cells promoted adhesion to hydrogel matrices and invasion into decellularized ovary scaffolds. Next, we sought to analyze the extracellular matrix (ECM) landscape of human fallopian tube and ovary tissues and identified proteins with a high affinity to integrin αvβ3. Mutant p53 FTSE cells had increased levels of integrin αvβ3 and decreased adhesive potential upon integrin αvβ3 blockage compared to wild-type FTSE cells. The results indicate that FTSE cells expressing mutant p53 upregulate integrin expression, which in turn alters their tissue-specific ECM interactions. Our findings give new insights in the early onset of HGSOC and may help to understand the role of p53 in the cells of origin of HGSOC. Citation Format: Laura SM Lecker, Caterina Trevisan, Robin Delaine-Smith, Eleni Maniati, Oliver Pearce, Christoph Meinert, Marcin Iwanicki, Ronny Drapkin, Daniela Loessner, Frances Balkwill. Mutant p53 increases integrin-ECM interactions in early HGSOC. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A31.
Epigenetic immune cell counting in human blood samples for immunodiagnostics
Authors: Udo Baron, Jeannette Werner, Konstantin Schildknecht, Janika J. Schulze, Andargaschew Mulu, Uwe-Gerd Liebert, Ulrich Sack, Carsten Speckmann, Manfred Gossen, Ronald J. Wong, David K. Stevenson, Nina Babel, Dirk Schürmann, Tina Baldinger, Rosa Bacchetta, Andreas Grützkau, Stephan Borte, Sven Olek
Journal: Science Translational Medicine (2018)

Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3+ T, CD8+ T, CD4+ T, and FOXP3+ regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.
Abstract 1705: Systemic analysis of innate responses to anti-PD1/PD-L1 treatment in a melanoma model
Authors: Rodrigo Gassen, Alana Welm, Cristina Bonorino
Journal: Cancer Research (2018)

Abstract Response to anti-PD1 therapy for tumors is often thought to target T cells, directly and exclusively. However, while some patients, even with metastasis, respond completely, most patients do not respond to treatment as predicted. The mechanisms of response ad resistance to anti-PD-1 therapy need to be elucidated, in order to optimize treatment and prevent unnecessary adverse effects. Most innate cells, especially in tumor bearing individuals, express PD-1, not only in the tumor microenvironment, but systemically. Among those are macrophages and dendritic cells. The implications of PD-1 expression by these cells in their immune function are still unknown, and so are the signaling pathways activated by agonists or antagonists of this receptor. Although recent data suggest that PD-1+ tumor associated macrophages (TAMs) promote advanced tumor growth, little is known of the kinetics of PD-1 expression by innate cells during tumor progression. Using an immunocompetent murine melanoma model, we characterized PD-1 and PD-L1 expression in different innate cells, in lymphoid organs, blood, and tumor microenvironment. In NSG mice, using PDX grafts of triple negative breast cancers, we determined that such expression is independent of lymphocytes and NK cells. Treatment with anti-PD-1 mobilized an early (7 days) wave of DC migration that can be seen in the blood, preceding a CD4+ T cell mobilization that peaked ad day 14 after treatment. These early responses correlated with CD8+ T cell infiltration to the tumor microenvironment as well as tumor regression. PD-1 expression and migration in the blood was different among the DC subpopulations, and anti-PD-1 treatment enhanced survival as well as activation of dendritic cells. These findings are relevant to understanding the different outcomes of immunotherapy with anti-PD-1 and anti-PD-L1. Citation Format: Rodrigo Gassen, Alana Welm, Cristina Bonorino. Systemic analysis of innate responses to anti-PD1/PD-L1 treatment in a melanoma model [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 1705.