tbuckley/cabot-search huggingface dataset:
Abstract 877: Sigma 2 ligands kill pancreatic cancer cells via disruption of lysosomal cholesterol transport
Authors: Linda X. Jin, Suwanna Vangveravong, Narendra V. Sankpal, Darren R. Cullinan, Peter Goedegebuure, Dirk Spitzer, William G. Hawkins
Journal: Cancer Research (2018)

Abstract Introduction: The sigma 2 receptor is overexpressed in pancreatic cancer and has been an attractive target for development of cancer selective therapies. However, the mechanism of sigma 2 mediated cancer cell death remains elusive. The sigma 2 receptor has been recently identified as TMEM97, a lysosomal/endoplasmic reticulum protein involved in regulation of cholesterol export in conjunction with NPC1. Methods: Uptake of SW43 in pancreatic cancer cells was visualized using a NBD fluorophore conjugated ligand. Intracellular cholesterol staining was visualized using filipin staining. Protein expression was quantified by both Western blot and RT qPCR. Cell death was assayed in triplicate using Titer-Glo viability assay. Results: We hypothesized that sigma 2 ligands may kill pancreatic cancer cells through disruption of lysosomal cholesterol export. Using ASPC1 pancreatic cancer cells, we first demonstrate that sigma 2 ligand SW43 is rapidly taken up and targets to endo-lysosomal compartments, and that treatment with SW43 causes a rapid and dose dependent sequestration of cholesterol in lysosomal compartments as visualized by filipin cholesterol staining. This correlated to an increase in TMEM97 and corresponding decrease in NPC1 expression following SW43 treatment. We next demonstrate that this cholesterol sequestration phenotype is required for cell death, and might be related to the free amine side chain of SW43, as its N-phthalimide derivative fails to induce both lysosomal cholesterol sequestration and cell death despite high doses of ligand used. Lysosomal cholesterol sequestration from sigma 2 ligand treatment sensitizes cells to further targeting of cholesterol metabolism. Using low doses of simvastatin and SW43, we demonstrate that targeting both cholesterol export and cholesterol synthesis displays significant synergism in killing ASPC1 pancreatic cancer cells. Conclusions: These findings provide further insight into how the sigma 2 receptor/ligand interaction mediates cancer cell death and provides the basis for rationally combined targeted therapy regimens to be tested in vivo. This work was supported by NIH R01CA163764 and NIH T32CA009621-26A1 and the SUS Foundation Resident Research Award. Citation Format: Linda X. Jin, Suwanna Vangveravong, Narendra V. Sankpal, Darren R. Cullinan, Peter Goedegebuure, Dirk Spitzer, William G. Hawkins. Sigma 2 ligands kill pancreatic cancer cells via disruption of lysosomal cholesterol transport [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 877.
Exercise pulmonary haemodynamic response predicts outcomes in fibrotic lung disease
Authors: Arun Jose, Christopher S. King, Oksana A. Shlobin, A. Whitney Brown, Chengxi Wang, Steven D. Nathan
Journal: European Respiratory Journal (2018)

Pulmonary hypertension is diagnosed by an elevated mean pulmonary arterial pressure (mPAP) during resting right heart catheterisation (RHC) [1]. Although "exercise-induced pulmonary hypertension" is no longer a distinct clinical entity, recently, there has been renewed interest in the prognostic value of pulmonary haemodynamic responses to exercise, particularly in patients with fibrotic lung disease [1–4]. As the optimal use of exercise RHC in this cohort remains unknown, our main objective in this study was to study the relationship between exercise haemodynamics and outcomes in fibrotic lung disease patients [3–7]. Haemodynamic changes with exercise, including ΔmPAP/ΔCO, predict clinical worsening in fibrotic lung disease patients <http://ow.ly/uKno30lb5fF>
Insulin as a Vascular and Sympathoexcitatory Hormone
Authors: UrsScherrer, ClaudioSartori
Journal: Circulation (1997)

Abstract The past several years have witnessed a major surge of interest in the cardiovascular actions of insulin. This interest has stemmed on the one hand from epidemiological studies that demonstrated an association between obesity, insulin resistance, and hypertension, leading to the so-called insulin hypothesis of hypertension. On the other hand, this interest has been stimulated by experimental evidence suggesting that the vascular actions of insulin may play a role in its main action, namely the promotion of glucose uptake in skeletal muscle tissue. Two tenets have emerged about how insulin may exert its cardiovascular actions. First, it is now firmly established that acute insulin administration stimulates sympathetic nerve activity in both animals and humans. Second, there is increasing evidence that insulin stimulates muscle blood flow, an effect that appears to be mediated at least in part by an endothelium-dependent mechanism. This review summarizes the current understanding and gaps in knowle...
Expression of Costimulatory Molecule CD40 in Murine Heart With Acute Myocarditis and Reduction of Inflammation by Treatment With Anti-CD40L/B7-1 Monoclonal Antibodies
Authors: YoshinoriSeko, NaoyukiTakahashi, MiyukiAzuma, HideoYagita, KoOkumura, YoshioYazaki
Journal: Circulation Research (1998)

Abstract—Evidence has accumulated that antigen-specific T cells infiltrate the heart and play an important role in the pathogenesis of viral myocarditis. Costimulatory molecules such as B7s and CD40 expressed on antigen-presenting cells are known to play a critical role for antigen-specific T-cell activation to occur. To investigate the role for a costimulatory molecule, CD40, in the development of acute viral myocarditis, we first analyzed the expression of CD40 in the hearts of mice with acute viral myocarditis induced by Coxsackievirus B3. We also evaluated the induction of CD40 in cultured cardiac myocytes treated with interferon gamma in vitro. Second, we analyzed the cytokine production by cultured cardiac myocytes by stimulation with anti-CD40 monoclonal antibody (mAb) in vitro. Third, we examined the effects of in vivo administration of anti–CD40L/B7-1 mAbs on the development of acute viral myocarditis. We found that Coxsackievirus B3–induced murine acute myocarditis results in enhanced expression...
Abstract 15998: Inflammatory Cytokines and Kidney Dysfunction are Associated in Individuals With Hypertensive Emergency
Authors: Jose F Vilela-Martin, Days O Andrade, Luciana N Cosenso-Martin, Michele L Gregório, Moacir F Godoy, Doroteia R Souza, Juan C Yugar-Toledo
Journal: Circulation (2015)

Introduction: Chronic hypertension and kidney dysfunction are associated. However, scarce studies have evaluated the participation of the inflammatory process in the pathogenesis of acute elevation of blood pressure (BP) (characterized by hypertensive crisis - HC) and kidney dysfunction. Thus, this study had objectives: 1- to identify clinical profile and renal function of the individuals with HC, subdivided in urgency (HU) and hypertensive emergency (HE) and 2- to evaluate relationship between kidney function and inflammatory cytokines: interleukins (IL-1β, IL-6, IL-8, IL-18), tumoral necrosis factor (TNF-α) and anti-inflammatory cytokine 10 (IL-10) in subjects with HC (HU and HE). Methods: We studied 274 individuals: 74 normotensive (NT), 74 controlled hypertensive (CH), 50 with HU and 78 individuals with HE. The glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease equation (MDRD). The serum levels of cytokines were made by MULTIPLEX and ELISA technique. The Kruskall Wallis and Mann Whitney tests, and Spearman correlation were used for comparison between groups, with a significance level for p-value &lt;0.05. Results: The diastolic BP and heart rate were significantly higher in the HC group (120mmHg and 85bpm, respectively) compared to the CH group (75mmHg and 68 bpm, respectively). Individuals with HE were older. Potassium was significantly lower in HE group (4,2mEq/l) compared to NT, CH and HU groups (4.5, 4.4 and 4.4mEq/L, respectively; p&lt;0.05). The GFR was significantly lower in HE group (65ml/min/m2) in comparison to HU (73), CH (82) and NT (88mL/min/m2) (p&lt;0,001). All measured cytokines were significantly higher in patients with HE compared to NT and CH groups. It was observed negative correlation among GFR, diastolic BP, and creatinine for all the groups (p&lt;0,0001). There was also negative correlation between GFR and cytokines in HE individuals (p&lt;0,05). Conclusions: Individuals with HE present GFR reduction in comparison to others studied groups. It is also observed higher cytokines levels in HE group and negative correlation between GFR and inflammatory cytokines. This suggests the involvement of inflammatory cytokines in the pathogenesis of acute hypertensive event and kidney dysfunction.
Abstract 1129: Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian cancer
Authors: Kaitlyn A. Dorsett, Susan L. Bellis
Journal: Cancer Research (2018)

Abstract This study elucidates ST6Gal-I, a sialyltransferase, as a functional driver of a cancer stem cell (CSC) phenotype regulated by the stem cell transcription factor Sox2. ST6Gal-I is upregulated in 98% of ovarian cancers (OC); it functions to add an α2-6 sialic acid, a large, negatively charged sugar, to N-glycosylated proteins bound for the cell surface. Normal differentiated epithelia have very low expression of ST6Gal-I, however, expression is turned on in stem cell compartments and transformed tissues. Furthermore, our work has shown that ST6Gal-I plays a causal role in conferring hallmark CSC properties including greater tumor-initiating capabilities, promotion of recurrence, and resistance to tumor-associated stressors like chemotherapies, serum deprivation, and hypoxia. Even given this stark upregulation and apparent functional import of ST6Gal-I in cancers, very little work has been done to identify the transcriptional driver of ST6Gal-I expression. We identified that Sox2 and ST6Gal-I are both part of one of the most commonly enriched amplicons in human cancer, amplicon 3q26. We then examined the TCGA database and found that these two genes are co-amplified in 48/73 cancer cohorts, including ovarian cancer. In addition to being genetically co-amplified, Sox2 has been shown to bind to the promoter of ST6Gal-I, though no further analyses have been performed to assess a functional link. Herein we address a novel, glycosylation-dependent mechanism that drives a CSC phenotype. We hypothesize that Sox2, a key stem-associated transcription factor in CSCs, directly induces expression of ST6Gal-I. In our ovarian cancer cell model systems, we forced overexpression or knockdown of Sox2 and found that Sox2 expression directly correlated with ST6Gal-I expression. Overexpression or knockdown of Sox2 resulted in up- or down- regulation of CSC markers Oct4 and Nanog respectively. We then forced ST6Gal-I knockdown to inhibit the Sox2-induced ST6Gal-I upregulation and found that this prevented the enhanced expression of Oct4 and Nanog. Here we show that Sox2 requires ST6Gal-I expression to promote a CSC phenotype. Citation Format: Kaitlyn A. Dorsett, Susan L. Bellis. Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian 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 1129.
Abstract 2410: RIPK1-mediated induction of mitophagy compromises the viability of extracellular matrix-detached cells
Authors: Mark A. Hawk, Zachary T. Schafer
Journal: Cancer Research (2018)

Abstract For cancer cells to survive during ECM-detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to ROS generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a novel role for receptor-interacting protein kinase-1 (RIPK1) in the modulation of mitochondrial ROS levels and cell viability during ECM-detachment. We find that RIPK1 activation during ECM-detachment results in the induction of PINK1-dependent mitophagy through a mechanism requiring the mitochondrial phosphatase PGAM5. As a consequence of mitophagy induction, ECM-detached cells experience diminished IDH2-mediated NADPH production in the mitochondria and the subsequent elevation in mitochondrial ROS levels leads to non-apoptotic cell death. Furthermore, we find that antagonizing RIPK1 or PGAM5 enhances tumor formation in vivo. Intriguingly, upon mining a meta-analysis of published lung cancer patient microarray data sets, we find that low RIPK1 expression in lung cancer patients correlates with decreased overall and progression-free survival. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for novel therapeutics aimed at specifically eliminating ECM-detached cancer cells and deterring tumor progression. Citation Format: Mark A. Hawk, Zachary T. Schafer. RIPK1-mediated induction of mitophagy compromises the viability of extracellular matrix-detached 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 2410.
Abstract 1142: STK31 contributes to lung carcinogenesis through induction of stemness and resistance to EGFR-TKI therapy
Authors: Eunice Yuen-Ting Lau, Isabella Kit-Nam Chin, Alvin Hong-Wai Fong, Victor Wan-San Ma, William Chi-Shing Cho
Journal: Cancer Research (2018)

Abstract Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer, remains one of the leading causes of cancer-related deaths worldwide. With improving knowledge in the molecular aberrations underlying lung carcinogenesis, a large number of targeted therapies are being developed to better patient's survival. EGFR-activating mutations are one of the most frequent genetic alterations in advanced lung adenocarcinoma, and patients harbouring certain types of EGFR activating mutation confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite promising initial responses, majority of patients develop resistance to treatment and the mechanism of resistance remains unknown in up to 30% of patients. Recent studies revealed that cancer stem cells (CSCs) endowed with stem cell-like properties confer resistance to EGFR-TKI treatment. Identification of pathways maintaining stemness properties potentially provide novel drug targets to overcome treatment resistance. Protein phosphorylation is the most common form of reversible post-translational modification and is frequently involved in the deregulation of signal transductions associated with cancer development and progression. In this study, we have identified Serine/Threonine Kinase 31 (STK31) to be upregulated in enriched lung CSC populations, as well as in the erlotinib resistant derivatives from two LUAD cell lines. Through analysing The Cancer Genome Atlas (TCGA) data, mRNA expression of STK31 is observed to be higher in LUAD tumor when compared with paired normal tissues (p&amp;lt;0.001). High mRNA expression of STK31 was also found to be associated with poorer disease-free survival (p=0.0324) and overall survival (p=0.0012) in LUAD patients. Functional studies using shRNA based knockdown of STK31 in lung cancer cell lines revealed its regulatory role on cancer and stem cell-like properties in vitro and in vivo including tumorigenicity, self-renewal, drug resistance and metastasis. Repressing the expression of STK31 in erlotinib resistant cells re-sensitized the cells to drug treatment. Further studies will be done to delineate the downstream mechanism by which STK31 regulates lung CSCs and erlotinib resistance. Citation Format: Eunice Yuen-Ting Lau, Isabella Kit-Nam Chin, Alvin Hong-Wai Fong, Victor Wan-San Ma, William Chi-Shing Cho. STK31 contributes to lung carcinogenesis through induction of stemness and resistance to EGFR-TKI therapy [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 1142.
Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology
Authors: DanshiLi, PeterMelnyk, JianlinFeng, ZhiguoWang, KevinPetrecca, AlvinShrier, StanleyNattel
Journal: Circulation (2000)

Background—Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. Methods and Results—We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean±SEM capacitance, 89±2 pF versus 71±2 pF in control, n=160 cells per group, P<0.001). CHF significantly reduced the density of L-type Ca2+ current (ICa) by ≈30%, of transient outward K+ current (Ito) by ≈50%, and of slow delayed rectifier current (IKs) by ≈30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca2+ currents were not altered by CHF. CHF increased transient inward Na+/Ca2+ exchanger (NCX) current by ≈45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster ...
Abstract 11198: Heritability of Vascular Structure and Function: A Parent-child Study
Authors: Justin R Ryder, Nathan D Pankratz, Donald R Dengel, James S Pankow, David R Jacobs, Alan R Sinaiko, Vasu Gooty, Julia Steinberger
Journal: Circulation (2016)

Introduction: Vascular structure and function can be measured non-invasively in both children and adults. Understanding the heritability of these measures may aid in risk stratification and atherosclerosis prevention efforts. Data on the heritable contribution from parent to offspring for vascular measures are limited. Hypothesis: We hypothesized that measures of vascular structure and function would be modestly heritable in this large parent-child study. Methods: High-resolution ultrasound scans of the brachial and carotid arteries were obtained in parents (n=558; mean age=39.2±2.1) and their offspring (n=369; mean age 12.4±4.6). In the brachial artery, flow-mediated dilation (FMD) and lumen diameter (bLD) were measured. In the carotid artery, intima-media thickness (cIMT), lumen diameter (cLD), incremental elastic modulus (cIEM), diameter distensibility (cDD), and cross-sectional distensibility were measured (cCSD). Carotid-radial pulse wave velocity (PWV) was also obtained. Heritability analysis (h 2 , expressed as %) was performed using SOLAR on the entire cohort and adjusted for age, gender, race, body-mass index, smoking, and systolic blood pressure. Data are presented as mean (SE). Results: Measures of bLD (h 2 = 25.2(8.6), p&lt;0.001), cLD (h 2 = 55.4(8.8), p&lt;0.001), cIMT (h 2 = 28.1(12.6), p=0.014), cDD (h 2 = 28.2(7.1), p&lt;0.001), cCSD (h 2 = 27.1(6.9), p&lt;0.001), and PWV (h 2 = 26.3(8.9), p&lt;0.001) were significantly heritable. Only FMD (h 2 = 1.6(8.4), p=0.44), and cIEM (h 2 = 12.7(9.3), p=0.081) were not significantly heritable. Conclusions: These data suggest that the majority of non-invasive measures of vascular structure and function are modestly heritable from parent to child. Early interventions targeted at youth with elevated vascular risk and/or a high familial cardiovascular risk profile may be able to modify vascular structure and function to prevent further dysfunction as these children transition into adulthood.
Incidence, Causes, and Survival Trends From Cardiovascular-Related Sudden Cardiac Arrest in Children and Young Adults 0 to 35 Years of Age
Authors: LaurenMeyer, BenjaminStubbs, CarolFahrenbruch, ChrisMaeda, KimberlyHarmon, MickeyEisenberg, JonathanDrezner
Journal: Circulation (2012)

Background—Sudden cardiac arrest is a leading cause of death in children and young adults. This study determined the incidence, cause, and outcomes of cardiovascular-related out-of-hospital cardiac arrest (OHCA) in individuals <35 years of age. Methods and Results—A retrospective cohort of OHCA in children and young adults from 1980 through 2009 was identified from the King County (Washington) Division of Emergency Medical Services' Cardiac Arrest Database. Incidence was calculated from population census data and causes of arrest determined by review of autopsy reports and all available medical records. A total of 361 cases (26 cases 0–2 years of age, 30 cases 3–13 years of age, 60 cases 14–24 years of age, and 245 cases 25–35 years of age) of OHCA were treated by emergency medical services responders, for an overall incidence of 2.28 per 100 000 person-years (2.1 in those 0–2 years of age, 0.61 in those 3–13 years of age, 1.44 in those 14–24 years of age, and 4.40 in those 25–35 years of age). The most c...
Abstract 2111: The tumor microenvironment of preclinical tumor models may have an impact on the therapeutic index of nanotherapeutics
Authors: Stephane Ferretti, Nicolau Beckmann, laura Holzer, Michael Obrecht, Marjorie Berger, Michael Rugaard Jensen
Journal: Cancer Research (2018)

Abstract Rapid development in nanotechnology allows the incorporation of multiple therapeutic agents (e.g. liposomes) into nanoparticle with a size range from 1 to 1000 nm. These nanocarrier systems provide new approaches to treat aggressive malignancy. Nano-based delivery systems hold an advantage over traditional small molecule therapy in that they can deliver drugs preferentially to tumors due to the enhanced permeability and retention (EPR) effect. On one hand, high permeability of the tumor vessels and a lack of functional lymphatic vessels results in the EPR effect, driving nanoparticle extravasation. On the other hand, these phenomena lead to high interstitial fluid pressure (IFP), limiting nanoparticle extravasation. In this study, we have used dynamic-contrast enhanced (DCE) MRI with small (Dotarem, 5 nm) and large (Vistarem, 25 nm) contrast agents (CAs) to examine tumor vessel permeability in SJSA-1 osteosarcoma tumor-bearing rats. An inversion-recovery true fast imaging with steady state precession (TrueFISP) was employed to determine the transfer constant Ktrans in subcutaneous and intra-tibia tumor models. When the tumor cells were injected in both niches within the same animal, Ktrans was significantly lower in intra-tibia tumors with both CAs, and blood vessels significantly less and larger compared to subcutaneous tumors. Moreover, Ktrans negatively correlated with tumor bioluminescence for the intra-tibia model, suggesting that EPR decreased inversely with tumor size, while the opposite was noticed for the subcutaneous tumors. These data demonstrate for the first time that the EPR of tumors with a similar size within the same animal can be influenced by the microenvironment. Moreover, they show that the therapeutic index of a nanotherapeutics may be different if it's determined with either an orthotopic or ectopic model. Citation Format: Stephane Ferretti, Nicolau Beckmann, laura Holzer, Michael Obrecht, Marjorie Berger, Michael Rugaard Jensen. The tumor microenvironment of preclinical tumor models may have an impact on the therapeutic index of nanotherapeutics [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 2111.