tbuckley/cabot-search huggingface dataset:
Abstract 5702: Characterization of circulating tumor cells during immune checkpoint inhibition in metastatic renal cell carcinoma and malignant melanoma
Authors: Tian Zhang, SinJung Park, Daniella Runyambo, Michael J. Poellmann, Marco Reyes-Martinez, Zahra Mahbooba, Rebecca Green, Carrie Lee, Daniel J. George, Andrew J. Armstrong, Seungpyo Hong, Andrew Z. Wang
Journal: Cancer Research (2018)

Abstract Background: Although immune checkpoint inhibitors (ICIs) have shown efficacy in a range of solid tumors, there are no established circulating biomarkers able to identify early responders to treatment. Circulating tumor cells (CTCs) allow a non-invasive peripheral assessment of disease burden over time. We evaluated the prevalence of CTCs before and during treatment with ICIs. Methods: Patients were enrolled prospectively at Duke Cancer Center and UNC Lineberger Cancer Center and selected for metastatic renal cell carcinoma (mRCC) and metastatic malignant melanoma (mMM) receiving standard of care immunotherapy. Using E-selectin for slowing cell rolling and a nanoparticle dendrimer based technology for cell capture with EpCAM, HER2, and EGFR, the CapioCyte platform was used for CTC capture at baseline, during treatment, and upon disease progression. Results: We enrolled 5 subjects with mRCC and 4 subjects with mMM. Prior to treatment, subjects had a median of 293 CTCs/mL (all healthy volunteers (HVs, n=10) had &amp;lt;8 CTCs/mL). All subjects had more CTCs at baseline than HVs. One subject had CTCs rise within the first 4 weeks on ICI treatment, which corresponded to clinical disease progression. Several other subjects showed a rapid decrease in CTCs within 4 weeks but increased at the time of disease progression. In most cases of disease control, CTCs decreased by at least 50% at the 4-week timepoint and increased at time of disease progression. Conclusions: CapioCyte is a sensitive platform to detect CTCs in mRCC and mMM. Based on CTC detection, many patients had early response to ICI treatment, but rapid progression corresponding to clinical progression. This pilot data suggest that CTCs can be a valuable biomarker for monitoring the clinical benefit of cancer immunotherapies. Citation Format: Tian Zhang, SinJung Park, Daniella Runyambo, Michael J. Poellmann, Marco Reyes-Martinez, Zahra Mahbooba, Rebecca Green, Carrie Lee, Daniel J. George, Andrew J. Armstrong, Seungpyo Hong, Andrew Z. Wang. Characterization of circulating tumor cells during immune checkpoint inhibition in metastatic renal cell carcinoma and malignant melanoma [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 5702.
Arrestin Orchestrates Crosstalk Between G Protein-Coupled Receptors to Modulate the Spatiotemporal Activation of ERK MAPK
Authors: DavidCervantes, CatherineCrosby, YangXiang
Journal: Circulation Research (2010)

Rationale: G protein-coupled receptors (GPCRs) respond to diversified extracellular stimuli to modulate cellular function. Despite extensive studies investigating the regulation of single GPCR signaling cascades, the effects of concomitant GPCR activation on downstream signaling and cellular function remain unclear. Objective: We aimed to characterize the cellular mechanism by which GPCR crosstalk regulates mitogen-activated protein kinase (MAPK) activation. Methods and Results: Adrenergic receptors on cardiac fibroblasts were manipulated to examine the role of arrestin in the spatiotemporal regulation of extracellular signal-regulated kinase (ERK)1/2 MAPK signaling. We show a general mechanism in which arrestin activation by one GPCR is capable of regulating signaling originating from another GPCR. Activation of Gq coupled-receptor signaling leads to prolonged ERK1/2 MAPK phosphorylation, nuclear accumulation, and cellular proliferation. Interestingly, coactivation of these receptors with the β-adrenergi...
Abstract 18465: Human Adipose-Derived Stem Cells for a Vascular Graft
Authors: Julien H Arrizabalaga, Matthias U Nollert
Journal: Circulation (2013)

The objective of this study is to fabricate a small-diameter tissue engineered blood vessel (TEBV) by using human adipose-derived stem cells (ADSC) in combination with the human amniotic membrane as a mechanically-sound biological substrate. Our technology begins by differentiating adipose-derived stem cells into smooth muscle cells (SMC) and seeding them onto a flat sheet of the amniotic membrane. We assessed our hypothesis that several types of SMC can successfully attach and proliferate on this membrane by fluorescently staining cell nuclei with DAPI and characteristic SMC actin filaments with phallotoxins. The cell-seeded sheet was then wrapped around a 3mm O.D. removable mandrel with 6 revolutions. Human fibrinogen and thrombin were applied to glue the layers together and develop a tubular construct with architecture akin to that of a muscular artery’s tunica media layer. The mechanical integrity of this construct can be further improved upon its exposure to appropriate physiological conditions in a perfusion bioreactor. ADSC can also be differentiated into endothelial cells and seeded into the lumen of this construct to prevent platelet adhesion. The TEBV was characterized for its biochemical and mechanical properties. We examined the vasoactive properties of the vessel in response to agonists such as carbachol, norepinephrine and histamine, and compared our results with porcine coronary arteries. Burst pressure and elastic modulus tests were also performed. In conclusion, adipose-derived stem cells are a viable cell line for differentiation into smooth muscle cells and endothelial cells and may be used in tissue engineering of blood vessels. We have developed a small-diameter TEBV with off-the-shelf availability using a completely biological material seeded with patient-own stem cells.
The Clinical Impact of Comprehensive Genomic Testing of Circulating Cell-Free DNA in Advanced Lung Cancer
Authors: Smadar Laufer-Geva, Anna Belilovski Rozenblum, Tal Twito, Roxana Grinberg, Addie Dvir, Lior Soussan-Gutman, Maya Ilouze, Laila C. Roisman, Elizabeth Dudnik, Alona Zer, Ofer Rotem, Richard B. Lanman, Nir Peled
Journal: Journal of Thoracic Oncology (2018)
Ribozyme Oligonucleotides Against Transforming Growth Factor-β Inhibited Neointimal Formation After Vascular Injury in Rat Model
Authors: KeiYamamoto, RyuichiMorishita, NaruyaTomita, TakashiShimozato, HironoriNakagami, AkiraKikuchi, MotokuniAoki, JitsuoHigaki, YasufumiKaneda, ToshioOgihara
Journal: Circulation (2000)

Background—Because the mechanisms of atherosclerosis or restenosis after angioplasty have been postulated to involve an increase in transforming growth factor (TGF)-β, a selective decrease in TGF-β may have therapeutic value. Thus, we used the ribozyme strategy to actively cleave the targeted gene to selectively inhibit TGF-β expression. Methods and Results—We constructed ribozyme oligonucleotides (ONs) targeted to the sequence of the TGF-β gene that shows 100% homology among the human, rat, and mouse species. The specificity of ribozyme against TGF-β gene was confirmed by selective inhibition of TGF-β mRNA in cultured vascular smooth muscle cells as well as balloon-injured blood vessels in vivo. Importantly, the marked decrease in TGF-β resulted in significant inhibition of neointimal formation after vascular injury in a rat carotid artery model (P<0.01), whereas DNA-based control ONs and mismatched ribozyme ONs did not have any inhibitory effect on neointimal formation. Inhibition of neointimal formatio...
Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters
Authors: YasunoriMatsumoto, HajimeAihara, RikakoYamauchi-Kohno, YoshieReien, TakehikoOgura, HideoYabana, YoshiakiMasuda, ToshiakiSato, IsseiKomuro, HaruakiNakaya
Journal: Circulation (2002)

Background— The endothelin (ET) system is activated in failing hearts. Congestive heart failure frequently is associated with ventricular arrhythmias, which may result from electrical remodeling such as changes of ionic current density and heterogeneous action potential prolongation. We examined the effects of long-term ETA receptor blockade on the electrophysiological properties of ventricular cells, the surface ECG, and the survival in BIO 14.6 cardiomyopathic hamsters. Methods and Results— Membrane currents and action potentials were recorded from left ventricular cells isolated from normal F1β hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ETA receptor antagonist. In ventricular cells of untreated BIO 14.6 hamsters, the action potential duration was prolonged and the densities of the L-type Ca2+ current (ICa,L), the transient outward current (Ito), the delayed rectifier K+ current (IK), and the inward rectifier K+ current (IK1) were decreased compared...
Abstract 17925: Physical Exercise Reduces Angiopoietin-like 2 Circulating Levels Only in CAD Patients With Endothelial Dysfunction
Authors: CarolYu, DougHayami, MathieuGayda, Jean-FrancoisLarouche, GabrielLapierre, ChristineHenri, JeanLambert, MartinJuneau, JulieLalonge, NathalieThorin-Trescases, AndreArsenault, EricThorin, AnilNigam
Journal: Circulation (2014)

Introduction: Angiopoietin-like 2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein that induces endothelial dysfunction in mice. Plasma angptl2 levels are increased in diabetic or atherosclerotic patients, while a lifestyle intervention has been shown to decrease angptl2 expression in overweight, but otherwise healthy men. Whether angptl2 levels are sensitive to exercise in CAD patients is unknown. Hypothesis: Exercise training reduces angptl2 levels in patients with CAD and endothelial dysfunction. Methods: Stable and optimally treated CAD patients (n=31, 60±2 y/o, 7 females) were enrolled in a 3-month exercise-based prevention program at the Montreal Heart Institute. Blood samples were collected before and at the end of the study to measure plasma levels of angptl2 (ELISA) and of hs-CRP. Endothelial function was assessed by measuring the ratio of the slope of the nuclear tracer Myoview activity-time in the right to the left arm. A ratio lower than 3.55 is indicative of endothelial d...
Abstract 4369: Functional role of RhoGEF FGD4 in promotion of aggressive prostate cancer
Authors: Alexia Bossan, Richard Ottman, Domenico Coppola, Ratna Chakrabarti
Journal: Cancer Research (2018)

Abstract Hyperactivation of Rho family of GTPases including Rac, Cdc42 and Rho, as a result of deregulation of Rho guanine nucleotide exchange factors (GEF) is commonly noted in various cancers including prostate cancer. A number of GEFs are overexpressed in prostate and breast cancer cells and tissues, and show an association with poor prognosis. Earlier, we showed that a prolonged treatment with androgen receptor antagonist Casodex resulted in up regulation of a GEF FGD4, traditionally associated with hereditary motor and sensory neuropathies including Charcot-Marie-Tooth disease. FGD4 is a Cdc42 specific GEF and contains an actin binding domain FAB, in addition to the conserved FYVE domain, a DH domain for catalytic activity and two PH domains for targeting proteins to the membranes through phosphoinositide binding. Our study revealed that Casodex treatment of prostate cancer cells lead to down regulation of a microRNA cluster miR-17-92a that targets FGD4. Here we show that FGD4 is upregulated in cancerous prostate tissues compared to benign prostatic hyperplasia and PIN. FGD4 protein expression and altered localization gradually increase with increasing tumor grade and aggressiveness. Inhibition of FGD4 expression using siRNAs, reduced cell proliferation, resulted in a G2/M arrest, inhibited cell migration and reduced Cdc42 activity. Inhibition of FGD4 also improved sensitivity of androgen sensitive LNCaP cells to Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel. Our data demonstrate a tumor promoting function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells. Citation Format: Alexia Bossan, Richard Ottman, Domenico Coppola, Ratna Chakrabarti. Functional role of RhoGEF FGD4 in promotion of aggressive prostate 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 4369.
Abstract 5474: Activity of the S1P pathway promotes ovarian cancer and serves as a novel metabolic target of metformin
Authors: Peter C. Hart, Tatsuyuki Chiyoda, Marion Curtis, Xiaojing Liu, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, Jason Locasale, Ernst Lengyel, Iris L. Romero
Journal: Cancer Research (2018)

Abstract Sphingosine-1-phosphate (S1P), a metabolite of the phospholipid sphingosine, is a bioactive lipid that directly interacts with specific G-protein-coupled receptors to transduce signals that regulate growth, proliferation and motility. Sphingosine kinases (SPHK1 and 2) catalyze the formation of S1P from sphingosine, thereby regulating S1P homeostasis and the sphingolipid rheostat. Recently, using TCGA data, we noted SPHK1 amplification in several gynecologic cancers and that high expression of SPHK1 was associated with increased mortality in high-grade serous ovarian cancer (HGSOC). The findings reported here show that exposure of HGSOC tumor cells to exogenous S1P, or overexpression of SPHK1, induced migration, proliferation and clonogenecity in multiple ovarian cancer cell lines in vitro. Likewise, in a xenograft mouse model of ovarian cancer, overexpression of SPHK1 markedly enhanced tumor growth. In prior pre-clinical studies, we have demonstrated a strong protective effect of the diabetes medication metformin in ovarian cancer. Interestingly, we found that patients with HGSOC that use metformin for diabetes have reduced serum S1P levels compared to controls, suggesting that the sphingolipid rheostat may be a novel metabolic target of metformin in ovarian cancer. Supporting this, we identified that SPHK1 expression in ovarian cancer cell lines is reduced by treatment with metformin, and further that the reduction of SPHK1 by metformin was mediated through inhibition of transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Finally, we show that overexpression of SPHK1 in HGSOC cell lines enhanced the cytotoxic effects of metformin. Taken together, our data indicates that hypoxia-induced SPHK1 expression and downstream S1P signaling promote tumor progression in HGSOC, and that tumors utilizing this pathway may be particularly vulnerable to the anti-cancer effects of metformin. Citation Format: Peter C. Hart, Tatsuyuki Chiyoda, Marion Curtis, Xiaojing Liu, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, Jason Locasale, Ernst Lengyel, Iris L. Romero. Activity of the S1P pathway promotes ovarian cancer and serves as a novel metabolic target of metformin [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 5474.
Reduction of Cardiovascular Risk by Regression of Electrocardiographic Markers of Left Ventricular Hypertrophy by the Angiotensin-Converting Enzyme Inhibitor Ramipril
Authors: JamesMathew, PeterSleight, EvaLonn, DavidJohnstone, JanicePogue, QilongYi, JackieBosch, BruceSussex, JeffreyProbstfield, SalimYusuf
Journal: Circulation (2001)

Background Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction. Methods and Results In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in...
Abstract 16190: Subclinical Hyperthyroidism and Risk of Atrial Fibrillation: A Systematic Review and Meta-analysis
Authors: Vimalkumar Veerappan Kandasamy, Alok Saurav, Ajay Kumar Kaja, Venkata Mahesh Alla
Journal: Circulation (2015)

Introduction: Overt hyperthyroidism is a well-known risk factor for development of atrial fibrillation (AF). On the other hand, studies assessing risk of AF in patients with subclinical hyperthyroidism (SCH), have reported conflicting results on the directionality and the strength of this association. We therefore systematically reviewed published literature and performed a quantitative analysis to assess the risk of AF in these patients. Methods: A comprehensive search of articles assessing the risk of AF in patients with SCH was done in PUBMED and COCHRANE databases through May 2015. SCH was defined as decreased Thyroid stimulating hormone (TSH) level accompanied by normal concentrations of serum thyroid hormone in asymptomatic patients. After screening abstracts, full texts of potentially relevant studies were reviewed independently by two authors. Data was extracted on standardized forms. Meta-analysis was performed using random effects model (DerSimonian Laird). The main measure of association was relative risk with 95% confidence intervals. Results: A total of 7119 patients with SCH and 588,839 controls across 4 studies were included in the analysis based on predefined inclusion and exclusion criteria. The relative risk for AF was significantly increased in patients with SCH compared to controls [relative risk: 2.48 (CI: 1.50-4.09; p&lt; 0.001)] during a mean follow up of 5.5 years. There was no significant heterogeneity or publication bias. Sensitivity analysis by exclusion of individual studies had no impact on the summary effect estimate. One study reviewed but not included in the quantitative analysis demonstrated increased risk of AF in patients with low normal TSH compared to mid normal range. Conclusion: This analysis demonstrates that the risk of AF is &gt;2 fold higher in the presence of SCH. It remains to be seen whether treatment of these patients before development of overt hyperthyroidism decreases the risk of AF.
PTU-031 Outcomes from an international multicentre registry of patients with gastrointestinal bleeding undergoing endoscopic treatment with hemospray
Authors: D Alzoubaidi, C Magee, S Gulati, A Haji, J Morris, L Lovat, B Hayee, R Haidry
Journal: Gut (2017)

Introduction  Acute gastrointestinal bleeding (G.I.B) carries a poor prognosis unless prompt endoscopic haemostasis is achieved. Hemospray is a novel proprietary mineral blend that forms a mechanical barrier over the bleeding site when applied endoscopically. The primary aim of this international multicentre registry is to collect data on the successful endoscopic haemostasis of GI bleeding with Hemospray. Secondary outcomes are re-bleeding (within 72 hours), device safety and adverse events related to the treatment.  Method  Data were collected prospectively (January 2016 – October 2016) on the use of Hemospray in acute upper and lower G.I.B, from two initial centres in the international registry. The use of hemospray in GI bleeding was at the endoscopist’s discretion. Hemospray use was either as mono therapy, as dual-therapy with standard endoscopic measures or as rescue therapy once standard methods had failed.  Results  To date 36 cases have been recruited (27 male and 9 female). Hemospray was used in 15 patients (42%) as monotherapy, in 17 patients (47%) in combination with other modalities and in 4 patients (11%) used as rescue therapy where other modalities failed. The Forrest Classification of the bleeding lesion were in 7 (19%) cases Forrest Ia bleed, 23 (64%) Ib, 2 (6%) IIa, 2 (6%) IIb and 2 (6%) Forrest III bleed. Sources of G.I.B included Peptic Ulcer disease 17 (47%), Post endoscopic Therapy 8 (22%), Malignancy 6 (17%), inflammation 2 (6%), Duodenal diverticulum bleed 1 (3%), Post Radiation bleed 1 (3%) and Variceal Bleed 1 (3%). 8 patients (22%) were anticoagulated at the time of emergency endoscopy. 31 patients (86%) achieved immediate haemostasis after hemospray endoscopic therapy. There were 5 cases (14%) of re-bleeding of which 2 (6%) were immediate and 3 (8%) occurred more than 7 days later. Hemospray was used in combination with other modalities in all these 5 cases. Of these 3 passed away, 1 required radiological embolisation and 1 patient was stabilised with conservative management. There were no reported immediate or delayed complications from the treatment.  Conclusion  Early data from our registry show a high rate of immediate haemostasis (86%) with hemopsray and an excellent safety profile. The iminnet expansion of this registry to other centres in Europe will provide invaluable data on the efficacy of Hemospray in various disease and patient types over the coming years.  Disclosure of Interest  None Declared
Endothelial G Protein β-Subunits Trigger Nitric Oxide– but not Endothelium-Derived Hyperpolarizing Factor–Dependent Dilation in Rabbit Resistance Arteries
Authors: PhilippeVéquaud, EricThorin
Journal: Circulation Research (2001)

A single subtype of heterotrimeric G protein–coupled receptor controls both nitric oxide (NO) (sensitive to l-arginine analogues) and endothelium-derived hyperpolarizing factor (EDHF) (sensitive to high-external K+ and apamine) production by the vascular endothelium leading to dilation. We hypothesized that α- and βγ-subunits of the G protein serve as distinct intermediates to produce NO and EDHF. In pressurized resistance arteries, selective pinocytotic endothelial incorporation of specific antibodies (Abs) directed against αq/11-subunits abolished acetylcholine (Ach)-mediated dilation but failed to influence oxymetazoline (Oxy, α2-adrenergic receptor agonist)-induced dilation. In contrast, αi1-2-subunit Abs prevented Oxy- but not Ach-induced dilation. Thus, as expected, endothelial muscarinic and α2-adrenoceptors couple to Gq protein and Gi proteins, respectively. β-subunit Abs reduced both Ach- and Oxy-induced dilation. The β-subunit Abs abolished the nitro-l-arginine (L-NNA)-sensitive component but di...
Impairment of Endothelium-Dependent Dilation in Rabbit Renal Arteries by Oxidized Lipoprotein(a)
Authors: JanGalle, JensBengen, PeterSchollmeyer, ChristophWanner
Journal: Circulation (1995)

Background Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)–mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro. Methods and Results Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 μg/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 μg/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced...