tbuckley/cabot-search huggingface dataset:
Abstract 994: Cancer cells induce a protumorigenic senescent phenotype in fibroblasts through MMP1 but not autophagy in large cell carcinoma of the lung
Authors: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Noemí Reguart, Evette Radisky, Derek Radisky
Journal: Cancer Research (2018)

Abstract Large cell carcinoma (LCC) is among the most aggressive histologic subtypes of non-small cell lung cancer, but the mechanisms underlying such aggressive nature remain unknown. We recently showed that fibroblasts from LCC patients exhibit premature senescence in vitro, and that co-culturing LCC cells (but not cancer cells from other lung cancer subtypes) with normal fibroblasts in transwells is sufficient to induce senescence in the latter in an oxidative stress-dependent manner, supporting that fibroblast senescence is induced by a secreted factor(s) from LCC cells. Remarkably, we also found that senescent fibroblasts secrete factors that stimulate the growth and invasion of LCC cells beyond the stimulation elicited by nonsenescent fibroblasts, revealing that fibroblast senescence may contribute to the aggressive nature of LCC. Whole-genome transcriptional profiling of a panel of lung cancer cell lines identified MMP1 among the genes with larger expression in LCC compared to other lung cancer subtypes. Since MMPs can induce oxidative stress, we examined whether the excessive MMP1 expression in LCC cells was involved in the induction of fibroblast senescence in co-cultures. Knocking down MMP1 in LCC cells was sufficient to abrogate fibroblast senescence in co-cultures as well as the growth and invasion enhancement elicited by the conditioned medium of fibroblasts in LCC cells. In contrast, autophagy, which has been previously associated with fibroblast senescence in breast cancer, was not upregulated in fibroblasts upon co-culture with LCC cells. These results support that the selective aberrant expression of MMP1 in LCC cells plays a major role in their ability to induce a protumorigenic senescent phenotype in adjacent fibroblasts through a mechanism that is independent of autophagy. Moreover, our observations identify MMP1 as a potential therapeutic target against the aberrant cancer cell-fibroblast crosstalk in LCC. Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Noemí Reguart, Evette Radisky, Derek Radisky. Cancer cells induce a protumorigenic senescent phenotype in fibroblasts through MMP1 but not autophagy in large cell carcinoma of the lung [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 994.
Abstract 16020: The Illusion of Hypertrophy: Perioperative Complications of Transcatheter Aortic Valve Replacement in a Patient With Aortic Stenosis and Cardiac Amyloidosis
Authors: Mayank Sardana, Theo E Meyer, Gerard P Aurigemma
Journal: Circulation (2016)

Background: Cardiac amyloidosis is seen in a third of patients undergoing transcatheter aortic valve replacement (TAVR) and might lead to poor outcomes in these patients. Case: 87 year old man, with history of severe aortic stenosis (AS, mean trans-aortic gradient 37mmHg, calculated valve area 0.6cm2) and paroxysmal atrial fibrillation, presented to the cardiology clinic with symptoms of biventricular failure. He underwent TAVR with CoreValve two months ago for recurrent heart failure with preserved ejection fraction (HFpEF) exacerbations. His hospital course was complicated by post-procedure cardiac arrest, dual-chamber atrioventricular permanent pacemaker placement for complete heart block and left anterior descending artery dissection. A repeat echocardiogram revealed normal left ventricular ejection fraction, severe concentric increase in left ventricular thickness, normal trans-aortic gradients for CoreValve and moderate aortic insufficiency (Figure 1). Longitudinal ventricular strain analysis by Spe...
Abstract 918: A secondary <i>RET</i> mutation allosterically conferring resistance to vandetanib
Authors: Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Nino, Rakhee Chauhan, Phillip P. Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald, Koichi Goto
Journal: Cancer Research (2018)

Abstract Targeted therapy against oncogenic ALK and ROS1 fusion using type I tyrosine kinase inhibitors (TKIs), which bind to the ATP-binding cleft of kinases, is highly effective in lung adenocarcinoma (LADC); however, such cancers inevitably acquire resistance, which severely limits the efficacy of cancer treatments. The identification of these resistance mutations led to the development of novel TKIs to overcome acquired resistance. Here we report resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic LADC harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in substitution of an amino acid located outside the nucleotide binding cleft. The mutation conferred resistance to vandetanib by increasing the ATP affinity and auto-phosphorylation activity of RET kinase. A crystal structure of the mutant revealed a small hydrophobic core around the mutated amino acid likely to enhance basal kinase activity by stabilizing an active conformer. In addition, a thermal shift assay suggested that the mutation was less able to bind vandetanib. Molecular dynamics simulation supported the mutant underwent conformational changes decreasing the binding affinity of vandetanib. Our findings indicate that the missense mutation is able to increase kinase activity and confers drug resistance through allosteric effects. Citation Format: Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Nino, Rakhee Chauhan, Phillip P. Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald, Koichi Goto. A secondary RET mutation allosterically conferring resistance to vandetanib [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 918.
Abstract 461: An essential role of the iron-sulfur cluster assembly enzyme isu-1 in the aging and stress responses of <i>C. elegans</i>
Authors: Rui Xiao, Yi Sheng
Journal: Cancer Research (2018)

Abstract Iron is essential for animal cellular homeostasis by acting in the biogenesis of two important redox-reactive prosthetic groups of enzymes: iron sulfur clusters (ISC) and heme. Previous studies have indicated that the misregulated iron metabolism is associated with multiple aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, how iron metabolism modulates the aging process remains largely elusive.In the current study, we aim to reveal the roles and mechanisms of iron metabolism in the aging process of C. elegans, a well-established genetic model organism for aging research. Through our preliminary studies, we have found that the iron-sulfur cluster assembly gene isu-1 plays an important role in the lifespan modulation and stress resistance of C. elegans. Specifically, RNAi knocking-down of isu-1 causes a significantly upregulated mitochondrial unfolded protein response (mitoUPR). Furthermore, the isu-1 RNAi-treated worms are significantly more resistant to heat shock and oxidative stress. Lastly, isu-1 RNAi significantly extends lifespan (~25.7%).Currently, we are examining the transcription factors downstream of isu-1 in regulating aging and stress responses. Surprisingly, the isu-1 RNAi-triggered lifespan extension is independent of insulin and IGF pathway, an evolutionarily conserved master regulator of animal growth and aging. Next, we will characterize the mechanisms underlying the effects of iron-sulfur cluster in animal aging and stress response using various genetic and biochemistry approaches. Citation Format: Rui Xiao, Yi Sheng. An essential role of the iron-sulfur cluster assembly enzyme isu-1 in the aging and stress responses of C. elegans [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 461.
Abstract 17077: Nocturnal Intermittent Hypoxia and Short Sleep Duration were Independently Associated With Elevated C-reactive Protein Level in Patients With Coronary Artery Disease
Authors: RyomaFukuoka, TakashiKohno, ShunKohsaka, RyoYanagisawa, TakahikoNishiyama, YuichiroMaekawa, MotoakiSano, KeiichiFukuda
Journal: Circulation (2015)

Introduction: There is growing evidence of a relationship between sleep disorders and cardiovascular diseases including coronary artery disease (CAD). However, the mechanism of these association is not well established. Enhanced vascular inflammation is implicated as a pathophysiologic mechanism in CAD. The aim of this study was to evaluate the relationship among sleep-disordered breathing (SDB), sleep duration, and serum C-reactive protein (CRP) level in patients with CAD. Methods and Results: Consecutive 225 patients with CAD who underwent percutaneous coronary intervention were evaluated. We used a nocturnal pulse oximetry as a non-invasive screening method for nocturnal intermittent hypoxia, a surrogate marker of SDB. Nocturnal intermittent hypoxia was evaluated using 3% oxygen desaturation index (3% ODI) which was the number of oxygen desaturation measurement ≤ 3% per hour, and we divided the patients into nocturnal intermittent hypoxia group (3% ODI≥15; n=64) and control group (3% ODI<15; n=161). Sl...
Abstract 14660: Effect of PR Interval on Mortality Reduction With Cardiac Resynchronization Therapy - A Secondary Analysis of the COMPANION Trial
Authors: Jeffrey Lin, Kevin A Buhr, Ryan Kipp
Journal: Circulation (2015)

Introduction: Prolonged PR intervals may impair atrioventricular mechanical coupling and adversely affect cardiac performance. We hypothesize that patients with advanced systolic heart failure, wide QRS complexes, and prolonged PR intervals will have improved survival from cardiac resynchronization therapy with defibrillator (CRT-D) regardless of whether left bundle branch block (LBBB) or non-LBBB is present. Methods: Patients enrolled in the optimal pharmacologic therapy (OPT) and CRT-D arms of the COMPANION trial were included in a multivariable Cox model of all-cause mortality as a function of presence of LBBB and value of PR interval at baseline. Hazard ratios representing the mortality reduction for CRT-D versus OPT were estimated together with pointwise 95% confidence intervals (CIs). Results: A total of 308 OPT and 595 CRT-D patients were included in the analysis. In both the LBBB (n=648) and non-LBBB (n=255) subgroups, the mortality reduction associated with CRT-D compared to OPT was greater with increasingly prolonged baseline PR interval (Figure 1, p=0.02 for each subgroup). Hazard ratios for CRT-D versus OPT (with 95% CIs) for PR intervals of 200ms and 250ms were 0.51 [0.35,0.74] and 0.30 [0.18,0.50] respectively for the LBBB subgroup, and 0.86 [0.50,1.5] and 0.39 [0.18,0.86] respectively for the non-LBBB subgroup. For non-LBBB patients with PR interval ≤200ms, there was no evidence of mortality benefit with CRT-D (p=0.60). Conclusions: In patients with advanced systolic heart failure, wide QRS complexes, and prolonged PR intervals, restoration of atrioventricular mechanical coupling with CRT-D may improve survival in both LBBB and non-LBBB recipients. In patients with non-LBBB, a benefit from CRT-D may occur in patients with prolonged PR intervals. Figure 1: Risk for all-cause mortality by hazard ratios stratified according to PR interval quartiles.
Abstract 11330: Layer Specific Quanti[[Unable to Display Character: ﬁ]]cation of Myocardial Deformation by Strain Echocardiography May Detect Micro Vascular Obstruction and Hemorrhage in Patients With Acute Myocardial Infarction After Reperfusion
Authors: Xing ShengYang, ZhiqingQiao, Jing PingSun, HangZhao, HengGe, XuedongShen, ZhengLi, ChanghuaWei, JunPu, BenHe, Cheuk-ManYu
Journal: Circulation (2014)

Background: The myocardial reperfusion injury can paradoxically reduce the beneficial effects of myocardial reperfusion. We sought to detect the reperfusion injury using parameters of layer-specific myocardial deformation in patients with acute myocardial infarction (MI) after intervention therapy. Methods: Two-D speckle tracking echocardiography (2DSTE) was performed in 81 patients (mean age 57±9 years, 76 men) with acute MI after primary percutaneous coronary intervention (PCI). The peak systolic myocardial segmental layer longitudinal (LS) and circumferential (CS) strains were assessed by 2DSTE using an 18-segment model of left ventricle. The micro vascular obstruction (MVO) and intramyocardial haemorrhage (IMH) were determined by contrast-enhanced cardiac magnetic resonance imaging(ceCMR). Results: There were 422/1,458 segments with transmural necrosis in 81 patients. There were 58 patients with MVO and 46 patients with IMH. The amplitudes of myocardial layers LS and CS were significantly decreased in...
Tip110/SART3 regulates IL-8 expression and predicts the clinical outcomes in melanoma
Authors: Khalid Amine Timani, Balázs Győrffy, Ying Liu, Khalid S. Mohammad, Johnny J. He
Journal: Molecular Cancer (2018)

Tip110, an important regulator of several oncogenic proteins, was significantly downregulated in human metastatic melanoma cells exposed to a hypoxic condition. Therefore, in this study, we set to determine whether differential expression of Tip110 could be an important indicator for melanoma tumorigenesis and metastasis. We found that in melanoma, but not in other cancer types, Tip110 knockdown enhanced significant expression and secretion of IL-8 and melanoma cells invasions. This induction was further potentiated under hypoxia and by inflammatory cytokine and found independent of TNF-α autocrine signaling. We further showed that Tip110 knockdown-mediated IL-8 induction involved IL-8 mRNA stability. Furthermore, the transcriptomic profiling data and survival from 455 melanoma patients demonstrated that the correlation between Tip110 expression and the clinical outcomes in melanoma was stage-dependent. These findings uncover important roles of Tip110 in melanoma tumorigenesis and metastasis through regulation of IL-8 and hope to provide new clues for future therapeutic strategies.
Pharmacological Characterization of Adrenergic Alpha and Beta Receptors Mediating the Vasomotor Responses of Cerebral Arteries Ir Vitro
Authors: Larsedvinsson, Christerowman
Journal: Circulation Research (1974)

The adrenergic receptors in the isolated feline middle cerebral artery were characterized pharmacologically using a sensitive system for recording circular contractions in vitro. Epinephrine. norepinephrine, isoproterenol. and phenylephrine contracted the vessel in the mentioned order of potency. Together with the inhibitory patterns obtained with graded doses of piperoxan (reversible competitive inhibition) and dibenamine or phenoxybenzamine (irreversible competitive inhibition), these results showed that the contraction was mediated by alpha receptors. With piperoxan and norepinephrine, the mean value for pA2 was 7.06 and for K H1.24 x 10-7M. The mean value for K A calculated for norepinephrine before and after partial irreversible blockade of the alpha receptors with phenoxybenzamine was 1.73 x 10-6M. The norepinephrine response was not directly proportional to the amount of receptors occupied; ED50 was reached when only about 11% of the receptors were occupied and the EAm response was obtained when 75...
Pivotal Role of gp91phox-Containing NADH Oxidase in Lipopolysaccharide-Induced Tumor Necrosis Factor-α Expression and Myocardial Depression
Authors: TianqingPeng, XiangruLu, QingpingFeng
Journal: Circulation (2005)

Background— Lipopolysaccharide (LPS) induces cardiomyocyte tumor necrosis factor-α (TNF-α) production, which is responsible for myocardial depression during sepsis. The aim of this study was to investigate the role of gp91phox-containing NADH oxidase signaling in cardiomyocyte TNF-α expression and myocardial dysfunction induced by LPS. Methods and Results— In cultured mouse neonatal cardiomyocytes, LPS increased NADH oxidase (gp91phox subunit) expression and superoxide generation. Deficiency of gp91phox or inhibition of NADH oxidase blocked TNF-α expression stimulated by LPS. TNF-α induction was also inhibited by tempol, N-acetylcysteine, or 1,3-dimethyl-2-thiourea. NADH oxidase activation by LPS increased ERK1/2 and p38 phosphorylation, and inhibition of ERK1/2 and p38 phosphorylation blocked the effect of NADH oxidase on TNF-α expression. Isolated mouse hearts were perfused with LPS (5 μg/mL) alone or in the presence of apocynin for 1 hour. Myocardial TNF-α production was decreased in gp91phox-deficient...
Intrauterine Growth Retardation Is Associated With Reduced Activity and Expression of the Cationic Amino Acid Transport Systems y+/hCAT-1 and y+/hCAT-2B and Lower Activity of Nitric Oxide Synthase in Human Umbilical Vein Endothelial Cells
Authors: PaolaCasanello, LuisSobrevia
Journal: Circulation Research (2002)

Intrauterine growth retardation (IUGR) is associated with vascular complications leading to hypoxia and abnormal fetal development. The effect of IUGR on l-arginine transport and nitric oxide (NO) synthesis was investigated in cultures of human umbilical vein endothelial cells (HUVECs). IUGR was associated with membrane depolarization and reduced l-arginine transport (Vmax= 5.8±0.2 versus 3.3±0.1 pmol/μg protein per minute), with no significant changes in transport affinity (Km=159±15 versus 137±14 μmol/L). l-Arginine transport was trans-stimulated (8- to 9-fold) in cells from normal and IUGR pregnancies. IUGR was associated with reduced production of l-[3H]citrulline from l-[3H] arginine, lower nitrite and intracellular l-arginine, l-citrulline, and cGMP. IUGR decreased hCAT-1 and hCAT-2B mRNA, and increased eNOS mRNA and protein levels. IUGR-associated inhibition of l-arginine transport and NO synthesis, and membrane depolarization were reversed by the NO donor S-nitroso-N-acetyl-l,d-penicillamine. In s...
Abstract 3174: PLK4 is a rational target for very high-risk medulloblastoma
Authors: Carolina Nor, Mark Bray, Tak Mak, Michael Taylor
Journal: Cancer Research (2018)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite aggressive therapy (maximal safe surgical resection, craniospinal irradiation and/or chemotherapy) only 65% of patients survive, and survivors are left with severe neuro-cognitive sequelae. MB is comprised of at least four distinct molecular subgroups (SHH, Wnt, Group 3 and Group 4). Within the Sonic hedgehog (SHH) subgroup, a subset harboring inactivating mutations within TP53 represent a very high-risk group with almost universally fatal outcome. TP53 mutated SHH tumors have a high degree of genomic instability with frequent chromothripsis and are resistant to the current generation of SHH pathway inhibitors. The protein PLK4 has a key role in the maintenance of chromosome numeral integrity and as such dysregulation of PLK4 expression causes genomic instability. The PLK4 inhibitor (CFI-400945, produced by the Campbell Family Institute for Breast Cancer Research) was shown to increase genomic instability in aneuploid cells from adult solid tumors and induce these cells to die through mitotic catastrophy. Here we leverage a sporadic transposon based metastatic mouse model (Ptch+/-/Math1-SB11/T2Onc) that faithfully mimics very high-risk MB in children. In order to mimic treatment in children, tumors are microsurgically subtotally resected, followed with the oral administration of CFI-400945 and cranial MRI to monitor response. Blood brain barrier penetration of CFI-400945 was confirmed using mass spectroscopy, specifically pharmacokinetics study revealed an expected availability of CFI-400945 in the circulating blood and concentrated compound in the tumor compared to the normal brain. The administration of CFI-400945 confers an advantage of survival to the mice in this model, median of 18.5 days for surgery group and 49 days for surgery plus CFI-400945 group (p=0.005). In human tumor datasets PLK4 is highly expressed across a variety of malignancies, including MB. Specifically, across two independent, non-overlapping datasets higher PLK4 levels correlate with a trend toward worse outcome, however, when restricting this analysis only to SHH tumors, there is a significant survival difference between high and low PLK4 expression (p=0.012). In paired primary-metastatic MB PLK4 expression is retained at the time of recurrence, specifically in metastatic recurrences, suggesting PLK4 inhibition is a suitable treatment option at the time of recurrence. Taken together, the data reveals PLK4 inhibition as a novel and rational therapeutic target for a subset of very high risk MB and a broad range of other pediatric cancers. Citation Format: Carolina Nor, Mark Bray, Tak Mak, Michael Taylor. PLK4 is a rational target for very high-risk medulloblastoma [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 3174.
Response to Letter Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”
Authors: MarianneCanonico, EmmanuelOger, GenevièvePlu-Bureau, Pierre-YvesScarabin, JacquelineConard, GuyMeyer, HervéLévesque, NathalieTrillot, Marie-ThérèseBarrellier, DenisWahl, JosephEmmerich
Journal: Circulation (2007)
Neurological Outcomes After Immediate Aortic Repair for Acute Type A Aortic Dissection Complicated by Coma
Authors: TakuroTsukube, TaroHayashi, ToshihiroKawahira, TomonoriHaraguchi, RitsuMatsukawa, ShuichiKozawa, KyoichiOgawa, YutakaOkita
Journal: Circulation (2011)

Background—Management of acute type A aortic dissection (AADA) complicated by coma remains controversial. We analyzed our experience in managing AADA complicated by coma to determine the relationship of duration of preoperative coma to postoperative neurological recovery. Methods and Results—Between September 2003 and October 2010, 181 patients with AADA were treated, including 27 presenting with coma (Glasgow Coma Scale  5 hours (delayed group). The preoperative National Institutes of Health Stroke Scale score was 31.4±6.6 in the immediate group and 28.3±9.5 in the delayed group. Hos...