tbuckley/cabot-search huggingface dataset:
Abstract 4212: PD-L1 expression, <i>EGFR</i> and <i>KRAS</i> mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients
Authors: Deirdre Cronin-Fenton, Tapashi Dalvi, Elizabeth Hedgeman, Mette Norgaard, Lars Pedersen, Hanh Hansen, Jon Fryzek, Jill Walker, Anders Mellemgaard, Torben Rasmussen, Norah Shire, James Riggas, Danielle Potter, Stephen Hamilton-Dutoit, Henrik Sørensen
Journal: Cancer Research (2018)

Abstract Background: Anti-PD-L1 therapy may improve prognosis in advanced NSCLC. We examined the relation of PD-L1 expression, KRAS and EGFR mutations, with survival in unresectable stage III NSCLC patients. Methods: We obtained data on unresectable stage III NSCLC patients (defined via TNM AJCC staging and without surgery up to 120 days after diagnosis) diagnosed 2001-2012. We retrieved medical data from Danish population-based registries and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263) validated assay. We genotyped KRAS and EGFR using PCR-based kits. Follow-up began at NSCLC diagnosis and continued to death, emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HRs) and associated 95% confidence intervals (95%CI) for PD-L1, EGFR, and KRAS. Results: Among 305 patients, 183 (60%) were men, 167 (55%) were aged &amp;gt;65 years at diagnosis and none used immunotherapy; 148 (49%) had adenocarcinoma, 117 (38%) squamous histology, 96 (31.5%) had PD-L1 positive tumors (&amp;gt;=25%), 6 (2%) had EGFR mutations, and 69 (23%) had KRAS mutations. Among PD-L1 positive tumors, 55% had stage IIIA, 45% IIIB disease; 1% had EGFR and 34% had KRAS mutations. Among PD-L1 negative tumors, 54% had stage IIIA and 46% IIIB; 3% had EGFR and 16% had KRAS mutations. Median survival was similar in patients with KRAS wild-type and KRAS mutations (Hazards ratio (HR)=1.07; 95% CI=0.76-1.51). Patients with an EGFR mutation had a lower non-statistically significant risk of death (HR=0.75; 95% CI=0.28-2.06). Tumor cell positivity for PD-L1 (&amp;gt;=25% versus &amp;lt;25%) yielded an HR=0.80 (95%CI=0.60-1.07). Immune cell positivity for PD-L1 &amp;gt;=1% and &amp;gt;=25% yielded HRs of 0.50 (95%CI=0.39-0.66) and 0.45 (95%CI=0.30-0.67), respectively. Tumor infiltration by immune cells with PD-L1 measured as a continuous variable yielded an HR=0.96 (95%CI=0.93-0.99). Conclusion: Our findings suggest that PD-L1 expression and EGFR mutations, but not KRAS mutations, are associated with survival in this real-world Danish study of unresectable Stage III NSCLC patients. Citation Format: Deirdre Cronin-Fenton, Tapashi Dalvi, Elizabeth Hedgeman, Mette Norgaard, Lars Pedersen, Hanh Hansen, Jon Fryzek, Jill Walker, Anders Mellemgaard, Torben Rasmussen, Norah Shire, James Riggas, Danielle Potter, Stephen Hamilton-Dutoit, Henrik Sørensen. PD-L1 expression, EGFR and KRAS mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients [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 4212.
Abstract 1323: A p53-dependent switch between cytoprotective and nonprotective autophagy influences tumor cell sensitivity to cisplatin
Authors: Jingwen Xu, Tareq Saleh, Nipa Patel, Yingliang Wu, Santiago Lima, David Gewirtz
Journal: Cancer Research (2018)

Abstract Autophagy is a multi-step, homeostatic process through which cells turnover dysfunctional organelles and proteins. Previous work in our laboratory has identified multiple functional roles of autophagy, specifically cytoprotective, cytotoxic, cytostatic and nonprotective, when subjected to radiation and chemotherapy. Furthermore, we have reported on the existence of an autophagic switch between one functional form (generally cytoprotective) to the other forms. To further explore the autophagic switch, we utilized p53 wild type (p53 +/+) and p53 null (p53 -/-) H460 non-small cell lung cancer (NSCLC) cell lines exposed to cisplatin. The extent of autophagy was similar in both cell lines, but the rate and extent of apoptosis was higher in the p53 +/+ cells, which showed greater cisplatin sensitivity. Pharmacological (chloroquine, 3-Methyladenine) and genetic (ATG5 silencing) inhibition of autophagy failed to sensitize the p53 +/+ H460 cells to cisplatin, suggesting that autophagy has a nonprotective role. In contrast, autophagy inhibition (CQ, 3-MA, or shATG5) increased sensitivity to cisplatin in the p53 -/- H460 cells, indicative of a cytoprotective function of autophagy. These studies support the premise that cytoprotective autophagy may confer resistance to cisplatin. Moreover, we confirm the pivotal role of p53 in determining the function of autophagy induced by cisplatin. Finally, we provide an additional example of a switch between the nonprotective and protective forms of autophagy in p53 wild type and p53 null H460 non-small cell lung cancer (NSCLC) cells, respectively. Citation Format: Jingwen Xu, Tareq Saleh, Nipa Patel, Yingliang Wu, Santiago Lima, David Gewirtz. A p53-dependent switch between cytoprotective and nonprotective autophagy influences tumor cell sensitivity to cisplatin [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 1323.
Dynamin-2 Regulates Oxidized Low-Density Lipoprotein–Induced Apoptosis of Vascular Smooth Muscle Cell
Authors: YujiKashiwakura, MasamiWatanabe, NorihiroKusumi, KatsuhikoSumiyoshi, YasutomoNasu, HiroshiYamada, TatsuyaSawamura, HiromiKumon, KohjiTakei, HiroyukiDaida
Journal: Circulation (2004)

Background— On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin (a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC). Methods and Results— After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor–mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin-α (PFT) signi...
Derivation and Potential Applications of Human Embryonic Stem Cells
Authors: LiorGepstein
Journal: Circulation Research (2002)

Embryonic stem cells are pluripotent cell lines that are derived from the blastocyst-stage early mammalian embryo. These unique cells are characterized by their capacity for prolonged undifferentiated proliferation in culture while maintaining the potential to differentiate into derivatives of all three germ layers. During in vitro differentiation, embryonic stem cells can develop into specialized somatic cells, including cardiomyocytes, and have been shown to recapitulate many processes of early embryonic development. The present review describes the derivation and unique properties of the recently described human embryonic stem cells as well as the properties of cardiomyocytes derived using this unique differentiating system. The possible applications of this system in several cardiac research areas, including developmental biology, functional genomics, pharmacological testing, cell therapy, and tissue engineering, are discussed. Because of their combined ability to proliferate indefinitely and to diffe...
Abstract 11618: Low Antithrombin Level Correlates With Failing Fontan Circulation and Predicts the Mortality
Authors: NobuyukiTsujii, HideoOhuchi, YosukeHayama, JunNegishi, KanaeNoritake, OsamuSasaki, AyaMiyazaki, OsamuYamada
Journal: Circulation (2014)

Background: Antithrombin is one of natural anticoagulants produced by the liver and the activity (AT) decreases as a result of liver dysfunction. Fontan pathophysiology includes heart failure-related hepatopathy that accompanies coagulation abnormality. Purpose: To clarify clinical significance of AT in Fontan patients. Methods and Results: We prospectively measured AT in consecutive 303 Fontan patients (17±9 years) and compared with the clinical variables, including hemodynamics, peak oxygen uptake (PVO2), liver function, plasma brain natriuretic peptide (BNP), and unscheduled hospitalization (USH), including all-cause mortality. The AT was 109±14 (%, normal range: 80-120%) and it correlated inversely with age, central venous pressure (CVP), and plasma levels of BNP and creatinine, and positively with arterial oxygen saturation (Sat) and PVO2 (p < 0.001 for all). Patient with heterotaxy syndrome (HS) showed a low AT (p < 0.001). The lower plasma albumin level and platelet count and high total bilirubin l...
Abstract 3465: Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand
Authors: Remah Ali, Wells Brown, Jo Davisson, Michael Wendt
Journal: Cancer Research (2018)

Abstract Inhibition of EGFR signaling by small molecule kinase inhibitors and monocloncal antibodies has proven effective in the treatment of multiple metastatic cancers. In contrast, metastatic breast cancer (BC) derived from EGFR-driven mammary tumors is inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here we show that in contrast to primary tumors, ligand-mediated activation of EGFR is dominated by signaling transducer and activator of transcriptional 1 (STAT1) signaling in metastatic BC. This change in downstream signaling leads to apoptosis and growth inhibition in response to EGF in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal EGFR signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death without affecting EGFR:MAPK signaling. Pharmacologic blockade of MAPK signaling through the use of the MEK1/2 inhibitor trametinib led to a dramatic increase in EGF-mediated STAT1 phosphorylation and enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, use of a trametinib:EGF combination also facilitated the apoptotic switch in EGFR function in primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental switch in EGFR in metastatic BC. Furthermore, they demonstrate that pharmacological biasing EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway. Citation Format: Remah Ali, Wells Brown, Jo Davisson, Michael Wendt. Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand [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 3465.
Abstract 5445: A novel mechanism of inhibition of ovarian cancer growth by Compound C, dorsomorphin
Authors: Alia Ghoneum, Hesham M. Afify, Neveen Said
Journal: Cancer Research (2018)

Abstract High grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy with a five-year survival rate of 15%. As a highly aggressive cancer, HGSC has elevated energy demands to ensure its survival and proliferation in its unique peritoneal environment. Compound C or Dorsomophin is of particular interest as it is the only available cell permeable molecule that works selectively and competitively to inhibit Adenosine Monophosphate Protein-activated protein kinase or AMPK, a sensitive sensor of ATP levels. It has long been established that Compound C has a role as a BMP1 inhibitor during embryogenesis and as an inhibitor of AMPK activity in different contexts. However, the mechanism by which Compound C exerts anti-tumorigenic effects remains unknown. The purpose of this study is to understand how Compound C suppresses growth of HGSC. Our preliminary studies indicate that Compound C inhibits ovarian cancer cell proliferation and survival via a novel mechanism not only through inhibition of AMPK but also through the inhibition of upstream PI3K-Akt as well as TGFβ1/ TGFβ1/2 receptors/Smad 3,4 activation. These findings elucidate a novel mechanism of inhibition of ovarian cancer by Compound C, suggesting its potential use as a novel therapeutic agent inhibiting oncogenic and metabolic pathways. Citation Format: Alia Ghoneum, Hesham M. Afify, Neveen Said. A novel mechanism of inhibition of ovarian cancer growth by Compound C, dorsomorphin [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 5445.
Abstract 12098: S-nitrosoglutathione Reductase Deficiency Prevents Neurological Injury After Cardiac Arrest and Cardiopulmonary Resuscitation
Authors: Kei Hayashida, Shuichi Hirai, Kohei Ikeda, Shinihci Kai, Eizo Marutani, Fumito Ichinose
Journal: Circulation (2015)

Introduction: Nitric oxide (NO) exerts many of its effects via protein S-nitrosylation (SNO). Protein SNO levels are critically controlled by the activity of denitrosylase S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine the impact of enhanced protein SNO induced by GSNOR deficiency on the outcomes of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice. Methods and Results: Wild-type (WT) mice and mice deficient for GSNOR (GSNOR-/-) were subjected to CA for 8 min whereupon CPR was performed with chest compression and mechanical ventilation. There were no differences in characteristics before CA and during CPR except for lower mean blood pressure in GSNOR-/- mice at baseline. WT mice that were subjected to CA/CPR exhibited a poor 6-day survival rate (16.7%), depressed neurological function, and increased hydrogen peroxide production in the brain. In contrast, GSNOR-/- mice exhibited better neurological recovery, attenuated hydrogen peroxide production, and markedly improved 6-day survival rate (66.7%, P&lt;0.05 vs WT). The protective effects of GSNOR deficiency were associated with markedly reduced mitochondria complex I activity in the brain at 5 min after CPR compared with sham-operated GSNOR-/- mice as evidenced by the ATP turnover rate in isolated cerebral mitochondria. Administration of a mitochondria-targeted S-nitrosothiol MitoSNO to WT mice 1min before CPR similarly depressed cerebral mitochondrial complex I activity and improved neurological outcomes, and survival rate. These results suggest that SNO-based inhibition of mitochondrial activity prevents ischemic neurological injury after CA and CPR. Conclusions: GSNOR-deficiency improves outcomes after CA and CPR in mice at least in part by modulating mitochondrial complex I activity and reducing reactive oxygen species generation during early reperfusion phase. Pharmacological augmentation of protein SNO may limit long term neurological impairment and death after CA/CPR.
Abstract 17524: Nitrite Decreases Oxidative Stress Through Inhibition of Nuclear Factor-kappaB (NF-κB) Signaling Pathway During Chronic Ischemic-Induced Heart Failure
Authors: Kazi N Islam, Erminia Donnarumma, Shashi Bhushan, Hiroyuki Otsuka, Giuseppe Cirino, David J Lefer
Journal: Circulation (2014)

Background: Nitric oxide (NO) bioavailability is reduced in the setting of congestive heart failure (HF). We have previously reported that sodium nitrite (NaNO2) ameliorates acute myocardial ischemia-reperfusion (MI-R) when administered at reperfusion. NF-κB mediates cellular oxidative stress and its activation increases the severity of myocardial hypertrophy and heart failure (HF). However, no evidence exists as to whether increasing NO bioavailability via NaNO2- therapy attenuates chronic HF following acute myocardial infarction via inhibition of NF-κB activation. Methods: Male C57/BL6J mice (n=13-15/group) underwent 60 min. of MI induced by LCA occlusion followed by 4 weeks of reperfusion. NaNO2 or saline vehicle (VEH) was administered at a dose of 165 μg/kg (intra cardiac injection) at reperfusion and then daily for 4 weeks in the drinking water (100 mg/L). Left ventricular ejection fraction (LVEF) was determined at baseline and at 4 weeks of reperfusion using high frequency ultrasound. At 4 weeks of ...
Novel Human Vascular Endothelial Growth Factor Genes VEGF-B and VEGF-C Localize to Chromosomes 11q13 and 4q34, Respectively
Authors: KarriPaavonen, NinaHorelli-Kuitunen, DimitriChilov, EolaKukk, SariPennanen, Olli-PekkaKallioniemi, KatriPajusola, BirgittaOlofsson, UlfEriksson, VladimirJoukov, AarnoPalotie, KariAlitalo
Journal: Circulation (1996)

Background Vascular endothelial growth factor (VEGF) is an important regulator of endothelial cell proliferation, migration, and permeability during embryonic vasculogenesis as well as in physiological and pathological angiogenesis. The recently isolated VEGF-B and VEGF-C cDNAs encode novel growth factor genes of the VEGF family. Methods and Results Southern blotting and polymerase chain reaction analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH) of metaphase chromosomes were used to assess the chromosomal localization of VEGF-B and VEGF-C genes. The VEGF-B gene was found on chromosome 11q13, proximal to the cyclin D1 gene, which is amplified in a number of human carcinomas. However, VEGF-B was not amplified in several mammary carcinoma cell lines containing amplified cyclin D1. The VEGF-C gene was located on chromosome 4q34, close to the human aspartylglucosaminidase gene previously mapped to 4q34-35. Conclusions The VEGF-B locus in 11q13 and the VEGF-C locus in 4q34 are candi...
Abstract 20302: Ventricular Arterial Coupling: A Novel Echocardiographic Risk Factor for Disease Progression in Pediatric Dilated Cardiomyopathy
Authors: Christine A Capone, Josemiguel Lorenzo, Barbara Tria, Jaqueline M Lamour, Daphne T Hsu, Joseph Mahgerefteh
Journal: Circulation (2016)

Introduction: A higher (VA) coupling ratio measured non-invasively has been well described in adult heart failure patients and is associated with worse heart failure prognosis and response to treatment, largely due to increases in arterial elastance. There is no data regarding the importance of VA coupling in pediatric patients with heart failure Hypothesis: A higher VA coupling ratio will be associated with worse outcomes in pediatric patients with dilated cardiomyopathy (DCM). Methods: Demographic, clinical and echocardiographic (echo) data (including ventricular volumes, arterial elastance and LV elastance) were obtained in children with DCM. The association of VA coupling ratio with worse outcome (mechanical circulatory support, transplant, or death) was assessed. Results: Echos from 29 patients with DCM (23 idiopathic, 3 Duchenne, 3 other) were reviewed. Mean age at presentation was 6±7 years, mean age at echo was 10±4 years. At the time of echo, 9 patients were hospitalized for initiation of inotrop...
Abstract 359: IWS1 is essential for mouse development
Authors: Arturo Orlacchio, Claudia Foray, Tyler Sheetz, Erika Reese, Foued Amari, Aaron E. Stark, Krista La Perle, Ioannis Sanidas, Philip N. Tsichlis, Dario Palmieri, Vincenzo Coppola
Journal: Cancer Research (2018)

Abstract Iws1 (Interacts with Spt6) was originally identified in Saccharomyces Cerevisiae as a binding partner of Spt6, a histone H3/H4 chaperone.As a transcription factor, Iws1 plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts.Iws1 is phosphorylated, following stimulation with growth factors, by Akt3 and Akt1 at Ser720/Thr721 in human cells (Ser667/Thr668 in the mouse).Preliminary evidence supports a critical protumorigenic role of Iws1 and its phosphorylation in several types of malignancies such as lung cancer (NSCLC), mammary adenocarcinomas and melanomas.For example, it has been shown that, while IWS1 expression in normal human lung is very low, dramatically increases in many NSCLCs. Interestingly the level of IWS1 phosphorylation is variable between tumors and correlates with Akt3 expression.Moreover data from the TCGA database show that Iws1 is expressed at higher levels in tumors than in normal mammary gland specimens and also that basal and HER-2-enriched tumors express the highest levels. The genetic depletion of Iws1 in human mammary adenocarcinoma cell lines inhibits anchorage-independent growth in soft agar and mammosphere formation and growth. Similar experiment revealed that human melanoma cells were extraordinarily sensitive to the knockdown of Iws1. These experiments identify mammary adenocarcinomas and melanomas as tumors potentially addicted to Iws1. However, Iws1 biological functions are poorly characterized and there is no reported in vivo investigation about this RNA-processing factor.To begin to shed some light on the function of this protein at organismal level, we performed a thorough analysis of the expression of Iws1 and generated Iws1-deficient mice.The systematic analysis of expression in mouse tissues shows that Iws1 is ubiquitously expressed. We also report that ablation of Iws1 causes lethality at very early stages of mouse development. In fact, Iws1-deficient mouse embryos die at pre-implantation stage. Overall, these results show that Iws1 is an essential gene for mouse development and suggest a critical function in mammary adenocarcinomas as well as in melanoma. Citation Format: Arturo Orlacchio, Claudia Foray, Tyler Sheetz, Erika Reese, Foued Amari, Aaron E. Stark, Krista La Perle, Ioannis Sanidas, Philip N. Tsichlis, Dario Palmieri, Vincenzo Coppola. IWS1 is essential for mouse development [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 359.
Abstract 13486: Risk Stratification of Ventricular Fibrillation in Brugada Syndrome Using Non-invasive Scoring Methods
Authors: HiroshiKawazoe, YukikoNakano, TakehitoTokuyama, YukoUchimura, YoshikazuWatanabe, AkinoriSairaku, HiroyaMatsumura, ShinjiKishimoto, ShunsukeTomomori, YasukiKihara
Journal: Circulation (2014)

Aim: Risk stratification of ventricular fibrillation (VF) in Brugada syndrome remains controversial and it is difficult to describe using one parameter. We investigated whether we are able to assess VF risk using our non-invasive scoring method of each Brugada syndrome patients. Methods: We enrolled 46 patients with Brugada syndrome (45 men, average age 42 ± 3 years). Thirteen of the subjects had VF history or subsequent VF events (VF+) after implantable cardioverter defibrillator implantation. The frequency of Type1 Brugada ECG and positive TWA were significantly higher in VF+ patients than those without (Type 1 ECG 50% vs 4.8%, P=0.0003 and positive TWA 73.3% vs 6.7%, P<0.0001). We allocated each one point to type 1 Brugada type ECG, family history of sudden cardiac death, history of syncope, positive late potential, and positive time domain T wave alternance as Brugada risk score and count up the score the points in an each subject. The area under the receiver-operator characteristic (ROC) curve for ≥3...