tbuckley/cabot-search huggingface dataset:
Rates of <i>ERBB2</i> Alterations across Melanoma Subtypes and a Complete Response to Trastuzumab Emtansine in an <i>ERBB2</i>-Amplified Acral Melanoma
Authors: Lee S. Gottesdiener, Shannon O'Connor, Klaus J. Busam, Helen Won, David B. Solit, David M. Hyman, Alexander N. Shoushtari
Journal: Clinical Cancer Research (2018)

Patients with BRAF V600 wild-type melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. ERBB2 alterations may be amenable to targeted inhibition, but the rate of ERBB2 alterations across melanoma subtypes is not well described.All patients with nonuveal melanoma (cutaneous, acral, mucosal, and unknown primary) whose tumors underwent multigene sequencing with MSK-IMPACT at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 were reviewed for known or likely oncogenic somatic alterations in ERBB2 and the other known canonical driver genes BRAF, NRAS, KIT, NF1, GNAQ, and GNA11.A patient with acral melanoma resistant to checkpoint inhibition was found to have ERBB2 amplification and achieved a durable complete response to trastuzumab emtansine. Tumor sequencing results from 732 melanoma cases were analyzed for ERBB2 and canonical driver gene alterations. ERBB2 amplifications were detected in acral (3%) and mucosal (3%) melanomas. ERBB2 mutations were found in cutaneous (1%), acral (2%), and mucosal (2%) subtypes and frequently cooccurred with NF1 alterations. Among the 140 patients whose tumors lacked canonical driver alterations, ERBB2 amplifications were detected in acral (7%) and mucosal (6%) melanomas.ERBB2 amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in ERBB2 were identified in nonuveal melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes.
Recombinant Growth Hormone Therapy in Patients With Ischemic Cardiomyopathy
Authors: SabineGenth-Zotz, RainerZotz, StefanieGeil, ThomasVoigtländer, JürgenMeyer, HaraldDarius
Journal: Circulation (1999)

Background—We studied the effects of recombinant growth hormone (rhGH) on exercise capacity and cardiac function in patients with ischemic cardiomyopathy. Methods and Results—Seven patients (aged 55±9 years) with mild to moderate congestive heart failure (ejection fraction 31±4%) who were on standard therapy were included. The patients were studied at baseline, after 3 months of rhGH treatment, and 3 months after rhGH discontinuation. Cardiac function was assessed by exercise capacity, right heart catheterization at rest and after submaximal exercise, MRI, echocardiography, and Holter monitoring. When administered at a dose of 2 IU/d, rhGH doubled the serum concentration of insulin-like growth factor-I. rhGH improved clinical symptoms and exercise capacity significantly (New York Heart Association class 2.4±0.5 initially versus 1.4±0.5 at 3 months [mean±SD], P<0.05; Vo2max 13.6±3.8 versus 17.4±5.4 mL · kg−1 · min−1, P<0.05). Additionally, pulmonary capillary wedge pressures at rest and after submaximal e...
Induction of Cytokine Expression in Leukocytes by Binding of Thrombin-Stimulated Platelets
Authors: Franz-JosefNeumann, NikolausMarx, MeinradGawaz, KorbinianBrand, IlkaOtt, ClaudiaRokitta, ChristianSticherling, ChristianMeinl, AndreasMay, AlbertSchömig
Journal: Circulation (1997)

Background Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI. Methods and Results We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean±SE of fluorescence [channels] before PTCA: 77±16 versus 35±9; Pequals;.003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL)-1β, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated ...
Abstract 18878: Statin Use and the Risk of Cataracts: A Systematic Review and Meta-Analysis of Cohort and Case-Control Studies
Authors: Shandong Yu, Yanpeng Chu, Gang Li, Lu Ren, Qing Zhang, Lin Wu
Journal: Circulation (2016)

Objective: To determine whether statin use is correlated with the increased risk of cataracts. Methods: A systematic search of the electronic databases PubMed, EMBASE, and the Cochrane Library thro...
Role of Nitric Oxide in the Regulation of Cerebral Blood Flow in Humans
Authors: ShaharLavi, RaniaEgbarya, RonitLavi, GirisJacob
Journal: Circulation (2003)

Background— From animal studies it emerged that nitric oxide is important for the modulation of CO2-mediated cerebral blood flow (CBF chemoregulation) but not for the pressor-dependent mechanism (mechanoregulation). This hypothesis was tested in 18 healthy subjects. Methods and Results— Peak velocity (PV), diastolic velocity (DV), and mean velocity (MV) were measured by transcranial Doppler of the middle cerebral artery. Chemoregulation was assessed during normocapnia, hypocapnia, and after inhaled mixture of 95% O2+5% CO2. Mechanoregulation was evaluated by incremental doses of phenylephrine. Measurements were repeated during infusion of sodium nitroprusside (SNP). Regional cerebrovascular resistance (CVR) was calculated as mean blood pressure (BP)/MV. SNP infusion decreased mean BP by 7 mm Hg and CVR decreased from 1.38±0.08 to 1.29±0.09 mm Hg/cm · s−1; P=0.01, resulting in unaffected CBF. Phenylephrine (25 to 250 μg) caused a similar increase in BP in a dose-response fashion before and during SNP infus...
Abstract 5700: IDO1 high expression is associated with a poor prognosis in patients with esophageal cancer
Authors: Yuki Kiyozumi
Journal: Cancer Research (2018)

Abstract [Background] Esophageal cancer is the sixth most common cause of death from cancer worldwide. Although the development of multidisciplinary treatment for esophageal cancer, the prognosis of those patients remains poor. Recently, immunotherapy is expected as innovative therapy for several types of cancer. Indoleamine 2, 3- Dioxygenase (IDO1) is an enzyme responsible for the oxidation of tryptophan into kynurenine and implicated in immune modulation through its ability to limit T cell function and engage mechanisms of immune tolerance. IDO1 is focused as one of the immune subversion strategy and the therapy of targeting IDO1 is in clinical development for many types of cancer. IDO1 activation induces the downregulation of activating natural killer (NK) cell receptors on NK cells and inhibition of cytotoxic T cells by promotion of cell cycle arrest and apoptosis. However, the significance of IDO1 expression in esophageal cancer remains still unknown. The aim of this study is to examine the relationship between IDO1 expression and tumoral immune status, and its prognostic impact in esophageal cancer. [Methods] IDO1 expression, cluster of differentiation (CD8) expression as a marker of cytotoxic T cells, forkhead Box P3 (FOXP3) as a maker of regulatory T cells were evaluated by immunostaining in 305 clinical samples of curative resected esophageal cancer. [Result] In 305 clinical samples, high IDO1 high expression (n=71) was significantly associated with poor prognosis in overall survival(OS)(p=0.0034). In uni-and multivariate analysis, IDO1 high expression was an independent prognostic factor for OS. In those patients, CD8 low expression was also associated with poor prognosis in OS (p = 0.025). Furthermore, double immunostaning with IDO1 and CD8 revealed that CD8 expression levels was inverse correlated with IDO1 expression levels in those patients. In combination analysis of IDO1 and CD8 expression, IDO1 high expression and CD8 low expression group experienced worse overall survival (p=0.0024). Conversely, IDO1 low expression and CD8 high expression group was shown the best overall survival. In addition, IDO1 high expression group is correlate with the high counts of FOXP3 positive cells (p = 0.02). [Conclusion] IDO1 expression was associated with an unfavorable clinical outcomes by induced immune tolerance and the classification of IDO1 and CD8 expression levels might serve as a predictive biomarker in esophageal cancer. The correlation between IDO1 and FOXP3 expression suggested that IDO1 involved in immune tolerance in esophageal cancer. These findings indicate that IDO1 would be a regulator of, and candidate therapeutic target in esophageal cancer. Citation Format: Yuki Kiyozumi. IDO1 high expression is associated with a poor prognosis in patients with esophageal 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 5700.
Abstract 45: The Identification and Hierarchy of Bone Marrow-derived Artery-resident Mesodermal Progenitor Cells and their Dynamics in Atherosclerosis
Authors: Hyun-Jai Cho, Hyun-Ju Cho, Yoo-Wook Kwon, Young-Bae Park, Hyo-Soo Kim
Journal: Circulation Research (2014)

Background: We recently identified bone marrow (BM)-derived artery resident calcifying progenitor cells. Sca-1+PDGFRα- cells may possess bipotent (osteoblastic/osteoclastic) characteristics. However, the nature of progenitor cells remains elusive. Therefore, we investigated developmental hierarchy of progenitor cells and in vivo dynamics in atherosclerosis. Methods and Results: We harvested cells from BM and artery of C57 mice. In BM, Lin-CD29+Sca-1+PDGFRα- cells showed hematopoietic potential and differentiated into osteoclasts OC). They also possessed mesenchymal stem cell property including osteoblastic (OB) differentiation, suggesting that Sca-1+PDGFRα- cells could be mesodermal progenitor cells. Interestingly, BM-derived artery-resident, clonal Sca-1+PDGFRα- cells maintained bipotency (OB/OC) but lost hematopoietic nature. In contrast, Sca-1+PDGFRα+ cells in BM and artery only showed unipotency (OB). When we overexpressed or knocked down PDGFRα, there was no alteration in OB or OC differentiation of Sca-1+PDGFRα- cells and no effect on OB differentiation of Sca-1+PDGFRα+ cells, indicating PDGFRα as a surface marker but not a functional player. In hyperlipidemic ApoE-KO mice compared with control, Sca-1+PDGFRα- cells were less mobilized from BM to peripheral circulation and less infiltrated into atherosclerotic plaque, whereas Sca-1+PDGFRα+ cells were not significantly affected. Multiplex cytokine assay of serum and artery revealed that IL-1β was significantly increased and IL-5 was markedly decreased in atherosclerotic mice. IL-1β decreased the migration of Sca-1+PDGFRα- cells by 5 folds compared with TNFα, and IL-5 increased the migration as much as TNFα. But the migration of Sca-1+PDGFRα+ cells was not altered. These data indicate that atherosclerosis-related humoral factors mainly regulated mesodermal progenitor cells’ dynamics. Conclusion: We demonstrate that Sca-1+PDGFRα- cell is a mesodermal progenitor cell that possesses both hematopoietic and mesenchymal potentials. In atherogenesis, the mobilization and infiltration of Sca-1+PDGFRα- progenitor cells were regulated by IL-1β and IL-5. These data provide a novel mechanism regarding the role of bipotent progenitor cells in atherosclerosis.
Movement of Labeled Cholesterol Between Plasma Lipoprotein and Normal Arterial Wall across the Intimal Surface
Authors: Seymourdayton, Samhashimoto
Journal: Circulation Research (1966)

Normal rat aortas were incubated with their intimal surfaces in contact with a lipoprotein solution containing isotopically labeled free cholesterol. Uptake of cholesterol by the tissue increased with increasing concentration toward a plateau level. Maximum uptake of free cholesterol was estimated to be 13 µg/cm2 per 24 hours, and uptake at physiological cholesterol concentration was 7.9 µg/cm2 per 24 hours. Aortas containing labeled cholesterol were prepared by intragastric administration of cholesterol-7α-3H to normal rats. Experiments in vitro with these aortas demonstrated that efflux across the intimal surface was dependent upon presence of lipoprotein in the medium. This efflux was not retarded by prior boiling of the tissue. These results support suggestions that movement of labeled free cholesterol from plasma into the arterial wall may be largely the result of a physicochemical exchange between lipoprotein and endothelium.
Abstract 20439: Sam68 Negatively Modulates Macrophage Autophagy in Atherosclerosis
Authors: Jiawei Shi, Shuling Han, Junlan Zhou, Liu Yang, Baron Arnone, Chan Boriboun, Congcong He, Gangjian Qin
Journal: Circulation (2016)

Background: Macrophage autophagy regulates the pathogenesis of atherosclerosis. The Src-associated substrate during mitosis of 68 kDa (Sam68) belongs to the family of KH domain RNA binding protein; its role in macrophage autophagy and atherosclerosis has not been studied. Methods & Results: In Raw264.7 macrophages, lentivirus-shRNA mediated knockdown of Sam68 (Sam68-KDn) led to a reduced protein level of total LC3, LC3-II, and p62/sqstm1 under basal culture condition, however, to a greater accumulation of LC3 in the presence of autolysosome inhibitor Bafliomycin A1, suggesting that Sam68 is physiologically a repressor of autophagy flux. Consistently, in HeLa/GFP-LC3 cells with Sam68-KDn, Bafliomycin A1 treatment also led to a greater autophagy flux than in control HeLa/GFP-LC3 cells, as revealed by autophagosome punctae counting (immuno-fluorescent microscopy) and median fluorescent intensity (flow cytometry). Notably, the mRNA levels of well-known transcriptional targets of autophagy related genes (MAP1L...
Abstract 2358: Uncovering novel mechanisms of resistance in AML using integrative functional genomics
Authors: Azucena Ramos, Luis R. Millan Barea, Alexandre Puissant, Nina Fenouille, Gabriela Alexe, Kimberly Stegmaier, Michael T. Hemann
Journal: Cancer Research (2018)

Abstract Treatment options that effectively cure patients diagnosed with acute myeloid leukemia (AML) continue to represent an area of unmet need in oncology clinical care. While remission rates in AML patients can reach upwards of 90% under the current frontline therapy paradigm, nearly all patients relapse with treatment refractory disease less than 5 years after diagnosis. Relapse driven by therapy resistant cells that persist in the body after treatment (defined as minimal residual disease, or MRD) is the principal source of fatality in AML patients. Therefore, understanding how and where these leukemic cells survive treatment in vivo may help advance the rational development of highly synergistic combination therapies for the treatment of AML. Using a functional genomic approach (in vivo RNAi) and a new mouse model of AML chemoresistance (ChemoR) generated in our labs, we have identified several putative mediators of therapy resistance. Transcriptional profiling of the ChemoR model allowed us to generate a chemoresistance gene signature that we overlapped with the results of the shRNA screen to identify high-confidence genes of interest. The top genes from a ranked list of the most highly overexpressed (OE) genes in ChemoR cells and the top depleted genes from the shRNA screen in the context of therapy treatment were selected as high interest hits and subsequently tagged for individual follow-up experiments. Early validation studies suggest that some of our hits protect leukemic cells resident only at specific anatomical niches from therapy, while other proteins appear to be general chemosensitizers both in vivo and in vitro, and in both murine and human AML. Subsequent work will focus on elucidating the mechanisms by which these proteins promote resistance to frontline therapies in AML. Citation Format: Azucena Ramos, Luis R. Millan Barea, Alexandre Puissant, Nina Fenouille, Gabriela Alexe, Kimberly Stegmaier, Michael T. Hemann. Uncovering novel mechanisms of resistance in AML using integrative functional genomics [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 2358.
Noninvasive Quantification of Coronary Blood Flow Reserve in Humans Using Myocardial Contrast Echocardiography
Authors: KevinWei, MichaelRagosta, JerrelThorpe, MatthewCoggins, SallyMoos, SanjivKaul
Journal: Circulation (2001)

Background—We hypothesized that coronary blood flow (CBF) reserve could be quantified noninvasively in humans using myocardial contrast echocardiography (MCE). Methods and Results—Eleven patients with normal epicardial coronary arteries (group I) and 19 with single-vessel coronary stenosis (group II) underwent quantitative coronary angiography, MCE, and CBF velocity measurements at rest and during intravenous adenosine infusion. In group I patients, MCE-derived myocardial blood flow (MBF) velocity reserve (2.4±0.08) was similar to CBF velocity reserve using a Doppler flow wire (2.4±1.1). Patients with a single risk factor had a significantly higher MBF reserve (3.0±0.89) than those with ≥2 risk factors (1.7±0.22). In group II patients, significant differences were found in MBF velocity reserve in patients with mild ( 75%) stenoses (2.2±0.40, 1.6±0.65, and 0.55±0.19, respectively; P=0.005). A linear relation was found between flow velocity reserve determined using t...
Antithrombin III Prevents Early Pulmonary Dysfunction After Lung Transplantation in the Dog
Authors: AngelSalvatierra, RafaelGuerrero, MarianoRodriguez, AntonioAlvarez, FuensantaSoriano, RosarioLopez-Pedrera, RafaelRamirez, JuliaCarracedo, FernandoLopez-Rubio, JavierLopez-Pujol, FranciscoVelasco
Journal: Circulation (2001)

Background— Ischemia-reperfusion injury with the resulting inflammatory response is a devastating complication of lung transplantation; much of the tissue damage could be diminished by control of the inflammatory response. Recent studies have show that antithrombin III (AT III) has an anti-inflammatory effect in addition to its established role in the regulation of blood coagulation. Thus, we hypothesized that the administration of AT III might help to prevent ischemia-reperfusion injury after lung transplantation. Methods and Results— The study was performed in a dog model of orthotopic lung transplantation. Dogs were randomly assigned to receive either vehicle (controls) or AT III. We observed that in control dogs, during the 180-minute period after lung transplantation, the arterial O2 partial pressure decreased and both the alveolar-arterial O2 difference and the pulmonary vascular resistance increased. By contrast, these parameters remained unchanged in the group of dogs receiving AT III. Dogs with t...
RICOCHET stuty: Receipt of curative resection or palliative care for hepatopancreaticobiliary tumours
Authors: S. McKay, G. Baker, D. Haldar, P. Harvey, M. Kalisvaart, G. Layton, A. Marley, R. Pandé, B. Stephenson, R. Wilkin, K. Roberts, N. Trudgill
Journal: International Journal of Surgery (2018)
Abstract 13635: Atorvastatin for the Prevention of Major Vascular Events in Patients Undergoing Non-Cardiac Surgery: The LOAD-Pilot Randomized Clinical Trial
Authors: Otavio Berwanger, Rafael M Soares, Dimas T Ikeoka, Denise M Paisani, Beatriz G Silva, Sabrina Bernardez-Pereira, Pedro G Barros, Philip J Devereaux, Renato D Lopes
Journal: Circulation (2015)

Background: There is not a single established effective and safe intervention to prevent major perioperative vascular complications that commonly occur in the first 30 days after noncardiac surgery. Hypothesis: We evaluated the feasibility of a multicenter randomized controlled trial (RCT) testing the perioperative effects of statins. Methods: This is a double blind, placebo-controlled RCT testing a short course of atorvastatin 80mg before surgery, followed by 40mg 12 hours after surgery and then 40mg/day for 7 days in patients undergoing noncardiac surgery who were at risk of a major perioperative vascular complication. The primary outcome (major vascular events) was a composite of all-cause mortality, nonfatal myocardial infarction, MINS (myocardial injury after noncardiac surgery) without myocardial infarction and nonfatal stroke at 30 days after randomization. All analysis followed the intention-to-treat principle. Results: We enrolled 587 patients from 30 centers in Brazil. Mean age was 66.6 years, 37.1% were males, 22.0% had previous cardiovascular disease, 50.2% had diabetes and 89.7 % had hypertension. The majority of participants underwent general (35.9%), orthopedic (30.0%), gynecologic (8.4%), urologic (7.3%), and vascular (6.6%) surgery. A total of 51 out of 300 patients (17.0%) suffered a major vascular complication in the atorvastatin group compared to 49 out of 287 patients (17.1%) in the control group at 30 days (hazard ratio [HR] 1,02; 95% confidence interval (CI) 0.68 to 1.52; P = 0.93). No significant effect was observed on the 30-day secondary outcomes of death or myocardial infarction (8.0% versus [vs.] 7.7%, respectively; HR 0.94; 95% CI 0.52 to 1.70; P = 0.84), myocardial infarction (3.7% vs. 4.5%, respectively; HR 0.84; 95% CI 0.37 to 1.93; P = 0.68), MINS (14.0% vs.15.0%; HR 0.94; 95% CI 0.53 to 1.67; P = 0.84), and all-cause mortality (4.7% vs. 4.5%; HR 1.22; 95% CI 0.53 to 2.78; P = 0.64). Conclusions: The LOAD Trial confirms that a multicenter perioperative statin trial is feasible and highlights the need for large RCTs to establish effective and safe interventions. The study also suggests that effects of a perioperative statin on major vascular complications are, at best, moderate in size, questioning the robustness of prior data.
Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats
Authors: Pierre-LouisTharaux, ChristosChatziantoniou, DanielCasellas, LauraFouassier, RaymondArdaillou, Jean-ClaudeDussaule
Journal: Circulation (1999)

Background—The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process. Methods and Results—Treatment of rats for 4 weeks with the NO synthase inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) 50 mg · kg−1 · d−1 increased systolic blood pressure to 159±12 mm Hg. In animals treated with L-NAME, histological evaluation of renal sections revealed an increased formation of extracellular matrix (Masson’s trichrome), and specifically of collagens (Sirius red). A part of this fibrosis was attributed to abnormal collagen I presence, because mRNA expression of the collagen I α1 chain (reverse transcription–polymerase chain reaction) and procollagen I formation (radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the renal resistance vessels of hypertensive animals. In s...