tbuckley/cabot-search huggingface dataset:
Regulation of Tissue Plasminogen Activator in Sickle Cell Anemia
Authors: George Phillips, John Hartman, V. Antoine Keller, Manuel A. Santiago, Salvatore Pizzo
Journal: American Journal of Hematology (1990)

Abstract Evidence of activation of the clotting system in individuals with sickle cell anemia (SCA) has been observed by several investigators. It has been suggested that the clotting and fibrinolytic systems may play a role in the pathophysiology of vaso‐occlusion in SCA. We reported previously evidence of abnormal fibrinolytic activity as reflected in decreased releasable tissue plasminogen activator (t‐PA) using a functional assay. We have examined the mechanism of the decreased functional releasable t‐PA in individuals with SCA. We studied 12 patients with respect to releasable t‐PA, fast acting inhibitor to t‐PA (or PAI‐1), and immunoreactive or antigenic t‐PA. These SCA individuals were at their baseline states and not taking medications known to interfere with the fibrinolytic or clotting systems. We found that the mean releasable t‐PA for the SCA individuals was 0.01 IU/ml of plasma with a standard error of mean (SEM) of 0.01. The mean releasable t‐PA of 118 healthy normal controls was 0.70 IU/ml with SEM 0.10 ( P &lt; 0.001). The mean level of fast‐acting inhibitor to t‐PA in unoccluded circulation of the SCA patients' plasma was 16.5 IU/ml with SEM of 3.54. The mean plasma levels of fast‐acting inhibitor to t‐PA in 56 healthy controls was 2.56 IU/ml with SEM of 0.29 ( P &lt; 0.0001). The SCA patients had a mean baseline t‐PA antigen level of 5.98 ng/ml with SEM of 1.72. The mean level of t‐PA antigen of 78 healthy controls using the same technique was 4.3 ng/ml with SEM of 2.7 (not significant). The mean baseline functional t‐PA for SCA individuals was 0.15 IU/ml with SEM 0.01 and the mean baseline functional t‐PA for 118 controls was 0.17 IU/ml with SEM 0.10. These data suggest that the mechanism of decreased releasable t‐PA in sickle cell anemia is related to an elevation of fast‐acting inhibitor to t‐PA and that antigenically t‐PA is present in normal quantities in the baseline plasma in this population.
The Role of <i>Brg1</i>, a Catalytic Subunit of Mammalian Chromatin-remodeling Complexes, in T Cell Development
Authors: Thomas C. Gebuhr, Grigoriy I. Kovalev, Scott Bultman, Virginia Godfrey, Lishan Su, Terry Magnuson
Journal: The Journal of Experimental Medicine (2003)

Mammalian SWI–SNF-related complexes use brahma-related gene 1 (Brg1) as a catalytic subunit to remodel nucleosomes and regulate transcription. Recent biochemical data has linked Brg1 function to genes important for T lymphocyte differentiation. To investigate the role of SWI–SNF-related complexes in this lineage, we ablated Brg1 function in T lymphocytes. T cell–specific Brg1-deficient mice showed profound thymic abnormalities, CD4 derepression at the double negative (DN; CD4− CD8−) stage, and a developmental block at the DN to double positive (CD4+ CD8+) transition. 5′-bromo-2′-deoxyuridine incorporation and annexin V staining establish a role for Brg1 complexes in the regulation of thymocyte cell proliferation and survival. This Brg1-dependent cell survival is specific for developing thymocytes as indicated by the presence of Brg1-deficient mature T lymphocytes that have escaped the developmental block in the thymus. However, reductions in peripheral T cell populations lead to immunodeficiency and compromised health of mutant mice. These results highlight the importance of chromatin-remodeling complexes at different stages in the development of a mammalian cell lineage.
Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells
Authors: Nikolaus Marx, Uwe Schönbeck, Mitchell A. Lazar, Peter Libby, Jorge Plutzky
Journal: Circulation Research (1998)

Abstract —Migration of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, contributes to VSMC migration. This process requires degradation of basal laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor family, regulate gene expression after activation by various ligands. Recent studies have suggested opposing effects of PPAR gamma (PPARγ) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPARα) and PPARγ and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPARα and PPARγ mRNA and protein. Treatment of VSMCs with the PPARγ ligands troglitazone and the naturally occurring 15-deoxy- Δ12,14 -prostaglandin J 2 (15d-PGJ 2 ) decreased phorbol 12-myristate 13-acetate–induced MMP-9 mRNA and protein levels, as well as MMP-9 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPARα activators lacked such effects. Addition of prostaglandin F 2α , known to limit PPARγ activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ 2 , further implicating PPARγ in these effects. Finally, troglitazone and 15d-PGJ 2 inhibited the platelet-derived growth factor-BB–induced migration of VSMCs in vitro in a concentration-dependent manner. PPARγ activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPARγ activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPARγ effects.
Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction
Authors: Monika K. Duda, Karen M. O'Shea, Anselm Tintinu, Wenhong Xu, Ramzi J. Khairallah, Brian R. Barrows, David J. Chess, Agnes M. Azimzadeh, William S. Harris, Victor G. Sharov, Hani N. Sabbah, William C. Stanley
Journal: Cardiovascular Research (2008)

Clinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)].We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha.Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.
Predicting Death in Patients With Acute Type A Aortic Dissection
Authors: Rajendra H. Mehta, Toru Suzuki, Peter G. Hagan, Eduardo Bossone, Dan Gilon, Alfredo Llovet, Luis C. Maroto, Jeanna V. Cooper, Dean E. Smith, William F. Armstrong, Christoph A. Nienaber, Kim A. Eagle
Journal: Circulation (2002)

Given the high mortality rates in patients with type A aortic dissection, predictive tools to identify patients at increased risk of death are needed to assist clinicians for optimal treatment.Accordingly, we evaluated 547 patients with this diagnosis enrolled in the International Registry of Acute Aortic Dissection (IRAD) between January 1996 and December 1999. Univariate testing followed by multivariate logistic regression analysis was performed to identify independent predictors of death. In-hospital mortality rate was 32.5% in type A dissection patients. In-hospital complications (neurological deficits, altered mental status, myocardial or mesenteric ischemia, kidney failure, hypotension, cardiac tamponade, and limb ischemia) were increased in patients who died compared with survivors (P<0.05 for all). Logistic regression identified the following presenting variables as predictors of death: age > or =70 years (OR, 1.70; 95% CI, 1.05 to 2.77; P=0.03), abrupt onset of chest pain (OR 2.60; 95% CI, 1.22 to 5.54; P=0.01), hypotension/shock/tamponade (OR, 2.97; 95% CI, 1.83 to 4.81; P<0.0001), kidney failure (OR, 4.77; 95% CI, 1.80 to 12.6; P=0.002), pulse deficit (OR, 2.03; 95% CI, 1.25 to 3.29, P=0.004), and abnormal ECG (OR, 1.77; 95% CI, 1.06 to 2.95; P=0.03) (area under receiver operating curve, 0.74; Hosmer-Lemeshow statistic, P=0.75).The in-hospital mortality rate in acute type A aortic dissection is high and can be predicted with the use of a clinical model incorporated in a simple risk prediction tool. This tool can be used to educate patients with dissection about their predicted risk and in clinical research for risk adjustment while comparing outcomes of different therapies.
Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor- and PTGS2
Authors: Urszula Dougherty, Dario Cerasi, Ieva Taylor, Masha Kocherginsky, Ummuhan Tekin, Shamiram Badal, Lata Aluri, Amikar Sehdev, Sonia Cerda, Reba Mustafi, Jorge Delgado, Loren Joseph, Hongyan Zhu, John Hart, David Threadgill, Alessandro Fichera, Marc Bissonnette
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined. Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR. Results: Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P &amp;lt; 0.05) and cancer incidence (43.9 versus 16.7; P &amp;lt; 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon. Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)
SURFACE TENSION OF SERUM
Authors: P. Lecomte du Noüy
Journal: The Journal of Experimental Medicine (1922)

1. The surface tension of pure serum, heated at 55 degrees C., decreases progressively and regularly until the serum coagulates. A drop of 8.2 dynes was observed in 168 hours. The mean drop was 5.7 dynes in 120 hours and 4 dynes in 96 hours. 2. The initial surface tension of solutions of serum at the concentrations 10(-1) up to 10(-6) is practically not affected by heat, but the time-drop in 2 hours is modified. 3. Each serum seems to react in its own particular way as far as the time-drop is concerned. However, there is a general tendency for the solution to show an increase of time-drop at the concentrations 10(-1), 10(-2), 10(-3) and 10(-5), and a decrease at 10(-4), when heated at 55 degrees C. a decrease of the time-drop at the concentrations 10(-1), 10(-2) and 10(-3), and an increase at 10(-4) when heated at 100 degrees C. 4. Nevertheless, only the changes observed below 10(-3) are constant in sign, within 75 or 80 per cent of the cases. The concentration 10(-4) seems to correspond to a state of greater instability. This confirms the hypothesis of the existence of a monomolecular layer at that concentration, which was assumed on the basis of the existence of a maximum drop at 10(-4). Should this be true, and provided the principle of Gibbs could be transformed so as to be applicable to mixed solutions of colloids and crystalloids, an idea of the size, or at least of one of the dimensions of the molecules or group molecules composing the serum could probably be obtained. 5. 1 drop of the solutions at 1:10 evaporated on glass and examined under the microscope shows the marked differences brought about by heating at different temperatures.
Cyclooxygenase-2–Derived Prostaglandin E <sub>2</sub> Promotes Injury-Induced Vascular Neointimal Hyperplasia Through the E-prostanoid 3 Receptor
Authors: Jian Zhang, Fangfang Zou, Juan Tang, Qianqian Zhang, Yanjun Gong, Qingsong Wang, Yujun Shen, Lixia Xiong, Richard M. Breyer, Michael Lazarus, Colin D. Funk, Ying Yu
Journal: Circulation Research (2013)

Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E₂ is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown.This study investigates the impact of COX-2-derived PGE₂ on neointima formation after injury.Vascular remodeling was induced by wire injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 knockout mice as compared with controls, whereas these parameters were enhanced in COX-1>COX-2 mice, in which COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE₂ by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE₂ enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by decreasing small GTPase activity and restricted vascular neointimal hyperplasia, whereas overexpression of EP3α and EP3β aggravated neointima formation. Inhibition or deletion of EP3α/β, a Gαi protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE₂ could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3β signaling in VSMCs through Gβγ subunits on EP3α/β activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration.COX-2-derived PGE₂ facilitated the neointimal hyperplasia response to injury through EP3α/β-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.
Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer
Authors: Aung Naing, Razelle Kurzrock, Angelika Burger, Sachin Gupta, Xiudong Lei, Naifa Busaidy, David Hong, Helen X. Chen, Lawrence A. Doyle, Lance K. Heilbrun, Eric Rohren, Chaan Ng, Chandtip Chandhasin, Patricia LoRusso
Journal: Clinical Cancer Research (2011)

Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab.Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD).Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3.Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.
Concerted Potent Humoral Immune Responses to Autoantigens Are Associated with Tumor Destruction and Favorable Clinical Outcomes without Autoimmunity
Authors: Taylor Sittler, Jun Zhou, Joosang Park, Noah K. Yuen, Stefanie Sarantopoulos, Joseph Mollick, Ravi Salgia, Anita Giobbie-Hurder, Glenn Dranoff, F. Stephen Hodi
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy. Experimental Design: Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non–small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies. Results: Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients. Conclusions: This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.
Interferon γ Stabilizes the T Helper Cell Type 1 Phenotype
Authors: Yongkang Zhang, Ron Apilado, John Coleman, Shlomo Ben-Sasson, Sharon Tsang, Jane Hu-Li, William E. Paul, Hua Huang
Journal: The Journal of Experimental Medicine (2001)

T helper cell (Th)1-primed CD4 T cells from wild-type donors make little interleukin (IL)-4 when restimulated under Th2 conditions. However, such restimulation of Th1-primed cells from interferon (IFN)-gamma(2/-) or IFN-gamma receptor (IFN-gammaR)(-/-) mice resulted in substantial production of IL-4 and other Th2 cytokines. Adding IFN-gamma to the priming culture markedly diminished the capacity of Th1-primed IFN-gamma(2/-) cells to express IL-4. Even IFN-gamma-producing cells from IFN-gammaR(-/-) mice could acquire IL-4-producing capacity. Thus, IFN-gamma is not required for the development of IFN-gamma-producing capacity, but it plays a critical role in suppressing the IL-4-producing potential of Th1 cells.
Influence of Panic-Agoraphobic Spectrum Symptoms on Treatment Response in Patients With Recurrent Major Depression
Authors: E Frank, M K Shear, P Rucci, J M Cyranowski, J Endicott, A Fagiolini, V J Grochocinski, P Houck, D J Kupfer, J D Maser, G B Cassano
Journal: American Journal of Psychiatry (2000)

The authors tested the hypothesis that a lifetime history of panic-agoraphobic spectrum symptoms predicts a poorer response to depression treatment.A threshold for clinically meaningful panic-agoraphobic spectrum symptoms was defined by means of receiver operating characteristic curve analysis of total scores on the Structured Clinical Interview for Panic-Agoraphobic Spectrum in a group of 88 outpatients with and without panic disorder. This threshold was then applied to a group of 61 women with recurrent major depression, who completed a self-report version of the same instrument, in order to compare treatment outcomes for patients above and below this clinical threshold.Women with high scores (> or =35) on the Panic-Agoraphobic Spectrum Self-Report were less likely than women with low scores (<35) to respond to interpersonal psychotherapy alone (43.5% versus 68.4%, respectively). Women with high scores also took longer (18.1 versus 10.3 weeks) to respond to a sequential treatment paradigm (adding a selective serotonin reuptake inhibitor when depression did not remit with interpersonal psychotherapy alone). This effect was only partially accounted for by the higher likelihood that patients with high scores required the addition of antidepressants. Although four domains from the Panic-Agoraphobic Spectrum Self-Report were individually associated with a longer time to remission, only stress sensitivity emerged as significant in multivariate regression analyses.A lifetime burden of panic-agoraphobic spectrum symptoms predicted a poorer response to interpersonal psychotherapy and an 8-week delay in sequential treatment response among women with recurrent depression. These results lend clinical validity to the spectrum construct and highlight the need for alternate psychotherapeutic and pharmacologic strategies to treat depressed patients with panic spectrum features.