tbuckley/cabot-search huggingface dataset:
Snail and Slug Play Distinct Roles during Breast Carcinoma Progression
Authors: Christophe Côme, Fabrice Magnino, Frédéric Bibeau, Pascal De Santa Barbara, Karl Friedrich Becker, Charles Theillet, Pierre Savagner
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype. As previously suggested, this regulation could involve transcription factors, Snail and Slug, known to promote epithelial-mesenchymal transitions during development. Here, we investigate the role of Snail and Slug in human breast cancer progression. Experimental Design: We analyzed Snail, Slug, and E-cadherin RNA expression levels and protein localization in large numbers of transformed cell lines and breast carcinomas, examined the correlation with tumor histologic features, and described, at the cellular level, Snail and Slug localization in carcinomas using combined in situ hybridization and immunolocalization. Results: In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas. Snail also colocalized at the cellular level with E-cadherin in tumors expressing high levels of Snail RNA. In addition, Snail was significantly expressed in tumor stroma, varying with tumors. Slug and Snail genes were significantly overexpressed in tumors associated with lymph node metastasis. Finally, the presence of semidifferentiated tubules within ductal carcinomas was linked to Slug expression levels similar to or above normal breast samples. Conclusions: These results suggest that Snail or Slug expression in carcinoma cells does not generally preclude significant E-cadherin expression. They emphasize a link between Snail, Slug, and lymph node metastasis in a large sampling of mammary carcinomas, and suggest a role for Slug in the maintenance of semidifferentiated structures. Snail and Slug proteins seem to support distinct tumor invasion modes and could provide new therapeutic targets.
Inhaled hypertonic saline, mechanisms, and improved lung function in cystic fibrosis
Authors: A Gondker
Journal: Thorax (2006)

▴ Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med2006;354:241–50 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] This study compared the effect of inhaled hypertonic saline on 24 patients with cystic fibrosis over a 28 day period. Subjects were assigned to two groups receiving pretreatment with either amiloride or placebo before saline inhalation. One hour mucus clearance rates, lung function tests, and quality … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DDonaldson%26rft.auinit1%253DS.%2BH.%26rft.volume%253D354%26rft.issue%253D3%26rft.spage%253D241%26rft.epage%253D250%26rft.atitle%253DMucus%2BClearance%2Band%2BLung%2BFunction%2Bin%2BCystic%2BFibrosis%2Bwith%2BHypertonic%2BSaline%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa043891%26rft_id%253Dinfo%253Apmid%252F16421365%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa043891&link_type=DOI [3]: /lookup/external-ref?access_num=16421365&link_type=MED&atom=%2Fthoraxjnl%2F61%2F4%2F283.2.atom [4]: /lookup/external-ref?access_num=000234661100004&link_type=ISI
Treatment of prolonged ventricular fibrillation. Immediate countershock versus high-dose epinephrine and CPR preceding countershock.
Authors: J T Niemann, C B Cairns, J Sharma, R J Lewis
Journal: Circulation (1992)

BACKGROUND Early countershock of ventricular fibrillation has been shown to improve immediate and long-term outcome of cardiac arrest. However, a number of investigations in the laboratory and in the clinical population indicate that immediate countershock of prolonged ventricular fibrillation most commonly is followed by asystole or a nonperfusing spontaneous cardiac rhythm, neither of which rarely respond to current therapy. The use of epinephrine in doses greater than those currently recommended has recently been shown to improve both cerebral and myocardial perfusion during cardiopulmonary resuscitation (CPR). The purpose of this study was to compare cardiac resuscitation outcome between immediate countershock of prolonged ventricular fibrillation with high-dose epinephrine therapy and conventional CPR before countershock of prolonged ventricular fibrillation in a canine model. METHODS AND RESULTS After sedation, intubation, induction of anesthesia, and instrumentation, ventricular fibrillation was electrically induced in 28 dogs. After 7.5 minutes of ventricular fibrillation, animals were randomly allocated to two treatment groups: group 1, immediate countershock followed by recommended advanced cardiac life support (ACLS) interventions, or group 2, 0.08 mg/kg epinephrine and manual closed-chest CPR before countershock and ACLS. In both groups, ACLS was continued until a spontaneous perfusing rhythm was restored or for 20 minutes (total arrest time, 27.5 minutes). A spontaneous perfusing rhythm was restored in three of 14 group 1 animals and in nine of 14 group 2 animals (p = 0.014 by sequential analysis method of Whitehead). Coronary perfusion pressure (aortic minus right atrial pressure during CPR diastole) before countershock was significantly greater in group 2 (21 +/- 7 mm Hg) when compared with mean circulatory pressure in group 1 (9 +/- 8, p less than 0.01). CONCLUSIONS The findings of this study suggest that a brief period of myocardial perfusion before countershock improves cardiac resuscitation outcome from prolonged ventricular fibrillation.
Hepatitis B: The virus and disease
Authors: Jake T. Liang
Journal: Hepatology (2009)

Abstract Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. Virological and serological assays have been developed for diagnosis of various forms of HBV-associated disease and for treatment of chronic hepatitis B infection. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. Most adults infected with the virus recover, but 5%-10% are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention. Extrahepatic manifestations of HBV infection are rare but can be difficult to diagnose and manage. The challenges in the area of HBV-associated disease are the lack of knowledge in predicting outcome and progression of HBV infection and an unmet need to understand the molecular, cellular, immunological, and genetic basis of various disease manifestations associated with HBV infection. (Hepatology 2009;49:S13–S21.)
Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti–Toll-Like Receptor-2 Antibody
Authors: Fatih Arslan, Mirjam B. Smeets, Luke A.J. O'Neill, Brian Keogh, Peter McGuirk, Leo Timmers, Claudia Tersteeg, Imo E. Hoefer, Pieter A. Doevendans, Gerard Pasterkamp, Dominique P.V. de Kleijn
Journal: Circulation (2009)

Background— Reperfusion therapy for myocardial infarction is hampered by detrimental inflammatory responses partly via Toll-like receptor (TLR) activation. Targeting TLR signaling may optimize reperfusion therapy and enhance cell survival and heart function after myocardial infarction. Here, we evaluated the role of TLR2 as a therapeutic target using a novel monoclonal anti-TLR2 antibody. Method and Results— Mice underwent 30 minutes of ischemia followed by reperfusion. Compounds were administered 5 minutes before reperfusion. Cardiac function and dimensions were assessed at baseline and 28 days after infarction with 9.4-T mouse magnetic resonance imaging. Saline and IgG isotype treatment resulted in 34.5±3.3% and 31.4±2.7% infarction, respectively. Bone marrow transplantation experiments between wild-type and TLR2-null mice revealed that final infarct size is determined by circulating TLR2 expression. A single intravenous bolus injection of anti-TLR2 antibody reduced infarct size to 18.9±2.2% ( P =0.001). Compared with saline-treated mice, anti-TLR2–treated mice exhibited less expansive remodeling (end-diastolic volume 68.2±2.5 versus 76.8±3.5 μL; P =0.046) and preserved systolic performance (ejection fraction 51.0±2.1% versus 39.9±2.2%, P =0.009; systolic wall thickening 3.3±6.0% versus 22.0±4.4%, P =0.038). Anti-TLR2 treatment significantly reduced neutrophil, macrophage, and T-lymphocyte infiltration. Furthermore, tumor necrosis factor-α, interleukin-1α, granulocyte macrophage colony-stimulating factor, and interleukin-10 were significantly reduced, as were phosphorylated c-jun N-terminal kinase, phosphorylated p38 mitogen-activated protein kinase, and caspase 3/7 activity levels. Conclusions— Circulating TLR2 expression mediates myocardial ischemia/reperfusion injury. Antagonizing TLR2 just 5 minutes before reperfusion reduces infarct size and preserves cardiac function and geometry. Anti-TLR2 therapy exerts its action by reducing leukocyte influx, cytokine production, and proapoptotic signaling. Hence, monoclonal anti-TLR2 antibody is a potential candidate as an adjunctive for reperfusion therapy in patients with myocardial infarction.
Capturing intraoperative deformations: research experience at Brigham and Women’s hospital
Authors: Simon K. Warfield, Steven J. Haker, Ion-Florin Talos, Corey A. Kemper, Neil Weisenfeld, Andrea U.J. Mewes, Daniel Goldberg-Zimring, Kelly H. Zou, Carl-Fredrik Westin, William M. Wells, Clare M.C. Tempany, Alexandra Golby, Peter M. Black, Ferenc A. Jolesz, Ron Kikinis
Journal: Medical Image Analysis (2004)
Shared care or nursing consultations as an alternative to rheumatologist follow-up for rheumatoid arthritis outpatients with low disease activity—patient outcomes from a 2-year, randomised controlled trial
Authors: Jette Primdahl, Jan Sørensen, Hans Christian Horn, Randi Petersen, Kim Hørslev-Petersen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To compare patient outcomes of three regimes of follow-up care for rheumatoid arthritis (RA) outpatients with low disease activity. <h3>Methods</h3> RA outpatients (n=287) with Disease Activity Score (DAS28-CRP)&lt;3.2 and Health Assessment Questionnaire&lt;2.5 from two Danish rheumatology clinics were randomised to 2-year follow-up by either: (1) planned rheumatologist consultations, (2) shared care without planned consultations or (3) planned nursing consultations. The primary outcome was change in disease activity. DAS28-CRP, Health Assessment Questionnaire, visual analogue scale (VAS)-pain, fatigue, global health, confidence and satisfaction, quality-of-life by the Short Form 12 and self-efficacy measured by the RA Self-Efficacy questionnaire and the Arthritis Self-Efficacy Scale, were recorded annually and safety measures were recorded. x-Rays of hands and feet were taken at baseline and at 2-year follow-up. Mixed effect models were used to explore differences between the three groups over time. <h3>Results</h3> At 2-year follow-up, the group allocated to nursing consultations had lower disease activity than the group that underwent rheumatologist consultations (DAS28-CRP −0.3, p=0.049). The nursing group increased their self-efficacy (Arthritis Self-Efficacy Scale 18.8, p=0.001), confidence (10.7, p=0.001) and satisfaction (10.8, p&lt;0.001) compared with the rheumatologist group. The shared care group reported a transient lower satisfaction compared with the rheumatologist group after 1 year (−8.8, p=0.004). No statistically significant differences were seen in other outcome variables. <h3>Conclusions</h3> It is safe to implement shared care and nursing consultations as alternatives to rheumatologist consultations for RA outpatients with low disease activity without deterioration in disease control. Nursing consultations can enhance patients' self-efficacy, confidence and satisfaction.
Sexually dimorphic behavioral responses to prenatal dioxin exposure.
Authors: Rieko Hojo, Sander Stern, Grazyna Zareba, Vincent P Markowski, Christopher Cox, James T Kost, Bernard Weiss
Journal: Environmental Health Perspectives (2002)

Pregnant Sprague-Dawley rats received a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin on day 8 of gestation. Each litter contributed a single male-female pair trained to press a lever to obtain food pellets under two operant behavior procedures. Initially, each lever press was reinforced. The fixed-ratio (FR) requirement was then increased every four sessions from the initial setting of 1 to values between 6 and 71. We then studied responses for 30 days under a multiple schedule combining FR 11 and another schedule requiring a pause of at least 10 sec between responses (DRL 10-sec). TCDD evoked a sexually dimorphic response pattern. Generally, TCDD-exposed males responded at lower rates than control males. In contrast, exposed females responded at higher rates than controls. Each response measure from the mult-FR DRL schedule yielded a male-female difference score. We used the differences in response rate to calculate benchmark doses based on the relative displacement from modeled zero-dose performance of the effective dose at 1% (ED(01)) and 10% (ED(10)), as determined by a second-order polynomial fit to the dose-effect function. For the male-female difference in FR rate of responding, the mean ED(10) was 2.77 ng/kg with a 95% lower bound of 1.81 ng/kg. The corresponding ED(01) was 0.27 ng/kg with a 95% lower bound of 0.18 ng/kg. For the male-female difference in DRL rate, the mean ED(10) was 2.97 ng/kg with a 95% lower bound of 2.02 ng/kg. The corresponding ED(01) was 0.30 ng/kg with a 95% lower bound of 0.20 ng/kg. These values fall close to, but below, current estimates of human body burdens of 13 ng/kg, based on TCDD toxic equivalents.
The new hepatitis C virus bottleneck: Can delaying therapy be justified?
Authors: Tracey G. Simon, Raymond T. Chung
Journal: Hepatology (2015)

1Brigham and Women's HospitalBostonMA 2Massachusetts General HospitalBostonMA *Address reprint requests to: Raymond T. Chung, Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E‐mail: [email protected]
A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1
Authors: Janesh Pillay, Vera M. Kamp, Els van Hoffen, Tjaakje Visser, Tamar Tak, Jan-Willem Lammers, Laurien H. Ulfman, Luke P. Leenen, Peter Pickkers, Leo Koenderman
Journal: Journal of Clinical Investigation (2011)

Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMβ2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.
Pseudomonas aeruginosa pili bind to asialoGM1 which is increased on the surface of cystic fibrosis epithelial cells.
Authors: L Saiman, A Prince
Journal: Journal of Clinical Investigation (1993)

The basis for the unique association of Pseudomonas aeruginosa and the cystic fibrosis (CF) lung has remained obscure despite major advances in the understanding of the molecular genetic cause of this disease. There is evidence to suggest that abnormalities in CF transmembrane conductance regulator function result in alterations in the glycosylation of epithelial components. The number of asialoGM1 residues, as representative of a class of glycolipids which contain a GalNAc beta 1-4Gal sequence for P. aeruginosa attachment, was quantified by flow cytometric studies of respiratory epithelial cells in primary culture from both CF patients and normal subjects. Superficial asialoGM1 was detected on 12% of the CF cells as compared with 2.9% of the cells from normal control subjects (P = 0.03, chi 2 = 4.73), and more asialoGM1 residues were exposed on CF cells after modification by P. aeruginosa exoproducts. AsialoGM1, but not the sialylated glycolipid GM1, was demonstrated to be a receptor for 125I-labeled P. aeruginosa pilin, a major adhesin for this organism, and exogenous asialoGM1 was found to competitively inhibit P. aeruginosa adherence to epithelial cells, thus, confirming the biological role of the asialoGM1 receptor. Quantitative and qualitative differences in the sialylation of superficial glycolipids in CF epithelial cells may directly contribute to the colonization of the CF lung by P. aeruginosa.
Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer
Authors: Eva Pastille, Katrin Bardini, Diana Fleissner, Alexandra Adamczyk, Annika Frede, Munisch Wadwa, Dorthe von Smolinski, Stefan Kasper, Tim Sparwasser, Achim D. Gruber, Martin Schuler, Shimon Sakaguchi, Axel Roers, Werner Müller, Wiebke Hansen, Jan Buer, Astrid M. Westendorf
Journal: Cancer Research (2014)

Abstract Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3+ Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25− responder T cells ex vivo. Transient ablation of CD4+Foxp3+ Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFNγ/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC. Cancer Res; 74(16); 4258–69. ©2014 AACR.
Effects of Diphenylhydantoin on Excitability and Automaticity in the Canine Heart
Authors: J. THOMAS BIGGER, DANIEL I. WEINBERG, A. THOMAS W. KOVALIK, PAUL D. HARRIS, PAUL C. CRANEFIELD, BRIAN F. HOFFMAN
Journal: Circulation Research (1970)

Studies were performed on the dog heart in situ to determine the effects of diphenylhydantoin (DPH) on excitability and automaticity. DPH decreased automaticity in the His-Purkinje system, evidenced by an increase in the ventricular escape time both during vagal stimulation in intact dogs and after ventricular overdrive in dogs with heart block. The spontaneous ventricular rate of dogs with heart block was unaffected by doses up to 20 mg/kg. DPH had no significant effect on either atrial or ventricular diastolic threshold when this variable was tested with bipolar stimuli or with stigmatic anodal or cathodal stimuli. The effective refractory period of atrial and particularly of ventricular muscle was shortened by DPH (10 mg/kg); a leftward shift in the strength-interval curve occurred consistently. Multiple response threshold and fibrillation thresholds were elevated by DPH in both the ventricle and atrium (20 of 24 experiments). In anesthetized dogs, intraventricular conduction velocity increased minimally after DPH administration. DPH increased transmembrane threshold voltage and reduced the current required to stimulate isolated Purkinje fibers. The commercial solvent used clinically as a diluent for DPH was found to increase diastolic threshold and prolong the effective refractory period.
Outcome measures in chronic obstructive pulmonary disease (COPD)
Authors: A Dirksen
Journal: Thorax (2003)

Lung density determined by CT scanning may be a useful outcome measure in COPD

Forced expiratory volume in 1 second (FEV1) is by far the most well established outcome variable in obstructive pulmonary disease. Numerous studies have documented the correlation of this parameter with clinical variables such as severity of disease and mortality,1 and spirometric measurements have been standardised by international recommendations on lung function testing.2 Nevertheless, in real life the relevance of a maximal blow through a narrow tube is not always self-evident, and the intuitive clinical meaningfulness of this surrogate parameter is therefore perhaps less obvious. FEV1 has further limitations in chronic obstructive pulmonary disease (COPD). In general, dynamic lung volumes such as FEV1 and forced vital capacity (FVC) are highly effort dependent. However, in emphysematous subjects an abnormally low FEV1 is partly caused by the dynamic collapse of the airways which is also effort dependent. Therefore, in COPD the result of a more moderated manoeuvre is usually superior to the result of a maximal effort. This phenomenon adds to the variability of repeated measurements and, in COPD, the standard deviation of repeated measurements of FEV1 is larger than the annual decline, even in heavy smokers.3 For these reasons there is an increasing interest in other measures such as number of exacerbations or disease specific questionnaire scores as alternative outcome measures for monitoring the progress of emphysema in randomised clinical trials.

Another new outcome measure is lung density …
Loci at chromosomes 13, 19 and 20 influence age at natural menopause
Authors: Lisette Stolk, Guangju Zhai, Joyce B J van Meurs, Michael M P J Verbiest, Jenny A Visser, Karol Estrada, Fernando Rivadeneira, Frances M Williams, Lynn Cherkas, Panos Deloukas, Nicole Soranzo, Jules J de Keyzer, Victor J M Pop, Paul Lips, Corinne E I Lebrun, Yvonne T van der Schouw, Diederick E Grobbee, Jacqueline Witteman, Albert Hofman, Huibert A P Pols, Joop S E Laven, Tim D Spector, André G Uitterlinden
Journal: Nature Genetics (2009)