tbuckley/cabot-search huggingface dataset:
Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA
Authors: Daniel A. Haber, Victor E. Velculescu
Journal: Cancer Discovery (2014)

The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments.Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis.
Hepatic Uptake of Bile Acids in Man
Authors: Bo Angelin, Ingemar Björkhem, Kurt Einarsson, Staffan Ewerth
Journal: Journal of Clinical Investigation (1982)

This investigation was undertaken in order to (a) characterize the postprandial inflow of individual bile acids to the liver and (b) determine if peripheral venous bile acid levels always adequately reflect the portal venous concentration, or if saturation of hepatic bile acid uptake can occur under physiological conditions. In five patients with uncomplicated cholesterol gallstone disease, the umbilical cord was cannulated during cholecystectomy, and a catheter was left in the left portal branch for 5 to 7 d. The serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid in portal venous and systemic circulation were then determined at intervals of 15 to 30 min before and after a standardized meal. A highly accurate and specific gas chromatographic/mass spectrometric technique was used.
Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism
Authors: Guy Meyer, Eric Vicaut, Thierry Danays, Giancarlo Agnelli, Cecilia Becattini, Jan Beyer-Westendorf, Erich Bluhmki, Helene Bouvaist, Benjamin Brenner, Francis Couturaud, Claudia Dellas, Klaus Empen, Ana Franca, Nazzareno Galiè, Annette Geibel, Samuel Z. Goldhaber, David Jimenez, Matija Kozak, Christian Kupatt, Nils Kucher, Irene M. Lang, Mareike Lankeit, Nicolas Meneveau, Gerard Pacouret, Massimiliano Palazzini, Antoniu Petris, Piotr Pruszczyk, Matteo Rugolotto, Aldo Salvi, Sebastian Schellong, Mustapha Sebbane, Bozena Sobkowicz, Branislav S. Stefanovic, Holger Thiele, Adam Torbicki, Franck Verschuren, Stavros V. Konstantinides
Journal: New England Journal of Medicine (2014)

The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial.In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization.Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42).In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).
Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias
Authors: Bastiaan J.D. Boukens, Vincent M. Christoffels, Ruben Coronel, Antoon F.M. Moorman
Journal: Circulation Research (2008)

Reentry is the main mechanism of life-threatening ventricular arrhythmias, including ventricular fibrillation and tachycardia. Its occurrence depends on the simultaneous presence of an arrhythmogenic substrate (a preexisting condition) and a “trigger,” and is favored by electrophysiological heterogeneities. In the adult heart, electrophysiological heterogeneities of the ventricle exist along the apicobasal, left–right, and transmural axes. Also, conduction is preferentially slowed in the right ventricular outflow tract, especially during pharmacological sodium channel blockade. We propose that the origin of electrophysiological heterogeneities of the adult heart lies in early heart development. The heart is formed from several progenitor regions: the first heart field predominantly forms the left ventricle, whereas the second heart field forms the right ventricle and outflow tract. Furthermore, the embryonic outflow tract consists of slowly conducting tissue until it is incorporated into the ventricles and develops rapidly conducting properties. The subepicardial myocytes and subendocardial myocytes run distinctive gene programs from their formation onwards. This review discusses the hypothesis that electrophysiological heterogeneities in the adult heart result from persisting patterns in gene expression and function along the craniocaudal and epicardial–endocardial axes of the developing heart. Understanding the developmental origins of electrophysiological heterogeneity contributing to ventricular arrhythmias may give rise to new therapies.
Pituitary-specific transcription factor (Pit-1) binding site in the human renin gene 5'-flanking DNA stimulates promoter activity in placental cell primary cultures and pituitary lactosomatotropic cell lines.
Authors: J Sun, C Oddoux, M T Gilbert, Y Yan, A Lazarus, W G Campbell, D F Catanzaro
Journal: Circulation Research (1994)

Renin gene expression is limited to a number of specific tissues, including the kidney, adrenal glands, reproductive organs (of particular relevance to this study, the placenta), and the pituitary gland. In the present study, we investigated the human renin (hRen) 5'-flanking DNA sequences required to drive the expression of a luciferase reporter gene in placental and pituitary cells and in two cell lines, 293 and JEG-3, which have been proposed as model systems with which to study transcriptional regulation of renin genes. The activities of specific sequences in the hRen 5'-flanking DNA sequences in human placental cell primary cultures were very similar to those that we previously reported in pituitary cells, suggesting the involvement of common promoter elements and related transcription factors. Accordingly, the binding site for the pituitary-specific transcription factor (Pit-1) was the major determinant of renin promoter activity in both pituitary and placental cells. Gel mobility shift analysis showed a placental nuclear factor with a gel mobility different from that of Pit-1. However, Northern blot analysis failed to demonstrate abundant Pit-1-related mRNAs in renin-expressing cultures of chorionic and decidual cells, suggesting that the placental factor is not closely related to Pit-1. Although a factor from 293 cells also bound to the Pit-1 site, it had gel mobility shift characteristics different from Pit-1 and the placental factor. Moreover, the low promoter activity in 293 cells was independent of this site or, indeed, of sequences upstream from the TATA box. In JEG-3 cells, renin 5'-flanking DNA sequences showed virtually no transcriptional activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations
Authors: A M Valdes, T D Spector, S Doherty, M Wheeler, D J Hart, M Doherty
Journal: Annals of the Rheumatic Diseases (2008)

Variants in the growth differentiation factor 5 (GDF5) and in the double von Willebrand factor A (DVWA) have recently been reported to be associated with osteoarthritis (OA) in Asian populations.To assess the role of such variants in OA susceptibility in two independent UK samples of Caucasian origin.Polymorphisms rs11718863 and rs7639618 (DVWA) and rs143383 (GDF5) were genotyped in 999 patients with knee OA, 843 patients with hip OA and 1166 controls from two UK studies from Nottingham and Chingford.In agreement with previous reports, the major allele at rs143383 (GDF5) was associated with a higher risk of knee OA in our samples (OR(MH) = 1.29, 95% CI 1.14 to 1.47 p = 8 x 10(-5)). Conversely, the major allele at the DVWA SNP rs7639618, which increased risk in Asians, was not associated with a risk of knee OA, (OR(MH) = 0.88, 95% CI 0.74 to 1.04; p = 0.12). A meta-analysis of Asian and UK knee OA data indicated highly significant heterogeneity (I(2) = 92%, Q = 48.5, p = 7 x 10(-10)) and no significant association with knee OA using a random effects meta-analysis (OR(DL) = 1.18, 95% CI 0.86 to 1.63; p = 0.309).These data confirm that the GDF5 variant is consistently associated with the risk of knee OA. Considerable ethnic variation in allele frequencies at the DVWA gene was found and no significant association was found in UK samples or by combining UK and Asian samples. The results suggest that the effect of DVWA amino acid changes on tubulin binding is unlikely to influence the risk of OA in Caucasians.
Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice.
Authors: S H Gavett, D J O'Hearn, X Li, S K Huang, F D Finkelman, M Wills-Karp
Journal: The Journal of Experimental Medicine (1995)

Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
Assessment of Airway Function Using Partial Expiratory Flow–Volume Curves
Authors: MATTHIAS HENSCHEN, JANET STOCKS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We investigated the extent to which measurements of maximal expiratory flow at FRC (V˙ emaxFRC) are influenced by the dynamic increase of FRC in young infants by superimposing partial forced expiratory flow–volume curves on those obtained after lung inflation to 2 kPa (20 cm H2O) in 12 infants during the first month of life. The elastic equilibrium volume (EEV) of the respiratory system was estimated by extrapolating the passive expiratory time constant (obtained after lung inflation but prior to forced deflation) to zero flow. There was a very strong relationship between V˙ emaxFRC (which ranged from 11 to 190 ml/s) and the extent to which FRC was dynamically increased above EEV (range: 0 to 5 ml/kg), r2 = 0.88. The results of this study suggest that, although V˙ emaxFRC remains a useful means of measuring peripheral airway function in infants, its values should be interpreted with caution during the neonatal period. In particular, the relatively high V˙ emaxFRC values reported in healthy newborn infants may reflect differences in breathing strategy rather than airway structure. More meaningful within- and between-infant comparisons of peripheral airway function may be obtained by calculating forced expiratory flows at a fixed interval (e.g., 3 ml/kg) above EEV, rather than at the FRC that is operational at the time of measurement.
Vitamin C Affects Thrombosis/ Fibrinolysis System and Reactive Hyperemia in Patients With Type 2 Diabetes and Coronary Artery Disease
Authors: Dimitris Tousoulis, Charalambos Antoniades, Charalambos Tountas, Erini Bosinakou, Maria Kotsopoulou, Pavlos Toutouzas, Christodoulos Stefanadis
Journal: Diabetes Care (2003)

OBJECTIVE—To examine the effect of vitamin C on forearm vasodilatory response to reactive hyperemia and on plasma level of plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), tissue plasminogen activator (tPA), antithrombin III (ATIII), proteins C and S, and factors V (fV) and VII (fVII) in patients with both type 2 diabetes and CAD. RESEARCH DESIGN AND METHODS—A total of 39 patients with type 2 diabetes and CAD were divided into two groups and received vitamin C (2 g/day) or no antioxidant for 4 weeks. Forearm blood flow was determined using venous occlusion gauge-strain plethysmography at baseline and after treatment. Forearm vasodilatory response to reactive hyperemia (RH%) or nitrate (NTG%) was defined as the percent change of flow from baseline to the maximum flow during reactive hyperemia or after administration of nitrate, respectively. Biochemical markers were determined by enzyme-linked immunosorbent assay (ELISA) or other standard methods. RESULTS—RH% was significantly increased after treatment with vitamin C (from 62.4 ± 7.2 to 83.1 ± 9.3%, P = 0.024) but remained unaffected in the control group. Vitamin C decreased plasma levels of fV (from 143 ± 5.4 to 123 ± 6.03%, P = 0.038), vWF (from 133.5 ± 14.5 to 109.5 ± 11.4%, P = 0.016), and tPA (from 12.3 ± 0.99 to 8.40 ± 0.60 ng/ml, P = 0.001), whereas these levels remained unaffected in the control group. The changes in RH%, vWF, and tPA were significantly greater (P = 0.028, 0.036, and 0.007, respectively) in the vitamin C-treated group than in the control group. Levels of ATIII, proteins S and C, fVII, and PAI-1 remained unchanged in all groups. CONCLUSIONS—Short-term treatment with high doses of vitamin C improved RH% and decreased plasma levels of tPA and vWF in patients with type 2 diabetes and CAD.
Expression of cathepsin K and matrix metalloproteinase 1 indicate persistent osteodestructive activity in long-standing ankylosing spondylitis
Authors: M Neidhart, X Baraliakos, C Seemayer, C Zelder, R E Gay, B A Michel, H Boehm, S Gay, J Braun
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Ankylosing spondylitis (AS) is a common, largely genetically determined, rheumatic disease that is characterised by spinal inflammation and new bone formation. However, the exact pathogenesis and pathology are still not clear. <h3>Objective:</h3> To analyse tissue obtained at spinal surgery by immunohistochemistry and compare the specimen of patients with AS to those with degenerative disc disease (DDD). <h3>Methods:</h3> Bony and soft tissue specimens of 30 patients with AS and 20 with DDD were obtained during spinal osteotomy from different anatomic regions including articular and spinous processes, interspinous ligaments and intervertebral disks. Immunohistolochemistry was performed with established markers for cathepsin K, matrix metalloproteinase (MMP)1, MMP3 and receptor activator for nuclear factor κB (RANK) ligand. <h3>Results:</h3> Cathepsin K and MMP1-positive cells were only observed in AS specimens. Cathepsin K-positive multinucleated cells were detected at articular processes adjacent to fibrous tissues. MMP1 was expressed in smaller mononuclear cells attached to bone. Invasion of bone by MMP1 cells was seen at entheseal sites. In the intervertebral disks, most mononuclear cells were cathepsin K-positive. Isolated cells expressing these matrix-degrading enzymes found in DDD never showed signs of invasion. No differences were found for MMP3 between AS and DDD. Clear expression of RANK ligand was only detected in one patient with AS. <h3>Conclusions:</h3> Cathepsin K is strongly expressed in different regions of the spine in AS. Cathepsin K was mainly expressed by mononuclear cells, fibroblast-like cells and cells attached to bone and at sites of bone remodelling, suggestive of high osteoclastic activity. This supports the role of persistent inflammation in the pathogenesis of AS. How these changes relate to osteoproliferation remains to be determined.
FDG PET-CT Aids in the Preoperative Assessment of Patients with Newly Diagnosed Thymic Epithelial Malignancies
Authors: Marcelo F.K. Benveniste, Cesar A. Moran, Osama Mawlawi, Patricia S. Fox, Stephen G. Swisher, Reginald F. Munden, Edith M. Marom
Journal: Journal of Thoracic Oncology (2013)
Comparison of reporting of ethnicity in US and European randomised controlled trials
Authors: Aziz Sheikh, Gopalakrishnan Netuveli, Joe Kai, Sukhmeet Singh Panesar
Journal: BMJ (2004)

Increasing evidence shows that different ethnic groups respond differently to educational, psychosocial, and pharmacological interventions. If diverse communities are to benefit from the implementation of appropriately derived evidence then it is imperative that the ethnic diversity of populations under study are reflected in clinical trials. In the United States, since 1993, the National Institutes of Health have instituted policy insisting that minority groups are represented in study samples unless there is a compelling reason not to do so.1 However, no comparable legislation exists in Europe. We sought to compare reporting of ethnicity in published reports of US and European randomised controlled studies.

We searched Medline for reports of trials published in 2002 using the Cochrane optimal search strategy.2 We downloaded titles and abstracts of study reports into the reference manager database and randomly …
Response to antibiotics of women with symptoms of urinary tract infection but negative dipstick urine test results: double blind randomised controlled trial
Authors: Dee Richards, Les Toop, Stephen Chambers, Lynn Fletcher
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To assess the effectiveness of antibiotic treatment of women with symptoms of urinary tract infection but negative urine dipstick testing. <b>Design</b> Prospective, double blind, randomised, placebo controlled trial. <b>Setting</b> Primary care, among a randomly selected group of general practitioners in Christchurch, New Zealand. <b>Participants</b> 59 women aged 16-50 years presenting with a history of dysuria and frequency in whom a dipstick test of midstream urine was negative for both nitrites and leucocytes. Participants with complicated urinary tract infection were excluded. <b>Intervention</b> Trimethoprim 300 mg daily for three days or placebo. <b>Main outcome measures</b> Self reported diary of symptoms for seven days, recording the presence or absence of individual symptoms each day, followed by a structured telephone questionnaire after seven days. The main clinical outcome was resolution of dysuria at three and seven days and median time to resolution. Secondary outcomes were resolution of other symptoms. <b>Results</b> The median time for resolution of dysuria was three days for trimethoprim compared with five days for placebo (P = 0.002). At day 3, five (24%) of patients in the treatment group had ongoing dysuria compared with 20 (74%) in the placebo group (P = 0.005). This difference persisted until day 7: two patients (10%) in the treatment group <i>v</i> 11 (41%) in the placebo group; P = 0.02). The number needed to treat was 4. The median duration of constitutional symptoms (feverishness, shivers) was reduced by four days. <b>Conclusions</b> Although a negative dipstick test for leucocytes and nitrites accurately predicted absence of infection when standard microbiological definitions were used (negative predictive value 92%), it did not predict response to antibiotic treatment. Three days9 treatment with trimethoprim significantly reduced dysuria in women whose urine dipstick test was negative. These results support the practice of empirical antibiotic use guided by symptoms. Balancing the competing interests of symptom relief and the minimisation of antibiotic use remains a dilemma—further research is needed to determine clinical predictors of response to antibiotics.
Factor Xa Activation of Factor V Is of Paramount Importance in Initiating the Coagulation System
Authors: Tim J. Schuijt, Kamran Bakhtiari, Sirlei Daffre, Kathleen DePonte, Simone J.H. Wielders, J. Arnoud Marquart, Joppe W. Hovius, Tom van der Poll, Erol Fikrig, Matthew W. Bunce, Rodney M. Camire, Gerry A.F. Nicolaes, Joost C.M. Meijers, Cornelis van ‘t Veer
Journal: Circulation (2013)

Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin.Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5.Our data elucidate a unique molecular mechanism by which ticks inhibit the host's coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors.