tbuckley/cabot-search huggingface dataset:
Altered peripheral vascular responses to exogenous and endogenous endothelin-1 in patients with well-compensated cirrhosis
Authors: Ahmed Helmy, Rajiv Jalan, David Ernest Newby, Neil Russell Johnston, Peter Clive Hayes, David John Webb
Journal: Hepatology (2001)

Plasma endothelin concentrations are elevated in cirrhosis and correlate with disease severity. This study assessed forearm vascular responses to exogenous endothelin–1 (ET–1), and evaluated the contribution of endogenous ET–1 to the maintenance of basal peripheral vascular tone in patients with well–compensated cirrhosis (n = 11) and matched healthy controls (n = 8). Bilateral forearm blood flow (FBF) was measured at baseline and following unilateral, subsystemic, intrabrachial artery infusions of ET–1 (2 and 6 pmol/min); BQ–123, a selective ET A receptor antagonist (3 and 10 nmol/min); and BQ–788, a selective ET B receptor antagonist (0.3 and 1 nmol/min) using venous occlusion plethysmography. Baseline systemic hemodynamics and plasma ET–1 and big ET–1 concentrations were measured using electrical bioimpedance and radioimmunoassay, respectively. Patients and controls had similar baseline FBF, systemic hemodynamics, and plasma ET–1 and big ET–1 concentrations. In both groups, ET–1 and BQ–788 caused significant vasoconstriction ( P &lt; .001) and BQ–123 caused significant vasodilatation ( P &lt; .001). Compared with controls, cirrhotic patients had attenuated ET–1 responses ( P &lt; .001), augmented BQ–123 responses ( P &lt; .001), and similar BQ–788 responses ( P = .62). Despite normal systemic hemodynamics and plasma ET–1 concentrations, forearm vascular responses to exogenous ET–1 are reduced in cirrhotic patients. The augmented vasodilatation to BQ–123 in cirrhotic patients is consistent with a compensated vasodilated state, and a greater contribution of ET–1 to the maintenance of basal vascular tone acting through the ET A receptor.
Discovery of Novel Genes Derived from Transposable Elements Using Integrative Genomic Analysis
Authors: Douglas R. Hoen, Thomas E. Bureau
Journal: Molecular Biology and Evolution (2015)

Complex eukaryotes contain millions of transposable elements (TEs), comprising large fractions of their nuclear genomes. TEs consist of structural, regulatory, and coding sequences that are ordinarily associated with transposition, but that occasionally confer on the organism a selective advantage and may thereby become exapted. Exapted transposable element genes (ETEs) are known to play critical roles in diverse systems, from vertebrate adaptive immunity to plant development. Yet despite their evident importance, most ETEs have been identified fortuitously and few systematic searches have been conducted, suggesting that additional ETEs may await discovery. To explore this possibility, we develop a comprehensive systematic approach to searching for ETEs. We use TE-specific conserved domains to identify with high precision genes derived from TEs and screen them for signatures of exaptation based on their similarities to reference sets of known ETEs, conventional (non-TE) genes, and TE genes across diverse genetic attributes including repetitiveness, conservation of genomic location and sequence, and levels of expression and repressive small RNAs. Applying this approach in the model plant Arabidopsis thaliana, we discover a surprisingly large number of novel high confidence ETEs. Intriguingly, unlike known plant ETEs, several of the novel ETE families form tandemly arrayed gene clusters, whereas others are relatively young. Our results not only identify novel TE-derived genes that may have practical applications but also challenge the notion that TE exaptation is merely a relic of ancient life, instead suggesting that it may continue to fundamentally drive evolution.
Indoor Tanning — Science, Behavior, and Policy
Authors: David E. Fisher, William D. James
Journal: New England Journal of Medicine (2010)

An estimated 1 million times per day, someone in the United States uses ultraviolet (UV) radiation for skin tanning. According to the indoor tanning industry, tanning beds are used by 30 million Americans, or about 10% of the U.S. population, each year (www.theita.com/indoor). These users include minors, who often have ready access to tanning beds. In response to considerable grassroots and political opposition to indoor tanning, in late March the Food and Drug Administration (FDA) convened an advisory panel to review the safety of the procedure. The FDA is expected to announce a decision soon on whether and how to . . .
Phase 1 Study of Lumiliximab with Detailed Pharmacokinetic and Pharmacodynamic Measurements in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: John C. Byrd, Susan O'Brien, Ian W. Flinn, Thomas J. Kipps, Mark Weiss, Kanti Rai, Thomas S. Lin, James Woodworth, Dee Wynne, Jennifer Reid, Arturo Molina, Bryan Leigh, Sarah Harris
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Therapeutic antibodies have improved the outcome for patients with chronic lymphocytic leukemia (CLL). We conducted a phase 1, dose escalation and schedule optimization study of the primatized anti-CD23 antibody, lumiliximab, in patients with previously treated and refractory CLL. Experimental Design: Forty-six patients were assigned sequentially to cohorts 1 through 6 and received lumiliximab at 125, 250, or 375 mg/m2 weekly for 4 weeks; 500 mg/m2 weekly for 4 weeks [500(A)]; 500 mg/m2 thrice during week 1 then 500 mg/m2 weekly for the next 3 weeks [500(B)]; or 500 mg/m2 thrice a week for 4 weeks [500(C)], respectively. Results: The median age was 62 years (range, 47-80), and the median number of prior regimens was four (range, 1-13). No partial or complete responses were observed. Toxicity was limited and unrelated to dose. The pharmacokinetics of lumiliximab was similar to other IgG1 monoclonal antibodies with accumulation at doses ≥250 mg/m2 and a median terminal half-life of 7 days. Pharmacodynamic studies showed dose-dependent increases in soluble CD23, but no down-regulation of CD23 antigen. Saturation of CD23 receptors occurred at 250 mg/m2 and was maintained for ≥1 week following completion of therapy at ≥375 mg/m2. Conclusions: Treatment with lumiliximab seemed to be well tolerated and to have clinical activity in patients with relapsed or refractory CLL.
Active case finding of tuberculosis in Europe: a Tuberculosis Network European Trials Group (TBNET) survey
Authors: G. H. Bothamley, L. Ditiu, G. B. Migliori, C. Lange
Journal: European Respiratory Journal (2008)

Tuberculosis control depends on successful case finding and treatment of individuals infected with Mycobacterium tuberculosis . Passive case finding is widely practised: the present study aims to ascertain the consensus and possible improvements in active case finding across Europe. Recommendations from national guidelines were collected from 50 countries of the World Health Organization European region using a standard questionnaire. Contacts are universally screened for active tuberculosis and latent tuberculosis infection (LTBI). Most countries (&gt;70%) screen those with HIV infection, prisoners and in-patient contacts. Screening of immigrants is related to their contribution to national rates of tuberculosis. Only 25 (50%) out of 50 advise a request for symptoms in their guidelines. A total of 36 (72%) out of 50 countries recommend sputum examination for those with a persistent cough; 13 countries do not, even if the chest radiograph suggests tuberculosis. Nearly all countries (49 out of 50) use tuberculin skin testing (TST); 27 (54%) out of 50 countries also perform chest radiography irrespective of the TST result. Interpretation of the TST varies widely. All countries use 6–9 months of isoniazid for treatment of LTBI, with an estimated median (range) uptake of 55% (5–92.5%). Symptoms and sputum examination could be used more widely when screening for active tuberculosis. Treatment of latent tuberculosis infection might be better focused by targeted use of interferon-γ release assays.
Divergent Siblings
Authors: Henning Ebelt, Nadine Hufnagel, Petra Neuhaus, Herbert Neuhaus, Praveen Gajawada, Andreas Simm, Ursula Müller-Werdan, Karl Werdan, Thomas Braun
Journal: Circulation Research (2005)

Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.
Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights from the <scp>GISSI‐HF</scp> and Val‐<scp>HeFT</scp> trials
Authors: Patrick Rossignol, Serge Masson, Simona Barlera, Nicolas Girerd, Angelo Castelnovo, Faiez Zannad, Francesco Clemenza, Gianni Tognoni, Inder S. Anand, Jay N. Cohn, Stefan D. Anker, Luigi Tavazzi, Roberto Latini
Journal: European Journal of Heart Failure (2015)
Randomized Comparison of Primary Stenting and Provisional Balloon Angioplasty Guided by Flow Velocity Measurement
Authors: Patrick W. Serruys, Bernard de Bruyne, Stéphane Carlier, José Eduardo Sousa, Jan Piek, Toshiya Muramatsu, Chris Vrints, Peter Probst, Ricardo Seabra-Gomes, Ian Simpson, Vasilis Voudris, Olivier Gurné, Nico Pijls, Jorge Belardi, Gerrit-Anne van Es, Eric Boersma, Marie-Angèle Morel, Ben van Hout
Journal: Circulation (2000)

Background —Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive. Methods and Results —To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is “optimal.” An optimal result was defined as a flow reserve &gt;2.5 and a diameter stenosis &lt;36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P =0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P =0.066). Conclusions —After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty.
Where Does Combination Therapy With an SGLT2 Inhibitor Plus a DPP-4 Inhibitor Fit in the Management of Type 2 Diabetes?
Authors: Muhammad Abdul-Ghani
Journal: Diabetes Care (2015)

Hyperglycemia is the critical risk factor for diabetic microvascular complications. Several landmark studies, e.g., UK Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT), have demonstrated that lowering the HbA1c by 1% decreases microvascular complications by approximately 35% (1,2). Despite the unequivocal evidence for the importance of achieving good glycemic control in patients with type 2 diabetes mellitus (T2DM), approximately half of individuals with T2DM fail to achieve the American Diabetes Association (ADA) goal of glycemic control (HbA1c <7.0%) (3). Thus, novel therapeutic agents and strategies are required to improve glycemic control in T2DM patients.

Two novel classes of antihyperglycemic drugs have been developed during the last decade for the treatment of T2DM: dipeptidyl peptidase-4 inhibitors (DPP-4i) (4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) (5).

DPP-4i have been in clinical use for the treatment of T2DM for more than a decade. DPP-4i inhibit the enzyme that degrades the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and result in elevated plasma GLP-1 and GIP concentrations. The increase in plasma GLP-1 and GIP concentrations stimulates insulin secretion from the β-cell and inhibits glucagon secretion from the α-cell, leading to inhibition of endogenous glucose production (EGP) and reduction in plasma glucose concentration (6).

SGLT2i are a novel class of antidiabetes drugs that recently have been approved for the treatment of T2DM. Members of this class reduce the plasma glucose concentration by inhibiting renal glucose reabsorption and producing glucosuria. Urinary glucose loss results in negative energy balance and because SGLT2i also block sodium absorption in the proximal tubule, they cause weight loss (∼2–3 kg) and decrease in blood pressure (4–6/1–2 mmHg systolic/diastolic) (5).

Because the pathogenesis of T2DM is complex and involves multiple metabolic defects (7), the …
Specification and quantitation of circulating immune complexes in the serum of patients with active pulmonary sarcoidosis.
Authors: N Schoenfeld, B Schmolke, M Schmitt, N Remy, P Ellensohn, U Wahn, R Loddenkemper
Journal: Thorax (1994)

BACKGROUND--Circulating immune complexes can be elevated in serum samples of patients with sarcoidosis and are associated with disease activity, but their diagnostic significance is not understood. METHODS--The different classes of circulating immune complexes containing immunoglobulin A, G, or M, and the content of complement in circulating immune complexes (polyethylene glycol precipitation) as well as levels of complement binding circulating immune complexes (complement binding assay) were determined in 19 patients with active, untreated pulmonary sarcoidosis. The results were compared with other parameters in the serum (soluble interleukin 2 receptor, angiotensin converting enzyme, immunoglobulin A, G, and M) and the bronchoalveolar lavage fluid (lymphocytes, helper cells, suppressor cells, activated T cells), and with radiological stage and functional parameters (FEV1, vital capacity, total lung capacity, transfer coefficient (KCO), and the alveolar-arterial oxygen difference during exercise). RESULTS--In all patients circulating immune complexes could be detected by polyethylene glycol precipitation and were similar to control subjects. The content of C1q in circulating immune complexes was higher than in controls, yet in all but one of the cases was still within normal limits. In contrast, elevated levels of complement binding circulating immune complexes were found in 67% of the patients. No correlation was seen between circulating immune complexes and any of the other parameters in the serum, bronchoalveolar lavage fluid, or lung function values. No differences were found between radiological type I and II presentations of sarcoidosis. CONCLUSIONS--The complement binding assay showed a much higher sensitivity for the detection of circulating immune complexes in active pulmonary sarcoidosis than the polyethylene glycol precipitation method. As there was no correlation between levels of circulating immune complexes and other parameters of the disease they are probably not useful for the assessment of disease activity.
Prior Aspirin Use and Outcomes in Elderly Patients Hospitalized With Acute Myocardial Infarction
Authors: Edward L. Portnay, JoAnne M. Foody, Saif S. Rathore, Yongfei Wang, Frederick A. Masoudi, Jeptha P. Curtis, Harlan M. Krumholz
Journal: Journal of the American College of Cardiology (2005)
<i>Trypanosoma cruzi</i> subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion
Authors: Maria Cecilia Fernandes, Mauro Cortez, Andrew R. Flannery, Christina Tam, Renato A. Mortara, Norma W. Andrews
Journal: The Journal of Experimental Medicine (2011)

Upon host cell contact, the protozoan parasite Trypanosoma cruzi triggers cytosolic Ca2+ transients that induce exocytosis of lysosomes, a process required for cell invasion. However, the exact mechanism by which lysosomal exocytosis mediates T. cruzi internalization remains unclear. We show that host cell entry by T. cruzi mimics a process of plasma membrane injury and repair that involves Ca2+-dependent exocytosis of lysosomes, delivery of acid sphingomyelinase (ASM) to the outer leaflet of the plasma membrane, and a rapid form of endocytosis that internalizes membrane lesions. Host cells incubated with T. cruzi trypomastigotes are transiently wounded, show increased levels of endocytosis, and become more susceptible to infection when injured with pore-forming toxins. Inhibition or depletion of lysosomal ASM, which blocks plasma membrane repair, markedly reduces the susceptibility of host cells to T. cruzi invasion. Notably, extracellular addition of sphingomyelinase stimulates host cell endocytosis, enhances T. cruzi invasion, and restores normal invasion levels in ASM-depleted cells. Ceramide, the product of sphingomyelin hydrolysis, is detected in newly formed parasitophorous vacuoles containing trypomastigotes but not in the few parasite-containing vacuoles formed in ASM-depleted cells. Thus, T. cruzi subverts the ASM-dependent ceramide-enriched endosomes that function in plasma membrane repair to infect host cells.
Growth properties and alloantigenic expression of murine lymphoblastoid cell lines.
Authors: R K Zwerner, R T Acton
Journal: The Journal of Experimental Medicine (1975)

Murine lymphoblastoid cell lines were evaluated for their expression of Thy-1 and thymus leukemia (TL) differentiation alloantigens. Two culture conditions were shown to affect this expression. Cells grown in fetal bovine serum (FBS)-enriched medium expressed up to 15 times the amount of TL as cells grown in horse serum (HS)-enriched medium. Thy-1 expression was less affected by the type of serum used for culture. The phase of growth when the cells were harvested, was demonstrated to affect the expression of Thy-1. The expression of Thy-1.2 for one cell line examined, L-251A, during logarithmic growth was threefold greater than cells collected during either lag or stationary growth. When culture conditions were standardized a ranking of the amount of Thy-1 and TL expressed by several cell lines was made. All cell lines, except one, L-1210, expressed Thy-1. There was a 450-fold difference in the expression of Thy-1 between the cell lines evaluated. Seven cell lines expressed TL-1,2,3 with a ninefold difference in the amount of expression. The L-251A cell line was cultured in a 14 liter fermentor for a 26 day period. During this time TL and Thy-1 expression did not vary significantly, demonstrating that lymphoblastoid cell lines can be cultured on a continuous basis and will continue to express their surface alloantigens.
Endothelial cell–specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation
Authors: Lucas Onder, Renzo Danuser, Elke Scandella, Sonja Firner, Qian Chai, Thomas Hehlgans, Jens V. Stein, Burkhard Ludewig
Journal: The Journal of Experimental Medicine (2013)

The development of lymph nodes (LNs) and formation of LN stromal cell microenvironments is dependent on lymphotoxin-β receptor (LTβR) signaling. In particular, the LTβR-dependent crosstalk between mesenchymal lymphoid tissue organizer and hematopoietic lymphoid tissue inducer cells has been regarded as critical for these processes. Here, we assessed whether endothelial cell (EC)–restricted LTβR signaling impacts on LN development and the vascular LN microenvironment. Using EC-specific ablation of LTβR in mice, we found that conditionally LTβR-deficient animals failed to develop a significant proportion of their peripheral LNs. However, remnant LNs showed impaired formation of high endothelial venules (HEVs). Venules had lost their cuboidal shape, showed reduced segment length and branching points, and reduced adhesion molecule and constitutive chemokine expression. Due to the altered EC–lymphocyte interaction, homing of lymphocytes to peripheral LNs was significantly impaired. Thus, this study identifies ECs as an important LTβR-dependent lymphoid tissue organizer cell population and indicates that continuous triggering of the LTβR on LN ECs is critical for lymphocyte homeostasis.
Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells
Authors: Toni Celià-Terrassa, Óscar Meca-Cortés, Francesca Mateo, Alexia Martínez de Paz, Nuria Rubio, Anna Arnal-Estapé, Brian J. Ell, Raquel Bermudo, Alba Díaz, Marta Guerra-Rebollo, Juan José Lozano, Conchi Estarás, Catalina Ulloa, Daniel ρlvarez-Simón, Jordi Milà, Ramón Vilella, Rosanna Paciucci, Marian Martínez-Balbás, Antonio García de Herreros, Roger R. Gomis, Yibin Kang, Jerónimo Blanco, Pedro L. Fernández, Timothy M. Thomson
Journal: Journal of Clinical Investigation (2012)

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.