tbuckley/cabot-search huggingface dataset:
Inside-out signaling through integrins.
Authors: R J Faull, M H Ginsberg
Journal: Journal of the American Society of Nephrology (1996)

Rapid and yet precisely controlled changes in cell adhesion are a hallmark of a number of basic physiological processes. Many of these processes directly impact upon nephrology, including: (1) cell migration, which occurs during leukocyte infiltration into inflammatory sites (e.g., in glomerulonephritis, interstitial nephritis, and renal transplant rejection) and during embryogenesis (e.g., in development of the genitourinary system): and (2) platelet aggregation at sites of clot formation (e.g., in glomerulonephritis). The integrins are a family of adhesion molecules whose function is controlled by the cells that express them, and this properly makes them eminently suitable receptors for those situations that demand flexibility of the cellular adhesive phenotype. The control of integrin function occurs via regulatory signals that originate within the cell cytoplasm and are then transmitted to the external ligand-binding domain of the receptor. The generation and transmission of these "inside-out" signals are the subjects of intensive research that will be summarized in this review article.
P-Glycoprotein Mediates Celecoxib-Induced Apoptosis in Multiple Drug-Resistant Cell Lines
Authors: Ornella Fantappiè, Michela Solazzo, Nadia Lasagna, Francesca Platini, Luciana Tessitore, Roberto Mazzanti
Journal: Cancer Research (2007)

Abstract In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein–mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 μmol/L celecoxib. We found that 10 μmol/L celecoxib reduced P-glycoprotein, Bcl-xL, and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 μmol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-xL and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression. [Cancer Res 2007;67(10):4915–23]
VITAMIN/MINERAL SUPPLEMENTATION AND NON-VERBAL INTELLIGENCE
Authors: P.W. Emery, M. Nelson, T.A.B. Sanders, J.E. Thomas, C.G. Geissler, P.A. Judd, D.J. Naismith, JaneL. Hutton, Deborah Ashby, John Yudkin, C.J. Bates, D.I. Thurnham, H.J. Powers, Alexander Macnair, Aidan Macfarlane, G.A. Rose, David Benton, A.E. Bender
Journal: The Lancet (1988)
Vandetanib Versus Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study
Authors: Ronald B. Natale, David Bodkin, Ramaswamy Govindan, Bethany G. Sleckman, Naiyer A. Rizvi, Adolfo Capó, Paul Germonpré, Wilfried E.E. Eberhardt, Paul K. Stockman, Sarah J. Kennedy, Malcolm Ranson
Journal: Journal of Clinical Oncology (2009)

Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. In this two-part phase II study, the efficacy and safety of vandetanib was compared with that of gefitinib, an inhibitor of EGFR signaling.Patients (N = 168) with locally advanced or metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC), after failure of first-line with or without second-line platinum-based chemotherapy, received once-daily vandetanib 300 mg (n = 83) or gefitinib 250 mg (n = 85) until disease progression or evidence of toxicity (part A). After a 4-week washout period, eligible patients had the option to switch to the alternative treatment (part B). Progression-free survival (PFS) was the primary efficacy assessment in part A, which was designed to have a higher than 75% power to detect a 33% prolongation of PFS at a one-sided significance level of .2.In part A, vandetanib prolonged PFS compared with gefitinib (hazard ratio = 0.69; 95% CI, 0.50 to 0.96; one-sided P = .013). Patients receiving vandetanib experienced adverse events that were manageable and generally consistent with inhibition of EGFR and VEGFR signaling, including diarrhea, rash, and hypertension. There were no unexpected safety findings with gefitinib. Overall survival, a secondary assessment, was not significantly different between patients initially randomly assigned to either vandetanib or gefitinib.The primary efficacy objective was achieved, with vandetanib demonstrating a significant prolongation of PFS versus gefitinib. Vandetanib 300 mg/d is currently being evaluated as a monotherapy in two randomized phase III studies in advanced NSCLC.
Transport of Bifunctional Proteins Across Respiratory Epithelial Cells via the Polymeric Immunoglobulin Receptor
Authors: THOMAS FERKOL, ELIZABETH ECKMAN, SHADI SWAIDANI, CATHERINE SILSKI, PAMELA DAVIS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Neutrophil elastase (NE) contributes to progression of the lung disease characteristic of cystic fibrosis (CF). We developed a strategy that permits the delivery of alpha(1)-antitrypsin (alpha(1)-AT) to inaccessible CF airways by targeting the respiratory epithelium via the polymeric immunoglobulin receptor (pIgR). A fusion protein consisting of a single-chain Fv directed against human secretory component (SC) and linked to human alpha(1)-AT was effectively transported in a basolateral-to-apical direction across in vitro model systems of polarized respiratory epithelium consisting of 16HBEo cells transfected with human pIgR complementary DNA, which overexpress the receptor, and human respiratory epithelial cells grown in primary culture at an air-liquid interface. When applied to the basolateral surface, the anti-SC Fv/alpha(1)-AT fusion protein penetrated the respiratory epithelia, with transcytosis of the fusion protein being related to the amount of SC detected at the apical surface. Significantly less fusion protein crossed the cells in the opposite direction. In addition, because the antihuman SC Fv/alpha(1)-AT fusion protein was transported vectorially and deposited into the small volume of apical surface fluid, the antiprotease component of this protein was concentrated atop the epithelium. Thus, in cell models, this system is capable of concentrating the antiprotease of the fusion protein, in the thin film of epithelial surface fluid to a level expected to be therapeutic in the airways of many patients with CF.
Determinants of Antiarrhythmic Drug Action
Authors: Dirk J. Snyders, Sarita W. Yeola
Journal: Circulation Research (1995)

Abstract The molecular basis of antiarrhythmic drug action is still poorly understood. We recently reported that block of the human cardiac hKv1.5 channel by quinidine displayed similarity with internal quaternary ammonium block of squid and Shaker potassium channels. To gain further insight into the molecular determinants of the affinity and the stereoselectivity of antiarrhythmic drug action, we studied the effects of quinine (a diastereomer of quinidine), clofilium (a quaternary ammonium class III agent), and tetrapentylammonium (TPeA, a biophysical reference probe for the internal quaternary ammonium binding site). For all compounds, block was voltage dependent, with a steep increase over the voltage range of channel opening and a superimposed weaker voltage dependence at more positive potentials. The latter electrostatic component was similar for all drugs, consistent with a binding reaction sensing ≈20% of the transmembrane electrical field. Clofilium and TPeA displayed a higher apparent affinity (0.15 and 0.28 μmol/L, respectively), and quinine displayed a lower one (21 μmol/L) compared with quinidine (6.2 μmol/L). Block development upon depolarization was time dependent for clofilium and TPeA but slow compared with quinidine. A time-dependent component was difficult to resolve for quinine, but the time course of deactivating tail currents was slower than in the control condition. The resulting crossover phenomenon was also observed for the quaternary drugs. Compared with TPeA alone, the combined application of quinine and TPeA resulted in a reduced current that decayed slower, consistent with competition. When a bimolecular model for open-channel block was used, the apparent association rate constants for these drugs were found to be similar [range, 4.5 to 7.7 (μmol/L) −1 · s −1 ]. The apparent dissociation rate constants for clofilium (1.9 s −1 ) and TPeA (3.6 s −1 ) were smaller compared with quinidine (34 s −1 ), whereas that for quinine was faster (≥125 s −1 ). This large range in dissociation rate constants could explain the differences between these drugs both in kinetics and affinity. The results are consistent with a general model in which these agents act as cationic open-channel blockers but with an affinity largely determined by the intrinsic stability of the drug-receptor complex. Hydrophobic interactions are most likely involved in this stabilization of binding.
Fibrocytes: potential new therapeutic targets for pulmonary hypertension?
Authors: K.R. Stenmark, M.G. Frid, M.E. Yeager
Journal: European Respiratory Journal (2010)

Pulmonary arterial hypertension (PAH) is a progressive fatal disease 1, 2. All forms of chronic pulmonary hypertension are characterised by cellular and structural changes in the walls of the pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are common 3. Virtually all of these changes are characterised, to a greater or lesser degree, by increased numbers of cells expressing smooth muscle α-actin (α-SMA), as well as the accumulation of inflammatory cells 4–7. At present, neither the origin of the accumulating cells, particularly those expressing α-SMA, nor the molecular mechanisms operating to cause their accumulation has been fully delineated. Traditionally, it has been thought that the α-SMA-expressing and/or collagen-producing cells accumulating in vascular lesions were exclusively derived from resident vascular cells. However, since the late 1990s, this concept has been extended by the fact that bone-marrow-derived circulating progenitor cells are recruited to sites of vascular injury and contribute to both the vascular repair and pathological remodelling by differentiating into cells expressing mesenchymal or even smooth-muscle-like characteristics 8–10.

Among the many populations of progenitor cells that may be recruited to the vessel wall and assume mesenchymal cell characteristics are fibrocytes. These cells were initially described by Bucala et al. 11 as circulating bone-marrow-derived cells with the ability to adapt a mesenchymal phenotype. They share certain features with both fibroblasts and monocytes, and this combination of connective tissue cell and myeloid cell characteristics permits their identification by a number of markers. Fibrocytes express the stem cell marker CD34, the pan-haematopoietic marker CD45 and monocyte markers, such as CD14 and CD11, and produce components of the connective tissue matrix, including collagen I, collagen III and vimentin 12, 13. Fibrocytes display many properties that are important for wound …
Induction of Mucosal and Systemic Immune Responses against Human Carcinoembryonic Antigen by an Oral Vaccine
Authors: Yujun Huang, Raja Fayad, Andrew Smock, Amanda M. Ullrich, Liang Qiao
Journal: Cancer Research (2005)

Abstract Carcinoembryonic antigen (CEA) is a tumor-associated antigen targeted for the development of colorectal tumor vaccines. In this study, we developed papillomavirus pseudoviruses encoding the truncated CEA without NH2-terminal signal peptide (PV-CEA) as an oral vaccine to induce CEA-specific CTL responses. In CEA transgenic (CEA-Tg) mice orally immunized with PV-CEA, the immunologic tolerance to CEA as a “self-antigen” was overcome and both mucosal and systemic CEA-specific cytolytic activities were detected by in vitro 51Cr release assays. In a tumor prevention model, the growth rate of CEA+ tumors was significantly delayed in CEA-Tg mice orally immunized with PV-CEA when compared with the control vaccine. Further, the IFN-γ enzyme-linked ImmunoSPOT and in vitro 51Cr release assay results showed that HLA-A2-restricted, CEA-specific CTL responses were induced in both mucosal and systemic lymphoid tissues in A2 transgenic mice after oral immunization with PV-CEA. Finally, we showed that coadministration of papillomavirus pseudoviruses encoding interleukin-2 with PV-CEA enhanced the generation of A2-restricted, CEA-specific CTLs in aged CEA/A2 double transgenic mice, which were more clinically relevant. Our data suggest that PV-CEA pseudovirus vaccine is a promising oral CEA vaccine for humans to induce CEA-specific CTLs at the site of colorectal tumors (i.e., intestinal mucosa), which might efficiently eliminate CEA+ colorectal tumor cells in the mucosa.
Combination Therapy with Conditionally Replicating Adenovirus and Replication Defective Adenovirus
Authors: Choon-Taek Lee, Kyung-Ho Park, Kiyoshi Yanagisawa, Yasushi Adachi, Joyce E. Ohm, Sorena Nadaf, Mikhail M. Dikov, David T. Curiel, David P. Carbone
Journal: Cancer Research (2004)

Abstract Low gene transfer rate is the most substantial hurdle in the practical application of gene therapy. One strategy to improve transfer efficiency is the use of a conditionally replicating adenovirus (CRAD) that can selectively replicate in tumor cells. We hypothesized that conventional E1-deleted adenoviruses (ad) can become replication-competent when cotransduced with a CRAD to selectively supply E1 in trans in tumors. The resulting selective production of large numbers of the E1-deleted ad within the tumor mass will increase the transduction efficiency. We used a CRAD (Δ24RGD) that produces a mutant E1 without the ability to bind retinoblastoma but retaining viral replication competence in cancer cells with a defective pRb/p16. Ad-lacZ, adenovirus-luciferase (ad-luc), and adenovirus insulin-like growth factor-1R/dominant-negative (ad-IGF-1R/dn; 482, 950) are E1-deleted replication-defective adenoviruses. The combination of CRAD and ad-lacZ increased the transduction efficiency of lacZ to 100% from 15% observed with ad-lacZ alone. Transfer of media of CRAD and ad-lacZ cotransduced cells induced the transfer of lacZ (media transferable bystander effect). Combination of CRAD and ad-IGF-1R/dn increased the production of truncated IGF-1R or soluble IGF-1R &amp;gt; 10 times compared with transduction with ad-IGF-1R/dn alone. Combined intratumoral injection of CRAD and ad-luc increased the luciferase expression about 70 times compared with ad-luc alone without substantial systemic spread. Combined intratumoral injection of CRAD and ad-IGF-1R/482 induced stronger growth suppression of established lung cancer xenografts than single injections. The combination of CRAD and E1-deleted ad induced tumor-specific replication of CRAD and E1-deleted ad and increased the transduction rate and therapeutic efficacy of these viruses in model tumors.
Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease
Authors: Jon T Giles, Sonye K Danoff, Jeremy Sokolove, Catriona A Wagner, Robert Winchester, Dimitrios A Pappas, Stanley Siegelman, Geoff Connors, William H Robinson, Joan M Bathon
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown. <h3>Methods</h3> RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0–32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four non-citrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile. <h3>Results</h3> Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46–273% higher among RA patients with versus those without ILD (all p values &lt;0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0–16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion. <h3>Conclusions</h3> Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.
Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta
Authors: Daniel Wynn, Michael Kaufman, Xavier Montalban, Timothy Vollmer, Jack Simon, Jacob Elkins, Gilmore O'Neill, Lauri Neyer, James Sheridan, Chungchi Wang, Alice Fong, John W Rose
Journal: The Lancet Neurology (2010)
Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human
Authors: Kobra Haghighi, Fotis Kolokathis, Luke Pater, Roy A. Lynch, Michio Asahi, Anthony O. Gramolini, Guo-Chang Fan, Dimitris Tsiapras, Harvey S. Hahn, Stamatis Adamopoulos, Stephen B. Liggett, Gerald W. Dorn, David H. MacLennan, Dimitrios T. Kremastinos, Evangelia G. Kranias
Journal: Journal of Clinical Investigation (2003)

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca2+-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy.
ANTIGENIC PROMOTION
Authors: Chin-Yu Wu, Bernard Cinader
Journal: The Journal of Experimental Medicine (1971)

Rabbits were immunized with p-azobenzene arsonic acid derivatives of human serum albumin (HA-As) or of dissociated keyhole limpet hemocyanin. The IgM response to the hapten was evaluated in terms of the number of hapten-specific plaque-forming cells in the lymph node draining the injection site. In some experiments, antibody was measured by agglutination of tanned and sensitized erythrocytes. The hapten response of animals immunized with HA-As was increased (promoting effect) when the animals were injected with one of several structurally unrelated macromolecules: keyhole limpet hemocyanin (KLH), horse spleen ferritin (HSF), lysozyme (Lys), alum-precipitated human gamma globulin (alum-precipitated HGG). Different macromolecules differed in the magnitude of the promoting effect they induced, e.g., promotion by the associated form of KLH was greater than that by the dissociated form; alum-precipitated HGG was a better promoter than was soluble HGG. The relative magnitude of promotion by different macromolecules (associated vs. dissociated KLH, alum-precipitated vs. soluble HGG) correlated with the relative magnitude of the carrier effect, as judged by the hapten response induced by p-azobenzene arsonic acid conjugated to various proteins. Promotion was detected by agglutination assay of circulating antibody, by plaque assay of cells from the popliteal lymph node draining the site of preinjection, but not by plaque assay of cells from the contralateral lymph node. Promotion was dependent on the dose of the promoting macromolecule and on the dose of the hapten-protein conjugate. It was not observed in animals tolerant to the promoting macromolecule. Inhibition (i.e. antigenic competition), rather than promotion, was observed upon a secondary response to the preinjected macromolecule or when the hapten-protein conjugate was incorporated in Freund's adjuvant.
FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study
Authors: Susan P. Whitman, Kati Maharry, Michael D. Radmacher, Heiko Becker, Krzysztof Mrózek, Dean Margeson, Kelsi B. Holland, Yue-Zhong Wu, Sebastian Schwind, Klaus H. Metzeler, Jing Wen, Maria R. Baer, Bayard L. Powell, Thomas H. Carter, Jonathan E. Kolitz, Meir Wetzler, Joseph O. Moore, Richard M. Stone, Andrew J. Carroll, Richard A. Larson, Michael A. Caligiuri, Guido Marcucci, Clara D. Bloomfield
Journal: Blood (2010)
PULMONARY COMPLICATIONS OF HIV INFECTION
Authors: John F. Murray, M. D
Journal: Annual Review of Medicine (1996)

▪ Abstract Pulmonary disease is a major source of morbidity and mortality in HIV-infected persons. Pneumocystis carinii pneumonia has decreased substantially during the last eight years, but in the United States it remains the most common disorder that announces the onset of AIDS. In contrast, tuberculosis is by far the most important AIDS-associated indicator disease in developing countries. Community-acquired acute bacterial penumonia is a common HIV-linked complication throughout the world; pneumonia occurs at all levels of immune suppression but increases in frequency as CD4 counts decrease. Fungal infections mainly afflict persons who live or have lived in the various endemic areas. AIDS-related Kaposi's sarcoma and lymphoma generally do not involve the lungs until the malignancies are advanced. The increasing use of successful chemoprophylaxis against many important HIV-associated infections is increasing the incidence of other end-stage complications such as cytomegalovirus and disseminated MAC disease.