tbuckley/cabot-search huggingface dataset:
Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents
Authors: Ricardo Gómez, Ricardo Caballero, Adriana Barana, Irene Amorós, Sue-Haida De Palm, Marcos Matamoros, Mercedes Núñez, Marta Pérez-Hernández, Isabel Iriepa, Juan Tamargo, Eva Delpón
Journal: Cardiovascular Research (2014)

We hypothesize that some drugs, besides flecainide, increase the inward rectifier current (IK1) generated by Kir2.1 homotetramers (IKir2.1) and thus, exhibit pro- and/or antiarrhythmic effects particularly at the ventricular level. To test this hypothesis, we analysed the effects of propafenone, atenolol, dronedarone, and timolol on Kir2.x channels. Currents were recorded with the patch-clamp technique using whole-cell, inside-out, and cell-attached configurations. Propafenone (0.1 nM–1 µM) did not modify either IK1 recorded in human right atrial myocytes or the current generated by homo- or heterotetramers of Kir2.2 and 2.3 channels recorded in transiently transfected Chinese hamster ovary cells. On the other hand, propafenone increased IKir2.1 (EC50 = 12.0 ± 3.0 nM) as a consequence of its interaction with Cys311, an effect which decreased inward rectification of the current. Propafenone significantly increased mean open time and opening frequency at all the voltages tested, resulting in a significant increase of the mean open probability of the channel. Timolol, which interacted with Cys311, was also able to increase IKir2.1. On the contrary, neither atenolol nor dronedarone modified IKir2.1. Molecular modelling of the Kir2.1–drugs interaction allowed identification of the pharmacophore of drugs that increase IKir2.1. Kir2.1 channels exhibit a binding site determined by Cys311 that is responsible for drug-induced IKir2.1 increase. Drug binding decreases channel affinity for polyamines and current rectification, and can be a mechanism of drug-induced pro- and antiarrhythmic effects not considered until now.
Tumors, IGF-2, and Hypoglycemia: Insights From the Clinic, the Laboratory, and the Historical Archive
Authors: Yevgeniya Dynkevich, Kristina I. Rother, Ian Whitford, Sana Qureshi, Sneha Galiveeti, Alessandra L. Szulc, Ann Danoff, Tracy L. Breen, Nargess Kaviani, Michael H. Shanik, Derek LeRoith, Riccardo Vigneri, Christian A. Koch, Jesse Roth
Journal: Endocrine Reviews (2013)

Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2–related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate–containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non–islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non–islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.
Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032
Authors: Giles W. Robinson, Brent A. Orr, Gang Wu, Sridharan Gururangan, Tong Lin, Ibrahim Qaddoumi, Roger J. Packer, Stewart Goldman, Michael D. Prados, Annick Desjardins, Murali Chintagumpala, Naoko Takebe, Sue C. Kaste, Michael Rusch, Sariah J. Allen, Arzu Onar-Thomas, Clinton F. Stewart, Maryam Fouladi, James M. Boyett, Richard J. Gilbertson, Tom Curran, David W. Ellison, Amar Gajjar
Journal: Journal of Clinical Oncology (2015)

Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB).
Temporal trends in the epidemiology, management, and outcome of patients with cardiogenic shock complicating acute coronary syndromes
Authors: Leonardo De Luca, Zoran Olivari, Andrea Farina, Lucio Gonzini, Donata Lucci, Antonio Di Chiara, Gianni Casella, Francesco Chiarella, Alessandro Boccanelli, Giuseppe Di Pasquale, Stefano De Servi, Francesco Maria Bovenzi, Michele Massimo Gulizia, Stefano Savonitto
Journal: European Journal of Heart Failure (2015)
Rhinoscintigraphy
Authors: DANIELA DI GIUDA, JACOPO GALLI, MARIA LUCIA CALCAGNI, LUIGI CORINA, GAETANO PALUDETTI, FABRIZIO OTTAVIANI, GIUSEPPE DE ROSSI
Journal: Clinical Nuclear Medicine (2000)

This was a radioisotope study of nasal mucociliary clearance of total and subtotal nasal obstruction.Rhinoscintigraphy was performed by insufflating 1.85 MBq (69 mCi) Tc-99m MAA in 20 patients. Six cases were regarded as the control group, because the presence of small spurs does not affect nasal patency. The remaining 14 patients had various rhinopathic conditions. Two regions of interest were selected, one in the nasal cavity and one in the pharynx. Mucociliary transport speed was calculated.This parameter appeared to be a sensitive index for the assessment of the degree of mucociliary alteration. It showed that polyposis impairs mucociliary transport most severely, thus confirming the results of other published studies.Rhinoscintigraphy proved to be a reliable, easily reproducible, and harmless method, so it may be used for follow-up examinations in patients who have had surgery of the nose and paranasal sinuses, and for drug therapy of rhinopathic conditions.
Faecal Eosinophilic Protein X (f-EPX), Atopic Dermatitis, Sensitisation and Gastrointestinal Permeability in Infants Aged 3-6 Months
Authors: C. Peterson, T. Hansson, E. Hadley, C. Chaloner, A. Woodcock, A. Custovic, C. Gore
Journal: Journal of Allergy and Clinical Immunology (2006)
Effects of home rehabilitation on physical performance in patients with chronic obstructive pulmonary disease (COPD)
Authors: PJ Wijkstra, TW van der Mark, J Kraan, R van Altena, GH Koeter, DS Postma
Journal: European Respiratory Journal (1996)

We investigated whether 12 weeks of rehabilitation at home in patients with chronic obstructive pulmonary disease (COPD) had a beneficial effect on lactate production, metabolic gas exchange data, workload of the inspiratory muscles, and dyspnoea during a maximal bicycle ergometer test. A second aim was to assess whether a change in dyspnoea was related to a change of inspiratory muscle workload. Forty three COPD patients with severe airways obstruction were included in the study: mean forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 L (44% predicted), mean FEV1/inspiratory vital capacity (IVC) 37 +/- 8%. Twenty eight patients started a rehabilitation programme, whilst 15 patients received no rehabilitation. Rehabilitation was carried out at home; patients were supervised by a general practitioner, a physiotherapist and a nurse. Exercise tolerance was measured by means of a 6 min walking distance test (6MWD) and maximal workload (Wmax) during an incremental symptom-limited cycle ergometer test. Inspiratory muscle workload at Wmax was assessed with the Tension Time Index (TTI), and dyspnoea at Wmax with the Borg scale. After 12 weeks, the rehabilitation group showed a significantly larger increase in 6MWD (from 438 to 447 m) and in Wmax (from 70 to 78 W) compared with the control group. A significant improvement in oxygen consumption (V1O2) (from 1.0 to 1.1 L), lactate level (from 3.7 to 3.1 mEq.L(-1)), dyspnoea (from 6.0 to 4.5) and TTI (from 0.10 to 0.08) at Wmax occurred in the rehabilitation group during the programme. The reduction in TTI was not significantly correlated with the fall in dyspnoea, as assessed by the Borg scale. We conclude that 12 weeks of rehabilitation at home in COPD patients increases symptom-limited V1O2 in combination with an increased Wmax. At this significantly higher Wmax, there was a reduction in dyspnoea, lactate level and inspiratory muscle workload. The reduction in dyspnoea was not related to a decreased inspiratory muscle workload. This study shows that rehabilitation at home can produce beneficial physiological improvements during exercise in patients with chronic obstructive pulmonary disease.
A Case of Pemphigus Foliaceus
Authors: C. F. Cuthbert
Journal: BMJ (1894)

PEMPHIGUS FOLIACEUvS. [M3iDscL JOVLNAL 1237 probably lulmonary regurgitation fromn this cause would be moreb fre(quenit tilani it is were it niot for the safety-valve actioni of the riglht ventricle, and its occasional occurrence was poiinted out by l)r.Fothergill.1 I have little (loubt that it was pr-esent in the following case.
TGF-β and atherosclerosis in man
Authors: D GRAINGER
Journal: Cardiovascular Research (2007)

The transforming growth factor type-β (TGF-β) superfamily of ligands, receptors, binding proteins and ligand traps together plays a key role in the maintenance of normal blood vessel wall structure. Specific defects in genes encoding superfamily members have now been linked to a range of cardiovascular syndromes involving loss of healthy vessel architecture, including hypertension and aneurysm. However the contribution of TGF-β to the development of atherosclerosis is simultaneously more subtle and more complex. TGF-β ligands are produced by a range of different cell types, which also regulate release of the active cytokine that, in turn, signals through multiple receptor complexes on different cell types. Recent evidence suggests that the T cell may be both a key source of TGF-β1 and a key target for its effects during atherogenesis, as in other chronic inflammatory disorders. Here we review the evidence for the role of TGF-β in the human vasculature during atherogenesis, and evaluate the available data in the context of our knowledge from animal models of the disease.
Cytokine production from peripheral whole blood in atopic and nonatopic asthmatics: relationship with blood and sputum eosinophilia and serum IgE levels
Authors: J. Bettiol, P. Bartsch, R. Louis, D. De Groote, Y. Gevaerts, E. Louis, M. Malaise
Journal: Allergy (2000)

The cytokine network is thought to be essential in orchestrating airway inflammation in asthma. Although evidence has accumulated to suggest that atopic asthma is a Th2 disease, much less is known about nonatopic asthma.We have compared the production of IL-4, IL-6, IFN-gamma, and TNF-alpha from peripheral blood leukocytes between atopic (n=21) and nonatopic (n=22) asthmatics and healthy nonatopic subjects (n=20). Peripheral blood was incubated for 24 h either without stimulus or with LPS or PHA. Cytokines were measured by the immunotrapping technique (Dynamic Immunoassay).When compared to healthy nonatopic subjects, both atopic and nonatopic asthmatics showed increased blood and sputum eosinophilia associated with raised total serum IgE levels. Similarly, both asthma groups displayed spontaneous, endotoxin-induced overproduction of IL-6. Enhanced spontaneous, endotoxin-induced release of IL-4 combined with reduced spontaneous IFN-gamma production was seen only in atopic asthma. In this group of patients, the production of IL-4 was related to the extent of blood and sputum eosinophilia. In nonatopic asthmatics, serum levels of IgE were inversely related to the production of IFN-gamma.Both atopic and intrinsic asthma display raised blood and airway eosinophilia, raised total serum IgE, and overproduction of IL-6 from peripheral blood. Atopic asthma is also characterized by impaired spontaneous release of IFN-gamma and increased production of IL-4 that correlates with the magnitude of eosinophilic inflammation.
Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow
Authors: Andreas Schlitzer, V Sivakamasundari, Jinmiao Chen, Hermi Rizal Bin Sumatoh, Jaring Schreuder, Josephine Lum, Benoit Malleret, Sanqian Zhang, Anis Larbi, Francesca Zolezzi, Laurent Renia, Michael Poidinger, Shalin Naik, Evan W Newell, Paul Robson, Florent Ginhoux
Journal: Nature Immunology (2015)
Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis
Authors: Anne L. Fletcher, Jessica S. Elman, Jillian Astarita, Ryan Murray, Nima Saeidi, Joshua D’Rozario, Konstantin Knoblich, Flavian D. Brown, Frank A. Schildberg, Janice M. Nieves, Tracy S. P. Heng, Richard L. Boyd, Shannon J. Turley, Biju Parekkadan
Journal: Science Translational Medicine (2014)

Infusion of lymph node–derived fibroblastic reticular cells into septic mice increases survival at late time points after disease onset.
Unique tRNA Introns of an Enslaved Algal Cell
Authors: Oliver Kawach, Christine Voss, Jonci Wolff, Katalin Hadfi, Uwe-G Maier, Stefan Zauner
Journal: Molecular Biology and Evolution (2005)

Nucleomorphs are remnant nuclei of eukaryotic, secondary endosymbionts exclusively found in cryptophytes and chlorarachniophytes. The nucleomorph of the cryptophyte Guillardia theta codes for 36 transfer RNA (tRNA) genes, 15 of them predicted to contain introns and 1 pseudo-tRNA. Some of the predicted intervening sequences are manifested at positions not known in Eukarya, even tRNAs with more than one intron were suggested. By isolating reverse transcriptase-polymerase chain reaction products of the spliced tRNAs we verify the processing of all predicted intron-harboring tRNAs and demonstrate the splicing of the smallest introns (3 nt) investigated so far. However, the spliced intervening sequences are in some cases shifted in respect to the predicted ones. Moreover, we show that introns, if inserted into the B-box of tRNA genes in the nucleomorph of cryptophytes, mimic promoter regions and do not abolish transcription by RNA polymerase III. Consequently, internal nucleomorph-encoded tRNA promoter regions are in some cases dissected from the sequence of the mature tRNAs. By reanalyzing tRNA introns of a recently sequenced red algae we furthermore show that splicing of introns at unusual positions may be introduced in cryptophytes by its secondary endosymbiont. However, in contrast to the rest of the symbiont genome, introns are not minimized in quantity but are instead scattered along the tRNA genes.
A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus
Authors: Norbert Varga, Ieva Sutkeviciute, Renato Ribeiro-Viana, Angela Berzi, Rasika Ramdasi, Anna Daghetti, Gerolamo Vettoretti, Ali Amara, Mario Clerici, Javier Rojo, Franck Fieschi, Anna Bernardi
Journal: Biomaterials (2014)
Congenital dilatation of the intrahepatic bile ducts associated with the development of amyloidosis
Authors: J. Fevery, W. Tanghe, R. Kerremans, V. Desmet, J. De Groote
Journal: Gut (1972)

Two cases of pure congenital dilatation of the intrahepatic bile ducts are presented. One patient developed amyloidosis secondary to suppuration, and had isolated cysts in the renal medulla. The position of congenital dilatation of the intrahepatic bile ducts compared with cysts in the liver and its association with ;cystic' diseases of the kidneys is discussed.
Cystic Disease of the Kidney
Authors: Patricia D Wilson, Beatrice Goilav
Journal: Annual Review of Pathology Mechanisms of Disease (2007)

This review focuses on the mechanisms that underlie the development of human renal cystic diseases. A pathological, clinical, and pathophysiological overview is given. Initial analysis of the cell biology of inappropriate hyperproliferation accompanied by fluid secretion of cyst-lining epithelia has been followed by the elucidation of fundamental defects in epithelial polarity, cell-matrix and cell-cell interactions, and apoptosis, all of which are discussed. Identification of the genes and proteins responsible for several renal cystic diseases has led to a more complete understanding of defects in renal developmental programming, differentiation, and morphogenesis, all of which underlie cystic diseases of the kidney.
Cooperative Autocrine and Paracrine Functions of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor in the Progression of Skin Carcinoma Cells
Authors: Eva Obermueller, Silvia Vosseler, Norbert E. Fusenig, Margareta M. Mueller
Journal: Cancer Research (2004)

Abstract Tumor growth and progression are critically controlled by alterations in the microenvironment often caused by an aberrant expression of growth factors and receptors. We demonstrated previously that tumor progression in patients and in the experimental HaCaT tumor model for skin squamous cell carcinomas is associated with a constitutive neoexpression of the hematopoietic growth factors granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), causing an autocrine stimulation of tumor cell proliferation and migration in vitro. To analyze the critical contribution of both factors to tumor progression, G-CSF or GM-CSF was stably transfected in factor-negative benign tumor cells. Forced expression of GM-CSF resulted in invasive growth and enhanced tumor cell proliferation in a three-dimensional culture model in vitro, yet tumor growth in vivo remained only transient. Constitutive expression of G-CSF, however, caused a shift from benign to malignant and strongly angiogenic tumors. Moreover, cells recultured from G-CSF–transfected tumors exhibited enhanced tumor aggressiveness upon reinjection, i.e., earlier onset and faster tumor expansion. Remarkably, this further step in tumor progression was again associated with the constitutive expression of GM-CSF strongly indicating a synergistic action of both factors. Additionally, expression of GM-CSF in the transfected tumors mediated an earlier recruitment of granulocytes and macrophages to the tumor site, and expression of G-CSF induced an enhanced and persistent angiogenesis and increased the number of granulocytes and macrophages in the tumor vicinity. Thus both factors directly stimulate tumor cell growth and, by modulating the tumor stroma, induce a microenvironment that promotes tumor progression.
HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis
Authors: P C F Stokkers, P H Reitsma, G N J Tytgat, S J H van Deventer
Journal: Gut (1999)

Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR or -DQ phenotypes and either ulcerative colitis or Crohn's disease, but much of the data are still controversial.To estimate overall associations between HLA class II phenotypes and IBD, and to establish the relative risk conferred by HLA-DR and -DQ phenotypes by meta-analysis.Medline was searched for publications reporting on the relation between IBD and HLA class II phenotypes. Raw data were extracted by recalculating the number of phenotypes or the number of alleles of the main antigens. Odds ratios and confidence intervals were calculated according to the Mantel-Haenszel method.DR2, DR9, and DRB1*0103 were positively associated with ulcerative colitis, and a negative association was found for DR4 and ulcerative colitis. For Crohn's disease a positive association was found with DR7, DRB3*0301, and DQ4 and a negative association with DR2 and DR3.Both ulcerative colitis and Crohn's disease are associated with specific HLA class II phenotypes. Further analysis of these phenotypes and subgroup analysis may elucidate how these alleles contribute to susceptibility to IBD.
Thixotropic effects on operational chest wall volumes in healthy subjects
Authors: Guilherme Fregonezi, Fernando Henrique Fernandes Macedo, Maria Clara Goes, Rencio Bento Florencio, Vanessa Resqueti, Andrea Aliverti
Journal: European Respiratory Journal (2013)

Inspiratory muscle thixotropy can be achieved by muscle contraction at an inflated or deflated lung volume,causing muscle stiffness or slackness (Homma et al.). Here we aimed to assess the effects of thixotropy maneuver on operating volumes in healthy subjects.Ten subjects (5 f), age 24 yrs (IQR:22-27.5),BMI:24 Kg/m 2 (IQR:21.9-27.2),FVC% pred:97(IQR:89.2-104.2) and FEV 1 /FVC: 0.84 (IQR:0.82-0.86) were studied. End-inspiratory (EIV) and end-expiratory (EEV) volumes of Chest Wall [CW] were measured by Opto-Electronic Plethysmography before, during and immediately after inspiration at TLC and expiration at RV with occluded airways for 8 secs (apnea, AP). In addition,TLC and RV maneuvers were performed at occluded airways with inspiratory (INS) or expiratory (EXP) efforts sustained for 5 sec followed by 3 sec of relaxation. EEV and EIV variations were measured during the first 4 breaths immediately after each maneuver.Results are shown in figure 1a and 1b. After RV,maneuvers, chest wall EEV decrease significantly after INS and AP (p=0,0061 and p=0,0122, respectively); chest wall EIV decrease significantly during after INS (p=0,010).After TLC maneuvers, EIV increase significantly during INS,EX and AP maneuvers (p=0,0189, p=0,012 and p=0,0002, respectively).  Our results suggest that a thixotropic effect determines an increase of chest wall operational volumes after sustaining lung volumes at TLC and a decrease after sustaining lung volumes at RV.
MG-132 Sensitizes TRAIL-Resistant Prostate Cancer Cells by Activating c-Fos/c-Jun Heterodimers and Repressing c-FLIP(L)
Authors: Wenhua Li, Xiaoping Zhang, Aria F. Olumi
Journal: Cancer Research (2007)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it induces apoptosis in cancer cells but not in normal cells. Unfortunately, some cancer cells develop resistance to TRAIL-induced apoptosis. Therefore, it is clinically relevant to determine the molecular mechanisms that differentiate between TRAIL-sensitive and TRAIL-resistant tumors. Previously, we have shown that the antiapoptotic molecule cellular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis. We have found that c-FLIP(L) is transcriptionally regulated by the activator protein-1 (AP-1) family member protein c-Fos. Here, we report that MG-132, a small-molecule inhibitor of the proteasome, sensitizes TRAIL-resistant prostate cancer cells by inducing c-Fos and repressing c-FLIP(L). c-Fos, which is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter region of the c-FLIP(L) gene. In addition to activating c-Fos, MG-132 activates another AP-1 family member, c-Jun. We show that c-Fos heterodimerizes with c-Jun to repress transcription of c-FLIP(L). Therefore, MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating the AP-1 family members c-Fos and c-Jun, which, in turn, repress the antiapoptotic molecule c-FLIP(L).