tbuckley/cabot-search huggingface dataset:
The effect of a novel phosphoinositide 3-kinase δ inhibitor (PI3Kδ), GSK2269557, on potential biomarkers measured from the lungs of healthy male smokers
Authors: Sally Worsley, Augustin Amour, Amanda Deans, Iain McSherry, Mark Lennon, Sylvia Fung, Nicole Hamblin, Phillip Hawkins, Edith M. Hessel
Journal: European Respiratory Journal (2013)

Phosphatidylinositol (4,5)-bisphosphate (PIP2) is converted by PI3Kδ into Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This activates cellular functions including proliferation and differentiation.

PI3Kδ, which is inhibited by GSK2269557, is a promising therapeutic target for respiratory disease.

Aim: To identify markers of PI3Kδ target engagement.

Methods: In one part of a single centre, randomized, double blind, placebo controlled phase I study, 2 cohorts of healthy male smokers were given active dose and placebo in a cross over design (ERS 851005). Sputum or bronchioaveolar lavage (BAL) was taken 3 hours post dosing. In the sputum cohort, PIP3 levels were measured and normalised by PIP2. In the BAL cohort, cell surface L- selectin (CD62L) and phosphorylated forkhead box 01 (p-FOXO1) were measured.

Results: PIP3 levels in sputum were reduced by 20% & 23% at 400µg, 6400µg of GSK2269557 respectively [p<0.05].

P-FOXO1: BAL cell expression showed a decrease in the active group in both macrophage and neutrophil cytoplasm [p<0.05] which is maintained in macrophages when pFOXO1 is normalised to total FOXO-1 [p<0.05].

L-selectin : The proportion of cells with cell membrane associated L- selectin showed an increase of 48% for macrophages and 21% for neutrophils in the active groups compared with placebo [p<0.05].

Conclusions : PIP3 is a suitable biomarker to demonstrate GSK2269557 target engagement, as indicated by reduced levels of PIP3 in GSK2269557 treated subjects. Downstream of PIP3, reduced levels of p-FOXO1 and increased L-selectin cell surface expression were consistent with PI3K inhibition and support the PIP3 results.
Shamanism and Psychotherapy
Authors: Jozef Ph. Hes
Journal: Psychotherapy and Psychosomatics (1975)

Research Articles| February 12 2010 Shamanism and Psychotherapy Subject Area: Psychiatry and Psychology Jozef Ph. Hes Jozef Ph. Hes Ramat Hasharon Search for other works by this author on: This Site PubMed Google Scholar Psychother Psychosom (1975) 25 (1-6): 251–253. https://doi.org/10.1159/000286876 Article history Published Online: February 12 2010 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Jozef Ph. Hes; Shamanism and Psychotherapy. Psychother Psychosom 31 December 1975; 25 (1-6): 251–253. https://doi.org/10.1159/000286876 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsPsychotherapy and Psychosomatics Search Advanced Search Article PDF first page preview Close Modal 1975Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.
Thyroid Hormone Coordinates Respiratory Control Maturation and Adenine Nucleotide Translocator Expression in Heart In Vivo
Authors: Michael A. Portman, Yun Xiao, Kun Qian, Russell L. Tucker, Steven M. Parish, Xue-Han Ning
Journal: Circulation (2000)

Background —The signal transduction mechanism linking mitochondrial ATP synthesis with cytosolic ATP utilization in heart changes during postnatal development in vivo. This maturational process occurs in parallel with accumulation of mitochondrial adenine nucleotide translocator (ANT), which provides a possible site for respiratory control. We postulated that thyroid hormone regulates these maturational processes. Methods and Results —We used 31 P MR spectroscopy to determine the relationship between myocardial high-energy phosphates, phosphocreatine, and ADP and oxygen consumption (MV̇ o 2 ) during epinephrine stimulation in 32- to 40-day-old lambs thyroidectomized after birth (THY) and age-matched controls. Steady-state protein and mRNA levels for ANT isoforms and β-F 1 -ATPase were assessed from left ventricular tissues by Western and Northern blotting. With greater doses of epinephrine, THY attained lower peak MV̇ o 2 than controls ( P &lt;0.05). Controls maintained high-energy phosphate levels, unlike THY, which demonstrated significantly decreased phosphocreatine/ATP and increased cytosolic ADP despite lower peak MV̇ o 2 . No significant differences in β-F 1 -ATPase protein or mRNA occurred between groups. However, ANT isoform mRNA levels were 2-fold greater and protein levels 4-fold greater in control hearts. Conclusions —These data imply that the maturational shift away from ADP-mediated respiratory control is regulated by thyroid hormone in vivo. Specific thyroid-modulated increases in ANT mRNA and protein imply that this regulation occurs in part at a pretranslational level.
SELECTIVE INHIBITION BY PREPARATIONS OF STREPTOCOCCAL FILTRATES OF THE OXIDATIVE METABOLISM OF MITOCHONDRIA PROCURED FROM RABBIT MYOCARDIUM
Authors: Arthur S. Carlson, Aaron Kellner, Alan W. Bernheimer
Journal: The Journal of Experimental Medicine (1956)

When solutions of streptolysin O were added to Warburg flasks containing, among other constituents, suspensions of mitochondria from the myocardium of rabbits and citrate, fumarate, or alpha-ketoglutarate as the substrate, there followed regularly a sharp reduction, and eventually complete cessation, of oxygen consumption. This phenomenon was not observed when succinate was the substrate in the flasks, the finding pointing to a selective interference with DPN as the underlying change. The agent in the solutions of streptolysin O responsible for this effect was shown to be a streptococcal product, and to be non-dialyzable and heat-labile. It differed from streptolysin O in that it did not appear to require prior activation with cysteine, and its effectiveness was not diminished by treatment with cholesterol or antistreptolysin globulins.
Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis
Authors: S. Wandel, P. Juni, B. Tendal, E. Nuesch, P. M. Villiger, N. J. Welton, S. Reichenbach, S. Trelle
Journal: BMJ (2010)

<b>Objective</b> To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. <b>Design </b>Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points. <b>Main outcome measure</b> Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at −0.9 cm on a 10 cm visual analogue scale. <b>Data sources</b> Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. <b>Eligibility criteria for selecting studies</b> Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. <b>Results </b>10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was −0.4 cm (95% credible interval −0.7 to −0.1 cm) for glucosamine, −0.3 cm (−0.7 to 0.0 cm) for chondroitin, and −0.5 cm (−0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. <b>Conclusions C</b>ompared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.
Tumor suppressor miR-24 restrains gastric cancer progression by downregulating RegIV
Authors: Yantao Duan, Lei Hu, Bing Liu, Beiqin Yu, Jianfang Li, Min Yan, Yingyan Yu, Chen Li, Liping Su, Zhenggang Zhu, Ming Xiang, Bingya Liu, Qiumeng Yang
Journal: Molecular Cancer (2014)

microRNAs are small noncoding RNAs that modulate a variety of cellular processes by regulating multiple targets, which can promote or inhibit the development of malignant behaviors. Accumulating evidence suggests miR-24 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive. This study examined the role of miR-24 in gastric cancer (GC).The expression of miR-24 in GC tissues compared with matched non-tumor tissues and GC cells was detected by qRT-PCR. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vectors were used to regulate miR-24 expression in GC cells to investigate its function in vitro and in vivo.miR-24 was significantly downregulated in GC tissues compared with matched non-tumor tissues and was associated with tumor differentiation. Ectopic expression of miR-24 in SGC-7901 GC cells suppressed cell proliferation, migration and invasion in vitro as well as tumorigenicity in vivo by inducing cell cycle arrest in G0/G1 phase and promoting cell apoptosis. Furthermore, we identified RegIV as a target of miR-24 and demonstrated that miR-24 regulated RegIV expression via binding its 3' untranslated region.miR-24 functions as a novel tumor suppressor in GC and the anti-oncogenic activity may involve its inhibition of the target gene RegIV. These findings suggest the possibility for miR-24 as a therapeutic target in GC.
Association of Resolution of Major Depression With Increased Natural Killer Cell Activity Among HIV-Seropositive Women
Authors: Dean G Cruess, Steven D Douglas, John M Petitto, Thomas Ten Have, David Gettes, Benoit Dubé, Mark Cary, Dwight L Evans
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Depression is a potential risk factor for morbidity and mortality among patients with numerous medical conditions, including HIV disease, and it is also associated with decrements in immune function, such as natural killer (NK) cell activity. This study examined whether improvements in the diagnostic status of major depression are related to increases in NK cell activity among HIV-seropositive women. METHOD: HIV-seropositive women were recruited as part of a longitudinal cohort study and underwent comprehensive medical and psychiatric evaluations during a 2-year period. Fifty-seven women had complete NK cell activity and depression data measured at two time points and were examined for associations between changes in depression status and alterations in NK cell activity over time. RESULTS: Among the 57 HIV-seropositive women, improvements in the diagnostic status of depression and decreases in scores on the 17-item Hamilton Depression Rating Scale were significantly associated with increases in NK cell activity over time, as measured in lytic units. Eleven women (19.3%) had a major depression diagnosis that resolved over time, and this group also had a significant increase in cell activity measured in lytic units during this period. CONCLUSIONS: This study suggests that depression may impair certain aspects of innate cellular immunity relevant to delaying the progression of HIV disease and that these alterations are reversible with the resolution of a depressive episode. These findings support an examination of NK cell activity in assessments of the relationship between depression and morbidity and mortality in HIV disease.
Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses
Authors: Ingo Fricke, Noweeda Mirza, Jakob Dupont, Craig Lockhart, Autumn Jackson, Ji-Hyun Lee, Jeffrey A. Sosman, Dmitry I. Gabrilovich
Journal: Clinical Cancer Research (2007)

Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis.Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment.VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC.Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.
Randomised trial of intrapleural urokinase in the treatment of childhood empyema
Authors: A H Thomson
Journal: Thorax (2002)

Background: The role of intrapleural fibrinolytic agents in the treatment of childhood empyema has not been established. A randomised double blind placebo controlled trial of intrapleural urokinase was performed in children with parapneumonic empyema. Methods: Sixty children (median age 3.3 years) were recruited from 10 centres and randomised to receive either intrapleural urokinase 40 000 units in 40 ml or saline 12 hourly for 3 days. The primary outcome measure was length of hospital stay after entry to the trial. Results: Treatment with urokinase resulted in a significantly shorter hospital stay (7.4 <i>v</i> 9.5 days; ratio of geometric means 1.28, CI 1.16 to 1.41 p=0.027). A post hoc analysis showed that the use of small percutaneous drains was also associated with shorter hospital stay. Children treated with a combination of urokinase and a small drain had the shortest stay (6.0 days, CI 4.6 to 7.8). Conclusion: Intrapleural urokinase is effective in treating empyema in children and significantly shortens hospital stay.
Thrombomodulin domains attenuate atherosclerosis by inhibiting thrombin-induced endothelial cell activation
Authors: H.-J. Wei, Y.-H. Li, G.-Y. Shi, S.-L. Liu, P.-C. Chang, C.-H. Kuo, H.-L. Wu
Journal: Cardiovascular Research (2011)

Thrombin modulates the formation of atherosclerotic lesions by stimulating a variety of cellular effects through protease-activated receptor-1 (PAR-1) activation. Thrombomodulin (TM) inhibits thrombin effects by binding thrombin through its domains 2 and 3 (TMD23). We investigated whether recombinant TMD23 (rTMD23) could inhibit atherosclerosis via its thrombin-binding ability.Wild-type mouse rTMD23 and three mutants with altered thrombin-binding sites, rTMD23 (I425A), rTMD23 (D424A/D426A), and rTMD23 (D424A/I425A/D426A), were expressed and purified in the Pichia pastoris expression system. Wild-type rTMD23 and rTMD23 (D424A/D426A) could effectively bind thrombin, activate protein C, and prolong thrombin clotting time, whereas rTMD23 (I425A) and rTMD23 (D424A/I425A/D426A) lost these functions. Wild-type rTMD23, but not rTMD23 (I425A), decreased both the thrombin-induced surface PAR-1 internalization and the increase in cytoplasmic Ca(2+) concentrations in endothelial cells (ECs). Wild-type rTMD23 and rTMD23 (D424A/D426A) also inhibited thrombin-induced adhesion molecules and monocyte chemoattractant protein-1 expression and increased permeability in ECs, whereas rTMD23 (I425A) and rTMD23 (D424A/I425A/D426A) had no such effects. Furthermore, wild-type rTMD23 and rTMD23 (D424A/D426A) were effective in reducing carotid ligation-induced neointima formation in C57BL/6 mice and atherosclerotic lesion formation in apolipoprotein E-deficient (ApoE-/-) mice, whereas rTMD23 with the I425A mutation showed impairment of this function. Wild-type rTMD23, but not rTMD23 (I425A), also markedly suppressed the PAR-1, the adhesion molecules expression, and the macrophage content in the carotid ligation model and ApoE-/- mice.rTMD23 protein significantly reduces atherosclerosis and neointima formation through its thrombin-binding ability.
Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes
Authors: Quan Zhang, Reshma Ramracheya, Carolina Lahmann, Andrei Tarasov, Martin Bengtsson, Orit Braha, Matthias Braun, Melissa Brereton, Stephan Collins, Juris Galvanovskis, Alejandro Gonzalez, Lukas N. Groschner, Nils J.G. Rorsman, Albert Salehi, Mary E. Travers, Jonathan N. Walker, Anna L. Gloyn, Fiona Gribble, Paul R.V. Johnson, Frank Reimann, Frances M. Ashcroft, Patrik Rorsman
Journal: Cell Metabolism (2013)
Raised enzyme markers of chronic inflammation in asymptomatic farmers' lung.
Authors: C W Turton, G Firth, E Grundy, B G Rigden, J T Smyth, M Turner-Warwick
Journal: Thorax (1981)

Subclinical inflammatory activity may be one of the factors which influences the variable natural history of farmers9 lung. Serum lysozyme (LYS) and angiotensin converting enzyme (ACE) have been measured in 52 farmers with a previous history of farmers9 lung and in 51 healthy control farmers. The group with farmers9 lung assessed during the winter, although having had no recent acute symptoms, had significantly higher levels of LYS and ACE compared to both healthy control farmers seen in winter and farmers9 lung subjects seen in summer. There was a mild but significant negative correlation between LYS and farm size in the farmers9 lung subjects assessed in winter. The results suggest that active inflammation may be present in subjects with farmers9 lung in the absence of acute symptoms during the season when dust exposure occurs as the result of feeding cattle.
Fixed performance oxygen masks: an evaluation.
Authors: S L Hill, P K Barnes, T Hollway, R Tennant
Journal: BMJ (1984)

Fixed performance oxygen masks operate by supplying mixtures of oxygen and air at rates exceeding the inspiratory flow rate of the patient. In this study the oxygen concentration delivered by three fixed performance oxygen masks was determined non-invasively at various inspiratory flow rates. At low inspiratory flow rates all the masks studied acted as fixed performance devices. When the peak inspiratory rate increased the performance of all the masks showed some variability. The change from fixed to variable performance depended on the relation between inspiratory flow rate and the total gas flow delivered by the mask and was independent of the volume of the mask. Hence the use of low volume masks and high oxygen flow rates should produce more consistent results than high volume masks and lower flow rates.
Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin
Authors: Céline Jacquemont, Julian A Simon, Alan D D'Andrea, Toshiyasu Taniguchi
Journal: Molecular Cancer (2012)

Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA) pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin.Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407).Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor), CA-074-Me (cathepsin B inhibitor) and 17-AAG (HSP90 inhibitor), synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF), but not in FA-deficient isogenic cells (2008). In addition, geldanamycin (HSP90 inhibitor) and two CHK1 inhibitors (UCN-01 and SB218078) exhibited a significantly stronger synergism with cisplatin in FA-proficient cells when compared to FA-deficient cells, suggesting a contribution of their FA pathway inhibitory activity to cisplatin sensitization.Our findings suggest that, despite their lack of specificity, pharmaceutical inhibition of the FA pathway by bortezomib, CA-074-Me, CHK1 inhibitors or HSP90 inhibitors may be a promising strategy to sensitize cisplatin-resistant, FA pathway-proficient tumor cells to cisplatin. In addition, we identified four new small molecules which synergize with cisplatin. Further development of their analogs and evaluation of their combination with cisplatin may lead to the development of efficient cancer treatments.