tbuckley/cabot-search huggingface dataset:
Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial
Authors: Stuart R Dalziel, Vanessa K Lim, Anthony Lambert, Dianne McCarthy, Varsha Parag, Anthony Rodgers, Jane E Harding
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. <b>Design</b> Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. <b>Setting</b> Tertiary obstetric hospital in Auckland, New Zealand. <b>Participants</b> 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). <b>Interventions</b> Mothers received two doses of betamethasone or placebo 24 hours apart. <b>Main outcome measures</b> Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. <b>Results</b> No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. <b>Conclusions</b> Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.
IM-05 * MULTISPECIFIC CAR T CELLS FOR THE TREATMENT OF HIGH GRADE GLIOMA
Authors: K. Bielamowicz, K. Fousek, T. Byrd, K. Chow, Z. Yi, S. Krebs, G. Dotti, S. Gottschalk, M. Hegde, N. Ahmed
Journal: Neuro-Oncology (2015)

BACKGROUND: High grade gliomas (HGG) carry a dismal prognosis. Our group has shown that patients' HER2-specific chimeric antigen receptor (CAR) T-cells kill autologous HGG, yet 40% of tumors recur in experimental animals. Recurrences are composed of HER2 negative escape variant cells that maintain positivity for two other glioma antigens, IL13Rα2 and EphA2. We hypothesized that co-targeting of these escape variants will enhance the anti-glioma activity of CAR T cells. OBJECTIVES: Objectives: The intent of this project is to develop a multi-specific T-cell product for the adoptive immunotherapy of HGG. DESIGN/METHOD: We generated and tested the effector functions of patients' T-cells co-expressing CARs for HER2, IL13Rα2 and EphA2 against autologous HGG cells derived from surgical excision samples. RESULTS: Primary patient HGG samples exhibited varied expression of the three target antigens, HER2, IL13Rα2 and EphA2. In order to render single patients' T cells tri-specific, we designed a transgene incorporating 3 encoding regions for HER2, IL13Rα2 and EphA2 CARs separated by 2A sequences in a single cassette driven by a CMV promoter. We used a retroviral system to stably integrate this transgene into the primary T cell genome. CAR-specific flow cytometry indicated proportionate stable expression of individual CAR molecules on the T cell surface. These T cells show distinct specificity for each of the three glioma antigens evidenced by activation, proliferation, and cytolytic function in immunoassays. Further, preliminary in vitro testing in glioma cell lines shows the ability to target populations of tumor cells that are not eliminated by unspecific products. CONCLUSION: The heterogeneity of antigenic expression in HGG and antigen escape justify targeting multiple glioma antigens simultaneously. We have successfully generated and tested a multi-specific T cell product for adoptive transfer that could offset antigen escape and exhibit an enhanced anti-glioma efficacy.
Inhibition of Protein Kinase C Prevents Rapid Desensitization of Type 1B Angiotensin II Receptor
Authors: Hua Tang, Heigoro Shirai, Tadashi Inagami
Journal: Circulation Research (1995)

Abstract The type 1B angiotensin II (AT 1B ) receptor cloned from rat kidney was stably expressed in Chinese hamster ovary cells. The stably expressed receptor was characterized by radioligand binding studies and functional coupling to inositol 1,4,5-triphosphate (IP 3 ) formation. Exposure of cells expressing the AT 1B receptor to angiotensin II (Ang II) resulted in a rapid and dose-dependent homologous desensitization of receptor-mediated production of IP 3 , with an essentially complete desensitization at an agonist concentration &gt;10 nmol/L. Binding studies revealed no significant change in the number of AT 1B receptors in transfected cells exposed to 1 nmol/L Ang II, whereas exposure to 100 nmol/L Ang II caused a rapid decrease of cell surface receptors, with a 75% loss of receptor number seen at 1 hour. Rapid desensitization occurred in the absence of receptor internalization. Blockade of receptor internalization with concanavalin A had at most only a slight effect on the agonist-induced desensitization. This indicates that factors other than internalization are chiefly responsible for the rapid agonist-induced desensitization. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, caused rapid desensitization of the receptor-mediated IP 3 response. Neither tyrosine kinase inhibitors nor a protein kinase A activator affected the receptor-mediated IP 3 response. The specific PKC inhibitor GF109203X or PKC depletion by prolonged treatment with 1 μmol/L PMA completely blocked the PMA-dependent desensitization. Desensitization evoked by a low Ang II agonist concentration (1 nmol/L) was reversed by the PKC-specific inhibitor GF109203X or PKC depletion, whereas the desensitizing effect at a high agonist concentration (100 nmol/L) is only partially prevented by PKC inhibitory treatment. These results demonstrate that PKC plays a crucial role in the desensitization of the AT 1B receptor. They also suggest that receptor internalization and an additional PKC-independent pathway also contribute to desensitization of the AT 1B receptor in transfected cells.
Abstract 941: Suppression of the androgen receptor function by c-Jun in prostate cancer via a dual mechanism
Authors: Chih-Chao Hsu, Chang-Deng Hu
Journal: Cancer Research (2012)

Abstract Androgen receptor (AR) signaling plays a pivotal role in growth and survival of prostate cancer cells. Upon ligand binding, AR translocates into the nucleus and regulates expression of multiple genes through binding their promoter regions. Thus, altered expression and activity of AR contribute to disease progression. Consequently, significant effort has been undertaken to identify and characterize numerous coactivators and corepressors of AR. Here we report that the transcription factor c-Jun, a basic region leucine zipper (bZIP) transcription factor and is an important member of the AP-1 family, acts as a transcriptional repressor to inhibit the AR transcriptional activity. Furthermore, we have found that c-Jun also represses the transcription of AR. Overexpression of c-Jun in LNCaP prostate cancer cells inhibited luciferase reporters driven by the androgen-induced prostate-specific antigen (PSA) promoter, probasin promoter, mouse mammary tumor virus (MMTV) promoter and tandem repeats of androgen response elements in a dose-dependent manner. Conversely, knockdown of c-Jun enhanced androgen-stimulated AR activity in LNCaP cells. To further confirm the results, we generated a doxycycline-inducible c-Jun overexpression LNCaP stable cell line using lentivrial system. Consistent with the results of promoter activity assay, induction of c-Jun by doxycycline inhibited both steady state and androgen-induced PSA mRNA and protein levels. Interestingly, the protein and mRNA of AR were also downregulated when c-Jun was induced, suggesting that c-Jun suppresses AR expression at the transcriptional level. Moreover, c-Jun induction resulted in a significant reduction in cell number, suggesting that c-Jun suppresses LNCaP cell proliferation by antagonizing AR signaling. In summary, our results suggest that c-Jun negatively regulates the AR signaling by a dual mechanism. Future identification of negative regulators of c-Jun expression will provide a new opportunity to develop novel therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 941. doi:1538-7445.AM2012-941
Skin Intrinsic Fluorescence Is Associated With Coronary Artery Disease in Individuals With Long Duration of Type 1 Diabetes
Authors: Baqiyyah N. Conway, Vanita R. Aroda, John D. Maynard, Nathaniel Matter, Stephen Fernandez, Robert E. Ratner, Trevor J. Orchard
Journal: Diabetes Care (2012)

Skin intrinsic fluorescence (SIF) reflects many factors, including the presence of certain advanced glycation end products. We investigated whether SIF was associated with coronary artery disease (CAD) in type 1 diabetes and whether this relationship was independent of renal disease.SIF was measured in 112 subjects from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and 60 from MedStar Health Research Institute when mean age and diabetes duration were 48 and 36 years, respectively. Cumulative glycemic exposure (updated mean A1C) represented a mean of 18 years' follow-up in EDC and 10.3 in MedStar.Of the 172 participants, 30 had CAD (15 male and 15 female). SIF levels were higher in those with CAD (P < 0.0001). SIF was strongly associated with CAD (odds ratio [OR] 3.5 [95% CI 2.1-6.1]). After age, duration, and updated mean A1C were controlled for, SIF remained associated with CAD (2.4 [1.3-4.4]), more strongly in men (5.6 [2.1-14.6]) than in women (1.4 [0.61-3.3]). As there was no significant sex interaction, further analyses were conducted combining the sexes. Further accounting for sex and nephropathy status did not improve the model fit, though with nephropathy in the model, the OR for SIF was reduced to 1.7 (95% CI 0.89-3.4).SIF has a significant cross-sectional association with CAD. This association is strongly linked to age and duration and, to a lesser degree, to mean A1C and renal disease. SIF therefore may be a useful overall marker of CAD risk in type 1 diabetes.
Microtubule-associated protein-4 (MAP-4) inhibits microtubule-dependent distribution of mRNA in isolated neonatal cardiocytes
Authors: D SCHOLZ, P MCDERMOTT, M GARNOVSKAYA, T GALLIEN, S HUETTELMAIER, C DERIENZO, G COOPERIV
Journal: Cardiovascular Research (2006)

Active mRNA distribution in the form of ribonucleoprotein particles moving along microtubules has been shown in several cell types, but not yet in cardiocytes. This study addresses two hypotheses: 1) a similar mRNA distribution mechanism operates in cardiocytes; 2) decoration of microtubules with microtubule-associated proteins compromises this distribution.To visualize ribonucleoproteins in cultured neonatal rat cardiocytes, they were transfected with vectors encoding zipcode binding protein-1 and Staufen fused with GFP. The velocity of microtubular transport and elongation were calculated on time-lapse confocal pictures.ZBP-1 and Staufen labeled particles co-localized with each other and with microtubules and moved along microtubules over a distance of 1-20 microm with a mean speed of 80 nm/s. The average speed decreased about 50% after decoration of microtubules by adenoviral microtubule-associated protein-4 (MAP-4). The elongation speed measured using the GFP-tagged end-binding protein-1 exceeded 200 nm/s and was not influenced by MAP-4.We demonstrate for the first time ribonucleoprotein particles in cardiocytes, their microtubular-related movement, and its inhibition (but not of the microtubular elongation), by the MAP-4 decoration of microtubules.
Competitive Effects of Some Cations on Active Potassium Transport in the Human Red Blood Cell*
Authors: John R. Sachs
Journal: Journal of Clinical Investigation (1967)

The effect of some cations on the active potassium transport system of the human red blood cell has been investigated. At low extracellular potassium concentrations, extracellular sodium competitively inhibits the active potassium influx at all sodium concentrations investigated, and tetraethylammonium behaves in a fashion similar to that of sodium. At low extracellular concentrations of potassium, ammonium at low concentrations at first stimulates the active potassium influx, but at higher concentrations inhibits it. Tetramethylammonium at most slightly stimulates the active potassium influx, and calcium is without effect. The behavior is consistent with a model in which potassium is required at more than one site before transport occurs, and the sites are indistinguishable as far as their behavior toward the ions investigated is concerned. The affinity of the alkali metal cations for the sites appears to be explicable in terms of their physical characteristics.
Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development
Authors: Woo-Young Kim, Quanri Jin, Seung-Hyun Oh, Edward S. Kim, Youn Joo Yang, Dong Hoon Lee, Lei Feng, Carmen Behrens, Ludmila Prudkin, York E. Miller, J. Jack Lee, Scott M. Lippman, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee
Journal: Cancer Research (2009)

Abstract Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer. [Cancer Res 2009;69(18):7439–48]
Endoplasmic Reticulum Stress Gene Induction and Protection From Ischemia/Reperfusion Injury in the Hearts of Transgenic Mice With a Tamoxifen-Regulated Form of ATF6
Authors: Joshua J. Martindale, Rayne Fernandez, Donna Thuerauf, Ross Whittaker, Natalie Gude, Mark A. Sussman, Christopher C. Glembotski
Journal: Circulation Research (2006)

Ischemia/reperfusion (I/R) affects the integrity of the endoplasmic reticulum (ER), the site of synthesis and folding of numerous proteins. Therefore, I/R may activate the unfolded protein response (UPR), resulting in the induction of a collection of ER stress proteins, many of which are protective and function to resolve the ER stress. In this study, we showed that when mouse hearts were subjected to ex vivo I/R, the levels of 2 ER stress-inducible markers of the UPR, the ER-targeted cytoprotective chaperones glucose-regulated proteins 78 and 94 (GRP78 and GRP94), were increased, consistent with I/R-mediated UPR activation in the heart. The UPR-mediated activation of ATF6 (Activation of Transcription Factor 6) induces cytoprotective ER stress proteins, including GRP78 and GRP94. To examine whether ATF6 protects the myocardium from I/R injury in the heart, we generated transgenic (TG) mice featuring cardiac-restricted expression of a novel tamoxifen-activated form of ATF6, ATF6-MER. When NTG and ATF6-MER TG mice were treated with or without tamoxifen for 5 days, only the hearts from the tamoxifen-treated TG mice exhibited increased levels of many ER stress-inducible mRNAs and proteins; for example, GRP78 and GRP94 transcript levels were increased by 8- and 15-fold, respectively. The tamoxifen-treated TG mouse hearts also exhibited better functional recovery from ex vivo I/R, as well as significantly reduced necrosis and apoptosis. These results suggest that the UPR is activated in the heart during I/R and that, as a result, the ATF6 branch of the UPR may induce expression of proteins that can function to reduce I/R injury.
Conventional DMARDs in axial spondyloarthritis: wishful––rather than rational—thinking!
Authors: Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2015)

Conventional synthetic DMARD (csDMARD) therapy in patients with axial spondyloarthritis (SpA) is a matter of continuous debate. Part of this discussion is a dispute about methotrexate (MTX) comedication in patients with axial SpA treated with tumour necrosis factor inhibitors biologicals (TNFi). The dispute seems to be based on perceptions rather than scientific evidence and may have been fuelled by one of the European League Against Rheumatism task force on the management of rheumatoid arthritis (RA) recommendations. This recommendation states that in RA, TNFi-biologicals should be used in combination with MTX,1 which finds its justification in the results of multiple randomised clinical trials and careful posthoc analyses thereof.

According to the Assessment in SpondyloArthritis International Society (ASAS), however, axial SpA is not a disease in which csDMARDs including MTX should be prescribed.2 This bold conclusion has been framed by thorough systematic literature research that has failed to find evidence for efficacy of csDMARDs in axial SpA.3

Guidelines and recommendations are supposedly clear and unequivocal. However, clinicians prefer to manage ‘several shades of grey’ rather than ‘think in black and white’. They may argue that absence of evidence (for the efficacy of csDMARDs in axial SpA) does not necessarily mean evidence for the absence of such an effect. In fact, and in spite of current recommendations prescribing the opposite, many do treat patients with axial SpA with csDMARDs occasionally.

It must be easier to digest disobedience with guidelines if plausible scientific explanations can be employed to justify non-commitment: immunogenicity of TNF-inhibiting biologicals is one of those attractive theories that scientists may bring up in order to explain why combinations of MTX and a TNFi-biological work better in RA than monotherapy with a biological: MTX may prevent the formation of TNFi-neutralising antibodies, which in turn could be responsible for loss …
Total and regional coronary blood flow during acute right ventricular pressure overload
Authors: R. J. DOMENECH, A. H. AYUY
Journal: Cardiovascular Research (1974)

Total and regional coronary blood flow were measured with radioactive microspheres before and during acute right ventricular pressure overload. Coronary flow to the left ventricular wall decreased and coronary vascular resistance in this region increased during the overload. These changes do not appear to be due to metabolic changes of the left ventricle but rather seem to be mediated through alpha-adrenergic receptors of the coronary arteries.
Pathological lesions in colonic biopsies during Parkinson's disease
Authors: T Lebouvier, T Chaumette, P Damier, E Coron, Y Touchefeu, S Vrignaud, P Naveilhan, J-P Galmiche, S Bruley des Varannes, P Derkinderen, M Neunlist
Journal: Gut (2008)

Parkinson’s disease (PD) is a neurodegenerative condition that affects 1% of the population over 65 years of age. The two pathological hallmarks of PD are a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of cytoplasmic eosinophilic inclusions termed Lewy bodies (LBs), whose main component is phosphorylated α-synuclein.1 This degeneration of SN neurons leads to a dopamine deficiency responsible for the major motor symptoms. Nevertheless, it has become increasingly evident that PD is a multicentric neurodegenerative process that also affects neuronal structures outside the SN.2 In this context, various reports performed on surgical or autopsy specimens have shown that the enteric nervous system (ENS) is affected during PD.3 4 However, it is still a matter of debate whether these alterations occur early in the course of the disease. This is mainly due to a lack of accessibility to the ENS in the living patients. Therefore, demonstrating (1) the ability to study the ENS using routine colonic biopsies and (2) the presence of lesions characteristics …
A randomised controlled trial to assess the effectiveness and cost of a patient orientated self management approach to chronic inflammatory bowel disease
Authors: A P Kennedy
Journal: Gut (2004)

<b>Objectives:</b> We developed a patient centred approach to chronic disease self management by providing information designed to promote patient choice. We then conducted a randomised controlled trial of the approach in inflammatory bowel disease (IBD) to assess whether it could alter clinical outcome and affect health service use. <b>Design:</b> A multicentre cluster randomised controlled trial. <b>Setting:</b> The trial was conducted in the outpatient departments of 19 hospitals with randomisation by treatment centre, 10 control sites, and nine intervention sites. For patients at intervention sites, an individual self management plan was negotiated and written information provided. <b>Participants:</b> A total of 700 patients with established inflammatory bowel disease were recruited. <b>Main outcome measures:</b> Main outcome measures recorded at one year were: quality of life, health service resource use, and patient satisfaction. Secondary outcomes included measures of enablement—confidence to cope with the condition. <b>Results:</b> One year following the intervention, self managing patients had made fewer hospital visits (difference −1.04 (95% confidence interval (CI) −1.43 to −0.65); p&lt;0.001) without increase in the number of primary care visits, and quality of life was maintained without evidence of anxiety about the programme. The two groups were similar with respect to satisfaction with consultations. Immediately after the initial consultation, those who had undergone self management training reported greater confidence in being able to cope with their condition (difference 0.90 (95% CI 0.12–1.68); p&lt;0.03). <b>Conclusions:</b> Adoption of this approach for the management of chronic disease such as IBD in the NHS and other managed health care organisations would considerably reduce health provision costs and benefit disease control.