tbuckley/cabot-search huggingface dataset:
PF-03715455: An inhaled p38 inhibitor for the treatment of chronic obstructive pulmonary disease
Authors: Iain Kilty, Nick Clarke, David Fairmain, David Lamb, John Mathias, David Millan, Karen Wright, Christelle Perros-Huguet, Mike Yeadon
Journal: European Respiratory Journal (2013)

Rationale & Methods : There is an acute need for novel anti-inflammatory therapies for the treatment of COPD. A series of potent slow offset rapidly metabolised crystalline p38 inhibitors were identified and optimised for inhaled delivery. These compounds were screened in LPS / IL-1 induced primary monocyte and lung epithelial cells measuring a range of cytokines including TNFα, MIP1β, IL-6, IL-8. In addition, efficacy of IL-1 induced IL-8 inhibition in peripheral blood monocytes (PBMC) was compared to corticosteroids +/- co-incubation with cigarette smoke condensate (CSC). Topical in vivo activity was assessed in the dog segmental LPS challenge model.

Results :

![Figure][1] 



The maximal efficacy of PF-03715455 in reducing IL-1 mediated IL-8 production in human PBMC was modestly decreased by oxidative stress in the form of CSC (from 92% to 81%, respectively), while the potency of PF-03715455 was decreased 1.9-fold. However, the maximal efficacy of fluticasone propionate was dramatically decreased in the presence of CSC (from 73% to 39%, respectively), with a concomitant 3.1-fold decrease in relative potency. 1mg inhaled dry powder PF-03715455 resulted in a 48% inhibition of segmental LPS induced neutrophilia in dog.

Conclusion : PF-03715455 has broad anti-inflammatory effects in human lung cell systems and animal model systems and maintains activity under conditions of oxidative stress where corticosteroid efficacy is diminished.

 [1]: pending:yes
A BIO-PSYCHOLOGICAL APPROACH TO SOMATIC TREATMENTS IN PSYCHIATRY
Authors: GORDON T. HEISTAD
Journal: American Journal of Psychiatry (1957)

1. The view was expressed that behavioral effects of somatic treatment must occur within the context of lawful stimulus-response relationships. 2. The hypothesis was suggested that certain changes in the internal environment are included in the stimulus conditions which elicit emotional response and that somatic treatment procedures may change emotional behavior by changing the stimuli which elicit emotional responses. 3. Specific, testable predictions were derived from this theoretical point of view, and a limited number of animal experiments were discussed in relation to these predictions. 4. Possible practical applications of this point of view were suggested and discussed.
Cutting number of quangos will not save money, say MPs
Authors: A. O'Dowd
Journal: BMJ (2011)

The UK government has “botched” its attempt to axe many of the current non-departmental public bodies known as quangos, failing to save much money or improve accountability, MPs are claiming.

MPs on the parliamentary select committee on public administration published a report on 7 January that heavily criticises the process to cut the number of these arm’s length bodies.

The government announced in October last year that it would axe 192 public bodies and that 118 would be merged. Those axed included the National Patient Safety Agency, the Health Protection Agency, and the Joint Committee on Vaccination and Immunisations. They will cease to exist as quangos, with their work subsumed within the …
Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma
Authors: C. Feng, Y. Zhang, J. Yin, J. Li, R. Abounader, Z. Zuo
Journal: Neuro-Oncology (2014)

The biological functions of regulatory factor (RF)X1, a transcription factor, are not known. Since the RFX1 gene is often epigenetically silenced and clusters of differentiation (CD)44 proteins that regulate cancer cell biology are increased in human glioblastomas, we designed this study to determine whether RFX1 could regulate CD44 expression in glioblastoma. Regulatory factor X1 was overexpressed in 4 human glioblastoma cell lines. CD44 expression and cell proliferation, apoptosis, and invasion were assayed under in vitro conditions. In vivo growth of human glioblastoma xenografts was determined in mice. The expression of RFX1 and CD44 in human glioblastoma tissues was quantified. A putative RFX1 binding sequence existed in the first exon of the human CD44 gene. The transcription activity of the DNA fragment containing this putative sequence was decreased in cells overexpressing RFX1. Regulatory factor X1 bound to the CD44 gene in glioblastoma cells. It reduced CD44 expression and activated Akt and extracellular signal-regulated kinase, signaling molecules downstream of CD44 to regulate cell proliferation and survival. Overexpression of RFX1 inhibited the survival, proliferation, and transwell invasion of glioblastoma cells and in vivo growth of human glioblastoma xenografts. CD44 overexpression reversed RFX1 effects on cell proliferation. Finally, CD44 protein levels were inversely correlated with RFX1 protein levels in human glioblastoma tissues. These results suggest that RFX1 directly regulates CD44 expression. This mechanism may contribute to RFX1's effects on proliferation, survival, and invasion of glioblastoma cells. Our results provide initial evidence that RFX1 may be an important target/regulator of the malignancy of glioblastoma.
Mixed response to tocilizumab for ankylosing spondylitis
Authors: Joerg C Henes, Marius Horger, Ilhan Guenaydin, Lothar Kanz, Ina Koetter
Journal: Annals of the Rheumatic Diseases (2010)

Since the introduction of tumour necrosis factor (TNF) antagonists for the treatment of ankylosing spondylitis (AS) the majority of patients can be successfully treated. However, individual patients have persistent disease activity. We report on a 36-year-old male patient with HLA-B27-positive AS. No peripheral arthritis or extra-articular manifestation was documented. After insufficient response to standard treatment with non-steroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, methotrexate and all three available TNF antagonists (infliximab, etanercept and adalimumab), the last of these even in an intensified dose of 40 mg weekly, a rescue treatment with the interleukin 6 (IL-6) antagonist tocilizumab (TCZ; Roche Pharma, Roche Pharma, Grenzach-Wyhlen, Germany) was initiated.

TCZ was administered intravenously with 8 mg/kg bodyweight every 4 weeks. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) served as clinical response measure. For functional assessment the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were applied. For global …
Initial effects of anti-pronation tape on the medial longitudinal arch during walking and running
Authors: B Vicenzino, M Franettovich, T McPoil, T Russell, G Skardoon
Journal: British Journal of Sports Medicine (2005)

To investigate the effect of an augmented LowDye taping technique on the medial longitudinal arch of the foot during dynamic tasks such as walking and jogging, and to elucidate the relation between tape induced changes in static and dynamic foot posture.Seventeen subjects (mean (SD) age 27 (5.8) years) who were asymptomatic and exhibited a navicular drop greater than 10 mm were studied. Medial longitudinal arch height standardised to foot length during standing and at mid-stance of walking and jogging was measured from digital video images taken before and after the application of an anti-pronation taping technique. A no tape control condition was also included.Compared with the no tape control condition, tape produced a significant mean (SD) increase in the medial longitudinal arch height index of 0.031 (0.015), 0.026 (0.014), and 0.016 (0.017) during standing, walking, and jogging respectively (p < 0.05). The relative increase in medial longitudinal arch height represents an anti-pronation effect. The tape induced changes in the medial longitudinal arch height measured during standing correlated strongly with those measured during walking and jogging (Pearson's r = 0.7 and 0.76 respectively).The augmented LowDye tape was effective in controlling pronation during both static and dynamic activity. Tape induced changes in static foot posture paralleled those during walking and jogging.
Reduced Contraction and Altered Frequency Response of Isolated Ventricular Myocytes From Patients With Heart Failure
Authors: C.H. Davies, K. Davia, J.G. Bennett, J.R. Pepper, P.A. Poole-Wilson, S.E. Harding
Journal: Circulation (1995)

Background Previous work has failed to demonstrate reduced maximal contraction of isolated ventricular myocytes from failing human hearts compared with nonfailing control hearts. The effect of alterations in stimulation frequency and temperature on the contraction of isolated ventricular myocytes has been investigated. Left ventricular myocytes were isolated from the hearts of patients with severe heart failure undergoing heart transplantation and compared with myocytes isolated from myocardial biopsies from patients with coronary disease but preserved left ventricular systolic function or from myocytes from rejected donor hearts. Methods and Results Myocytes were exposed to either a maximally activating level of extracellular calcium at 37°C or to 2 mmol/L calcium at 32°C. There was no significant difference in the contraction amplitude between myocytes from failing and nonfailing hearts at 0.2 Hz. With increasing stimulation frequency, there was a reduction in contraction amplitude in cells from failing hearts relative to control hearts in both maximal calcium from 0.33 Hz (4.5% versus 6.6%) to 1.4 Hz (3.9% versus 8.8%) (ANCOVA, P &lt;.001) and at 2 mmol/L calcium from 0.50 Hz (2.3% versus 3.5%) to 1.4 Hz (1.8% versus 3.9%) (ANCOVA, P &lt;.001). The time to peak contraction and the times to 50% and 90% relaxation were prolonged in myocytes from failing hearts at stimulation rate of 0.2 Hz ( P &lt;.01), but only the time to 50% relaxation was prolonged at 1.0 Hz ( P &lt;.05). Conclusions Reduced contraction, slowed relaxation, and impaired frequency response occurring at the level of the individual ventricular myocyte can be demonstrated in human heart failure. This demonstrates that disruption of myocyte function can contribute to both the systolic and the diastolic abnormalities that occur in the failing human heart.
Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach
Authors: Guanglin Cui, Theodore J. Koh, Duan Chen, Chun-Mei Zhao, Shigeo Takaishi, Graham J. Dockray, Andrea Varro, Arlin B. Rogers, James G. Fox, Timothy C. Wang
Journal: Cancer Research (2004)

Abstract Recently we have reported synergistic effects between glycine-extended gastrin (G-gly) and amidated gastrin-17 on acid secretion in short-term infusion studies. In the present study, we examined the long-term effect of G-gly on the atrophy-promoting effects of amidated gastrin in the mouse stomach with or without Helicobacter infection. Transgenic mice overexpressing amidated gastrin (INS-GAS mice), G-gly (MTI/G-gly mice), and both peptides (INS-GAS/G-gly mice) were used for assessment of acid secretion and ulcer susceptibility and histologic examination and scoring of preneoplastic lesions in response to the 3 and 6 months Helicobacter felis (H. felis) infection. We found that MTI/G-gly mice had normal gastric histology and acid secretion. Double transgenic (INS-GAS/G-gly) mice showed 2-fold increases in acid secretion compared with INS-GAS mice. Acute peptic ulcers after pyloric ligation were noted in 50% of the INS-GAS/G-gly mice but in none of the INS-GAS mice at 6 months of age. Whereas male INS-GAS mice had a &amp;gt;50% decrease in the numbers of parietal cell and enterochromaffin-like cell at 6 months of age, the male double transgenic mice had no such decrease. Overexpression of G-gly reduced the scores of preneoplasia in the stomach; however, it did not prevent the development of amidated gastrin-dependent gastric cancer in both H. felis-infected mice and uninfected mice. We conclude that G-gly synergizes with amidated gastrin to stimulate acid secretion and inhibits parietal cell loss in INS-GAS/G-gly mice. The overexpression of G-gly seems to increase the susceptibility to peptic ulcer disease and delay the development of Helicobacter-mediated gastric preneoplasia in this model.
Sin3B Expression Is Required for Cellular Senescence and Is Up-regulated upon Oncogenic Stress
Authors: Kathryn B. Grandinetti, Petar Jelinic, Teresa DiMauro, Jessica Pellegrino, Rubén Fernández Rodríguez, Patricia M. Finnerty, Rachel Ruoff, Nabeel Bardeesy, Susan K. Logan, Gregory David
Journal: Cancer Research (2009)

Serial passage of primary mammalian cells or strong mitogenic signals induce a permanent exit from the cell cycle called senescence. A characteristic of senescent cells is the heterochromatinization of loci encoding pro-proliferative genes, leading to their transcriptional silencing. Senescence is thought to represent a defense mechanism against uncontrolled proliferation and cancer. Consequently, genetic alterations that allow senescence bypass are associated with susceptibility to oncogenic transformation. We show that fibroblasts genetically inactivated for the chromatin-associated Sin3B protein are refractory to replicative and oncogene-induced senescence. Conversely, overexpression of Sin3B triggers senescence and the formation of senescence-associated heterochromatic foci. Although Sin3B is strongly up-regulated upon oncogenic stress, decrease in expression of Sin3B is associated with tumor progression in vivo, suggesting that expression of Sin3B may represent a barrier against transformation. Together, these results underscore the contribution of senescence in tumor suppression and suggest that expression of chromatin modifiers is modulated at specific stages of cellular transformation. Consequently, these findings suggest that modulation of Sin3B-associated activities may represent new therapeutic opportunities for treatment of cancers.
Group X secreted phospholipase A2 induces lipid droplet formation and prolongs breast cancer cell survival
Authors: Anja Pucer, Vesna Brglez, Christine Payré, Jože Pungerčar, Gérard Lambeau, Toni Petan
Journal: Molecular Cancer (2013)

Alterations in lipid metabolism are inherent to the metabolic transformations that support tumorigenesis. The relationship between the synthesis, storage and use of lipids and their importance in cancer is poorly understood. The human group X secreted phospholipase A2 (hGX sPLA2) releases fatty acids (FAs) from cell membranes and lipoproteins, but its involvement in the regulation of cellular FA metabolism and cancer is not known.Here we demonstrate that hGX sPLA2 induces lipid droplet (LD) formation in invasive breast cancer cells, stimulates their proliferation and prevents their death on serum deprivation. The effects of hGX sPLA2 are shown to be dependent on its enzymatic activity, are mimicked by oleic acid and include activation of protein kinase B/Akt, a cell survival signaling kinase. The hGX sPLA2-stimulated LD biogenesis is accompanied by AMP-activated protein kinase (AMPK) activation, up-regulation of FA oxidation enzymes and the LD-coating protein perilipin 2, and suppression of lipogenic gene expression. Prolonged activation of AMPK inhibited hGX sPLA2-induced LD formation, while etomoxir, an inhibitor of FA oxidation, abrogated both LD formation and cell survival. The hGX sPLA2-induced changes in lipid metabolism provide a minimal immediate proliferative advantage during growth under optimal conditions, but they confer to the breast cancer cells a sustained ability to resist apoptosis during nutrient and growth factor limitation.Our results identify hGX sPLA2 as a novel modulator of lipid metabolism that promotes breast cancer cell growth and survival by stimulating LD formation and FA oxidation.
Differential Influence on Cytotoxic T Lymphocyte Epitope Presentation by Controlled Expression of Either Proteasome Immunosubunits or Pa28
Authors: Thorbald van Hall, Alice Sijts, Marcel Camps, Rienk Offringa, Cornelis Melief, Peter-M. Kloetzel, Ferry Ossendorp
Journal: The Journal of Experimental Medicine (2000)

The proteasome is the principal provider of major histocompatibility complex (MHC) class I–presented peptides. Interferon (IFN)-γ induces expression of three catalytically active proteasome subunits (LMP2, LMP7, and MECL-1) and the proteasome-associated activator PA28. These molecules are thought to optimize the generation of MHC class I–presented peptides. However, known information on their contribution in vivo is very limited. Here, we examined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycline-controlled, IFN-γ–independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The presence of either immunosubunits or PA28 did not alter the presentation of a subdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the presentation of the immunodominant MuLV-derived epitope was markedly enhanced upon induction of each of these two sets of genes. Thus, the IFN-γ–inducible proteasome subunits and PA28 can independently enhance antigen presentation of some CTL epitopes. Our data show that tetracycline-regulated expression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN-γ–inducible proteins on MHC class I processing may have a decisive influence on the quality of the CTL immune response.
Adrenaline inhibits adenosine diphosphate induced intravascular aggregation of rat platelets through stimulation of 2 adrenoceptors
Authors: A. O Oyekan, J. H Botting
Journal: Cardiovascular Research (1991)

Journal Article Adrenaline inhibits adenosine diphosphate induced intravascular aggregation of rat platelets through stimulation of α2 adrenoceptors Get access Adebayo O Oyekan, Adebayo O Oyekan A O Oyekan, J H Botting, Pharmacology Group, King's College (Chelsea Campus), University of London, Manresa Rd, London SW3, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jack H Botting Jack H Botting A O Oyekan, J H Botting, Pharmacology Group, King's College (Chelsea Campus), University of London, Manresa Rd, London SW3, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 25, Issue 5, May 1991, Pages 431–437, https://doi.org/10.1093/cvr/25.5.431 Published: 01 May 1991 Article history Received: 24 September 1990 Accepted: 11 January 1991 Published: 01 May 1991
Senescence induction; a possible cancer therapy
Authors: Matilde E LLeonart, Ana Artero-Castro, Hiroshi Kondoh
Journal: Molecular Cancer (2009)

Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.
Relating serum GGT to ALT activity enhances its predictability on treatment outcome in chronic hepatitis C
Authors: Ahmad Amanzada, Giuliano Ramadori, Sabine Mihm
Journal: Hepatology (2013)

We read the article by Everhart and Wright1 with great interest, noting serum gamma glutamyl transferase (GGT) activity both as a predictor of therapy outcome and as a prognostic indicator for disease outcome in chronic hepatitis C patients, based on data raised at the end of a 7-year observation period. Data were obtained from patients who were enrolled in the HALT-C study, meaning these patients had treatment before and were experiencing an advanced stage of liver disease. Everhart and Wright were also able to show a combined effect of serum GGT activity and IL28B rs12979860 genotype. They described that GGT activity adds particularly to predictability in carriers of the nonfavorable T allele featured by low virological response rates when compared to favorable CC homozygotes with high virological response rates. In the past, we also made the observation that serum GGT activity is predictive for virological responsiveness in patients with chronic hepatitis C.2 However, we found that a combined parameter, namely, the ratio of GGT and alanine aminotransferase (ALT) serum activity (ratio GGT/ALT) was clearly superior to serum GGT or serum ALT alone as a measure to indicate viral eradication. Although done in a much smaller and less homogenous cohort of out-patients, we were able to confirm our retrospective observation in a prospective approach.3 Moreover, with regard to IL28B rs12979860 genotypes, we recently were able to show that the GGT/ALT ratio improved IL28B rs12979860 genotype predictive efficiency from an odds ratio (OR) of 2.8, up to an OR of 26.7 in a cohort of 264 HCV type 1 patients.4, 5 In our hands the pretreatment GGT/ALT ratio has proven to be a more advantageous predictor than GGT or ALT serum activities alone. We therefore suggest that applying the ratio to the dataset analyzed by Everhart and Wright should yield even more persuasive data. Ahmad Amanzada, M.D. Giuliano Ramadori, M.D. Sabine Mihm, Ph.D. University Medical Center Goettingen, Department of Gastroenterology and Endocrinology Goettingen, Germany
Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome
Authors: Marcelo Britto Passos Amato, Carmen Silvia Valente Barbas, Denise Machado Medeiros, Ricardo Borges Magaldi, Guilherme Paula Schettino, Geraldo Lorenzi-Filho, Ronaldo Adib Kairalla, Daniel Deheinzelin, Carlos Munoz, Roselaine Oliveira, Teresa Yae Takagaki, Carlos Roberto Ribeiro Carvalho
Journal: New England Journal of Medicine (1998)

In patients with the acute respiratory distress syndrome, massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury. We determined whether a ventilatory strategy designed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome.