tbuckley/cabot-search huggingface dataset:
Three quarters of NHS trusts in deficit are cutting staff
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Just over three quarters of the NHS trusts that have acute financial problems have reduced their staff to try to balance the books. This is one early finding, published last week, from a survey of trusts in deficit by the NHS Confederation, the representative body for NHS organisations. Doctors' representatives are worried that care of patients is suffering and good working relationships with managers could be damaged.

The survey included responses from 35 chief executives out of the 63 trusts that are under government scrutiny because of their financial troubles. Of the respondents, 29 (82%) had imposed a vacancy freeze, 27 …
Pioglitazone attenuates endotoxin-induced acute lung injury by reducing neutrophil recruitment
Authors: Jochen Grommes, Mathias Mörgelin, Oliver Soehnlein
Journal: European Respiratory Journal (2012)

Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Activation and recruitment of neutrophils are regarded as key mechanisms in the progression of ALI. As pioglitazone holds potent pleiotropic anti-inflammatory effects, we explored its effects during ALI. C57Bl/6 mice were exposed to aerosolised lipopolysaccharides (LPSs) (500 μg·mL −1 ) and their alveolar, interstitial and intravascular neutrophils were assessed 4 h later. Lung permeability changes were evaluated by fluorescein isothiocyanate-dextran clearance and protein content in the bronchoalveolar lavage fluid. In vitro , human isolated neutrophils were pretreated with piolitazone (10 μM, for 1 or 3 h) and then activated with N -formyl- l -methionyl- l -leucyl- l -phenylalanine. Neutrophil activation, adhesion, release and formation of reactive oxygen species (ROS) and phagocytosis were measured thereafter. Pioglitazone treatment before or after induction of ALI significantly diminished alveolar (reduction by 73% and 67%, respectively) and interstitial neutrophil influx (reduction by 55% and 63%, respectively) and reduced lung permeability changes (reduction by 64% and 58%, respectively) indicating a protective role of pioglitazone treatment in ALI. Moreover, pioglitazone significantly reduced degranulation and adhesion of neutrophils without affecting ROS formation and release or bacterial phagocytosis. Pioglitazone reduces recruitment and activation of neutrophils thereby preventing LPS-induced ALI. Our results imply a potential role for pioglitazone treatment in the management of ALI.
Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis
Authors: Riccardo Candido, Terri J. Allen, Markus Lassila, Zemin Cao, Vicki Thallas, Mark E. Cooper, Karin A. Jandeleit-Dahm
Journal: Circulation (2004)

It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection.Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments.Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Nebulization of a bovine surfactant in cystic fibrosis: a pilot study
Authors: M Griese, P Bufler, J Teller, D Reinhardt
Journal: European Respiratory Journal (1997)

Cystic fibrosis (CF) is a lethal disorder which results in excessive airway secretions and in chronic inflammation of the airways. In vitro and in vivo studies have shown that a lack of surfactant results in the closure of the small airways. In this pilot study, we aimed to determine whether surfactant administered by aerosol might improve lung function on a short-term basis in patients with CF. In a randomized, crossover double-blind pilot study, 120 mg of a lipid-extracted bovine surfactant (Alveofact) or placebo was aerosolized to five young adult patients with CF over a period of 30 min for five consecutive days. The sample size had the power of 90% to detect an increase in forced expiratory volume in one second (FEV1) of 15% (p &lt; 0.05). Jet nebulization of surfactant produced particles of which more than 75% were the respirable range (&lt; 5 microns). The inhalations were well tolerated. No changes in serum antibody titres against the surfactant proteins-B and -C (SP-B/SP-C) were observed. No differences in FEV1 and forced vital capacity were found before, and 30 or 90 min after, the inhalation. This pilot study shows no acute or short-term benefits of surfactant inhalation in young adults with cystic fibrosis. However, a beneficial effect of exogenous surfactant cannot be excluded before other reasons for a lack of effect, such as insufficient quantity delivered, inhomogeneous distribution or inhibition of the surfactant in the lungs, have been completely ruled out.
Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging.
Authors: K M Kerr, D Lamb, C G Wathen, W S Walker, N J Douglas
Journal: Thorax (1992)

The use of computed tomography in mediastinal staging of lung cancer relies on the premiss that malignant lymph nodes are larger than benign ones. This hypothesis was tested by linking node size and presence or absence of malignancy and looking at factors possibly influencing the size of benign nodes.All accessible mediastinal lymph nodes were taken from 56 consecutive patients with lung cancer who underwent thoracotomy. Nodes were measured and histologically examined. Resected cancer bearing lung from 44 of these patients was assessed for degree of acute and chronic inflammation.Lymph node size was not significantly related to the presence of metastatic disease, 58% of malignant and 43% of benign lymph nodes measuring over 15 mm. Similarly, there was no statistically significant relation between size of lymph nodes and the likelihood of malignancy, 20% of lymph nodes of 10 mm or more but also 15% of those less than 10 mm being malignant. Thresholds of 15 and 20 mm showed similar results. The maximum size of benign lymph nodes was significantly greater in those patients with histological evidence of acute pulmonary inflammation than in those without.The study shows that in patients with lung cancer (1) malignant mediastinal lymph nodes are not larger than benign nodes; (2) small mediastinal lymph nodes are not infrequently malignant; and (3) benign adenopathy is more common in patients with acute pulmonary inflammation.
Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages
Authors: Antonio del Sol, Marcos J Araúzo-Bravo, Dolors Amoros, Ruth Nussinov
Journal: Genome biology (2007)

Abstract Background Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways. Results We show that protein domains consist of modules interconnected by residues that mediate signaling through the shortest pathways. These mediating residues tend to be located at the inter-modular boundaries, which are more rigid and display a larger number of long-range interactions than intra-modular regions. The inter-modular boundaries contain most of the residues centrally conserved in the protein fold, which may be crucial for information transfer between amino acids. Our approach to modular decomposition relies on a representation of protein structures as residue-interacting networks, and removal of the most central residue contacts, which are assumed to be crucial for allosteric communications. The modular decomposition of 100 multi-domain protein structures indicates that modules constitute the building blocks of domains. The analysis of 13 allosteric proteins revealed that modules characterize experimentally identified functional regions. Based on the study of an additional functionally annotated dataset of 115 proteins, we propose that high-modularity modules include functional sites and are the basic functional units. We provide examples (the Gα s subunit and P450 cytochromes) to illustrate that the modular architecture of active sites is linked to their functional specialization. Conclusion Our method decomposes protein structures into modules, allowing the study of signal transmission between functional sites. A modular configuration might be advantageous: it allows signaling proteins to expand their regulatory linkages and may elicit a broader range of control mechanisms either via modular combinations or through modulation of inter-modular linkages.
Definition of interferon gamma-response elements in a novel human Fc gamma receptor gene (Fc gamma RIb) and characterization of the gene structure.
Authors: P D Benech, K Sastry, R R Iyer, Q G Eichbaum, D P Raveh, R A Ezekowitz
Journal: The Journal of Experimental Medicine (1992)

The human Fc gamma RI (CD64) is a high affinity receptor for the Fc portion of immunoglobulin (Ig), and its constitutively low expression on the cell surface of monocyte/macrophage and neutrophils is selectively upregulated by interferon gamma (IFN-gamma) treatment (Perussia, B., E. T. Dayton, R. Lazarus, V. Fanning, and G. Trinchieri. 1983. J. Exp. Med. 158:1092). Three distinct cDNAs have been cloned and code for proteins that predict three extracellular Ig-like domains (Allen, J.M., and B. Seed. 1989. Science [Wash. DC]. 243:378). Several differences in the coding region of these cDNAs suggest that in addition to polymorphic differences a second Fc gamma RI gene could possibly exist. This alternative Fc gamma RI gene (Fc gamma RIb) was defined by the lack of a genomic HindIII restriction site (van der Winkel, J. G. J., L. U. Ernst, C. L. Anderson, and I. M. Chiu. 1991. J. Biol. Chem. 266:13449). We describe the characterization a second gene (Fc gamma RIb) that has a termination codon in the third extracellular domain and therefore predicts a soluble form of a termination codon in the third extracellular domain and therefore predicts a soluble form of the receptor. We also define two distinct IFN-gamma-responsive regions in the 5' flanking sequence of Fc gamma RIb that resemble motifs that have been defined in the class II major histocompatibility complex promoter. The Fc gamma RIb promoter does not possess canonical TATA or CCAAT boxes, but does possess a palindromic motif that closely resembles the initiator sequence identified in the terminal deoxynucleotidyl transferase/human leukocyte IFN/adeno-associated virus type II P5 gene promoters (Smale, S. T., and D. Baltimore. 1989. Cell. 57:103; Seto, E., Y. Shi, and T. Shenk. 1991. Nature [Lond.]. 354:241; Roy, A. L., M. Meisterernst, P. Pognonec, and R. C. Roeder. 1991. Nature [Lond.]. 354:245) virus type II P5 gene promoters raising interesting questions as to its role in the basal and myeloid-specific transcription of this gene.
Development and Use of a Rat Albumin cDNA Clone to Evaluate the Effect of Chronic Ethanol Administration on Hepatic Protein Synthesis†
Authors: Mark A. Zern, Prasanta R. Chakraborty, Nelson Ruiz-Opazo, Sing H. Yap, David A. Shafritz
Journal: Hepatology (1983)

A rat albumin cDNA probe (pBR alb 149) was developed in order to investigate the molecular mechanisms responsible for changes in hepatic protein synthesis after chronic administration of ethanol to rats. Rats fed a diet for up to 1 year in which 36% of calories were from ethanol, developed fatty livers but not cirrhosis. Cell-free protein synthesis with liver membrane-bound polysomes of ethanol-fed rats was increased as compared to control membrane-bound polysomes, whereas protein synthesis with free polysomes was unchanged. Total RNA extracted from liver membrane-bound polysomes and translated in a rabbit reticulocyte mRNA-dependent system showed a marked increase in albumin synthesis in the ethanol-fed group. Analysis of RNA molecules separated according to molecular weight by gel electrophoresis and hybridized with recombinant-cloned albumin cDNA demonstrated an increase in full-sized albumin mRNA species in ethanol-fed animals. Therefore, chronic ethanol administration appears to increase albumin synthesis by increasing the steady-state level of biologically active albumin mRNA in liver membrane-bound polysomes. Despite development of fatty liver, the protein synthesis machinery functions normally.
Intracardiac extension of lung cancer via the pulmonary vein
Authors: M-T Lin, S-C Ku, M-Z Wu, C-J Yu
Journal: Thorax (2008)

A 69-year-old male heavy smoker had intermittent haemoptysis for 1 month. He did not have exertional dyspnoea, palpitations or chest pain. Chest radiography showed a mass over the right lower lung (RLL). A CT scan of the chest revealed a dumbbell-shaped tumour with an irregular mass in the RLL field, with a tubular part extending along the right inferior …
<i>Gprc5a</i> Deletion Enhances the Transformed Phenotype in Normal and Malignant Lung Epithelial Cells by Eliciting Persistent Stat3 Signaling Induced by Autocrine Leukemia Inhibitory Factor
Authors: Yulong Chen, Jiong Deng, Junya Fujimoto, Humam Kadara, Taoyan Men, Dafna Lotan, Reuben Lotan
Journal: Cancer Research (2010)

Abstract Signal transducers and activators of transcription 3 (Stat3) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth, survival, and transformation. Previously, we found that mice with a deletion of the G protein–coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors, indicating that Gprc5a is a tumor suppressor. Herein, we show that epithelial cells from Gprc5a knockout mouse lung (Gprc5a−/− cells) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice (Gprc5a+/+ cells). Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a−/− than in Gprc5a+/+ cells. Both cell types secreted leukemia inhibitory factor (Lif); however, whereas Stat3 activation was persistent in Gprc5a−/− cells, it was transient in Gprc5a+/+ cells. Lung adenocarcinoma cells isolated from Gprc5a−/− mice also exhibited autocrine Lif-mediated Stat3 activation. The level of Socs3, the endogenous Stat3 inhibitory protein, was higher in Gprc5a+/+ than in Gprc5a−/− cells, and expression of the tumor suppressor stabilized Socs3. Inhibition of Stat3 signaling in Gprc5a−/− normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation. These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a−/− lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated, at least in part, by inhibition of Stat3 signaling through Socs3 stabilization. Cancer Res; 70(21); 8917–26. ©2010 AACR.
Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment
Authors: Joseph McEvoy
Journal: American Journal of Psychiatry (2006)

Objective: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. Method: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]). Results: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. Conclusions: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine’s serious side effects.
Vitamin E Succinate Induces Ceramide-Mediated Apoptosis in Head and Neck Squamous Cell Carcinoma <i>In vitro</i> and <i>In vivo</i>
Authors: Xinbin Gu, Xiaodong Song, Yongheng Dong, Hui Cai, Eric Walters, Renshu Zhang, Xiaowu Pang, Tianpei Xie, Yinhan Guo, Rajagopalan Sridhar, Joseph A. Califano
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Vitamin E succinate (α-TOS) inhibits the growth of cancer cells without unacceptable side effects. Therefore, the mechanisms associated with the anticancer action of α-TOS, including ceramide-mediated apoptosis, were investigated using head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Experimental Design: Five different human HNSCC cell lines (JHU-011, JHU-013, JHU-019, JHU-022, and JHU-029) were treated with α-TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated. The anticancer effect of α-TOS was also examined on JHU-022 solid tumor xenograft growth in immunodeficient mice. Results: α-TOS inhibited the growth of all the HNSCC cell lines in vitro in a dose- and time-dependent manner. Thus, JHU-013 and JHU-022 cell lines were more sensitive to α-TOS than the other cell lines. Cellular levels of ceramide, sphingomyelinase activity, caspase-3, and p53 were elevated with increasing time of exposure to α-TOS. The degradation of poly(ADP-ribose) polymerase protein in JHU-022 cells treated with α-TOS provided evidence for apoptosis. The amounts of nuclear factor κB, Bcl-2, and Bcl-XL proteins were reduced in the cells treated with α-TOS for 6 hours. The levels of caspase-9, murine double minute-2, and IκB-α proteins were unchanged after α-TOS treatment. I.p. administration of α-TOS slowed tumor growth in immunodeficient mice. Conclusions: α-TOS showed promising anticancer effects to inhibit HNSCC growth and viability in vivo and in vitro. The induction of enzymes involved in ceramide metabolism by α-TOS suggests that ceramide-mediated apoptosis may expand therapeutic strategies in the treatment of carcinoma.
Medical care at Mid Staffs is deemed unsafe as trust prepares to close
Authors: A. O'Dowd
Journal: BMJ (2014)

The level of medical care provided at the troubled Mid Staffordshire NHS Foundation Trust in recent months has been unsafe, the Care Quality Commission (CQC) has said.

Staff shortages, scarce clinical leadership, heavy reliance on agency staff, and difficulties in balancing the books have all made it difficult for the trust to continue operating, said the health service regulator in a new report.1 Mid Staffs and its trust special administrators, who were appointed to help determine the future of the organisation last year, said that they were doing everything they could to ensure that safe care is provided while the trust prepares to close next month.

A public inquiry2 into the trust last year found failures at every …
Combination of YM155, a Survivin Suppressant, with Bendamustine and Rituximab: A New Combination Therapy to Treat Relapsed/Refractory Diffuse Large B-cell Lymphoma
Authors: Naoki Kaneko, Keisuke Mitsuoka, Nobuaki Amino, Kentaro Yamanaka, Aya Kita, Masamichi Mori, Sosuke Miyoshi, Sadao Kuromitsu
Journal: Clinical Cancer Research (2014)

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models.Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts.The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab.These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.
A murine model of toluene diisocyanate–induced asthma can be treated with matrix metalloproteinase inhibitor
Authors: Yong Chul Lee, Chang Ho Song, Heung Bum Lee, Jong-Lark Ohc, Yang Keun Rhee, Hae Sim Park, Gou Young Koh
Journal: Journal of Allergy and Clinical Immunology (2001)