tbuckley/cabot-search huggingface dataset:
Defining a training framework for clinicians in respiratory critical care
Authors: Antonio Artigas, Julie-Lyn Noël, Laurent Brochard, Jamiu O. Busari, Dominic Dellweg, Miguel Ferrer, Jens Geiseler, Anders Larsson, Stefano Nava, Paolo Navalesi, Stylianos Orfanos, Paolo Palange, Paolo Pelosi, Gernot Rohde, Bernd Schoenhofer, Theodoros Vassilakopoulos, Anita K. Simonds
Journal: European Respiratory Journal (2014)

Defining a training framework for clinicians in respiratory critical care http://ow.ly/yExWjAs intensive care medicine (ICM) advances through technological developments, diagnostics and therapeutics, there are increasing demands on resources and healthcare budgets.For these reasons, there is a need to create adequate legal and administrative structures.There is also an increasing requirement for qualified specialised personnel and an internationally recognised high-standard training programme [1].This is especially relevant considering the multidisciplinary nature of ICM.Bearing these developments in mind, a way to progress ICM would be to involve, among other specialties, more respiratory physicians, who can be significant care providers for critically ill respiratory patients [2].
A Ras Inhibitor Tilts the Balance between Rac and Rho and Blocks Phosphatidylinositol 3-Kinase–Dependent Glioblastoma Cell Migration
Authors: Liat Goldberg, Yoel Kloog
Journal: Cancer Research (2006)

Abstract Glioblastoma multiforme are highly aggressive tumors for which no adequate treatment has yet been developed. Glioblastoma multiforme show large amounts of active Ras, considered an appropriate target for directed therapy. Here, we show that the Ras inhibitor S-trans, trans-farnesyl thiosalicylic acid (FTS) can avert the transformation of human glioblastoma multiforme cells by inhibiting both their migration and their anchorage-independent proliferation. FTS, by down-regulating Ras activity in glioblastoma multiforme cells, inhibited phosphatidylinositol 3-kinase signaling, resulting in decreased activity of Rac-1. At the same time, activation of RhoA was increased. These two small GTPases are known to control the arrangement of the actin cytoskeleton. By tilting the balance between Rac-1 and RhoA activities, FTS caused the glioblastoma multiforme cells to undergo profound changes in morphology, including rearrangement of actin into stress fibers and assembly of focal adhesions, both of which are governed by RhoA signaling. These morphologic changes allowed strong attachment of the cells to the matrix, rendering them immobile. The results show that FTS should be considered as a candidate drug for glioblastoma multiforme therapy because it targets not only cell proliferation but also cell migration and invasion, which together constitute the most problematic aspect of these malignancies. (Cancer Res 2006; 66(24): 11709-17)
Translating research into practice: how are guidelines implemented?
Authors: M.R. Partridge
Journal: European Respiratory Journal (2003)

Numerous guidelines have now been produced both nationally and internationally for the management of respiratory and nonrespiratory disease. They should be regarded as useful tools designed to aid the busy clinician, but their method of production, their value and especially their applicability to primary care and to low income countries need to be assessed critically. The production of guidelines needs to be carefully incorporated into a planned dissemination and implementation programme. This is likely to be most successful when use is made of interactive educational methods associated with intraconsultation prompting and use of reminders. Updating and life-long learning is necessary and guideline revisions need to be closely incorporated into continuing medical education programmes. National campaigns, the use of media and the “training” of patients to make them more effective partners in healthcare can all enhance a beneficial change in health professional behaviour. Recent research has enhanced the knowledge of a wide range of respiratory conditions and very effective therapies now exist for many conditions. However, too little attention is often given to the ways in which care is organised and to the important aspects of management that are nonpharmacological. When dealing with long-term conditions, long-term supervision and the teaching of self-management skills are as important as the prescription. In many parts of the world the ideals, as laid out in guidelines, remain dreams and will continue to be dreams until there is some global redistribution of wealth. Only then will research be translated into practice everywhere.
Analysis and results of prolonged resuscitation in cardiac arrest patients rescued by extracorporeal membrane oxygenation
Authors: Yih-Sharng Chen, Anne Chao, Hsi-Yu Yu, Wen-Je Ko, I-Hui Wu, Robert Jen-Chen Chen, Shu-Chien Huang, Fang-Yue Lin, Shoei-Shan Wang
Journal: Journal of the American College of Cardiology (2003)
LSC 2013 abstract - The role of inducible nitric oxide synthase (iNOS) for the remodeling of alveolar septa in surfactant protein D deficient mice
Authors: Lars Knudsen, Bastian Birkelbach, Elena Atochina-Vasserman, Beat Haenni, Andrew Gow, Michael F. Beers, Matthias Ochs
Journal: European Respiratory Journal (2013)

Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality worldwide. iNOS expressed by alveolar macrophages (AM) mediates lung remodeling in COPD-models. Surfactant Protein D (SP-D) modulates the immune system. SP-D deficient mice (DKO) develop an emphysematous phenotype with a fibrotic component with age and hyperplasia of alveolar epithelial type II cells. AM produce high amounts of iNOS. Thus, we hypothesize that iNOS mediates interstitial remodeling in SP-D knockout mice.

Using unbiased stereology, we compared DKO, SP-D/iNOS double-knockout mice (DiNOS) and wild type mice (wt) aged 29 weeks at light and electron microscopic level to quantitatively assess morphometric changes in the different components of the blood-gas barrier (alveolar epithelium, interstitial tissue and endothelium).

Septal wall thickness was significantly reduced in DiNOS compared to DKO (4.2+/-0.6μm vs. 6.8+/-1.0μm). We found a significant decrease in the absolute volume of the blood-gas barrier in DiNOS (121.8 vs. 77.4 vs. 66.9 mm3 in DKO, DiNOS and wt respectively). This effect can be attributed to a decrease in volumes of amorphous extracellular matrix (ECM) (22.2 vs. 14.5 vs. 16.0 mm3), interstitial cells (20.8 vs. 15.5 vs. 12.4 mm3) and alveolar epithelium (53.8 vs. 29.6 vs. 20.2 mm3). Volumes of collagen and elastin fibrils as well as endothelia remained virtually unchanged.

iNOS mediates remodeling of septal walls e.g. deposition of amorphous ECM in DKO. Our results underscore the hypothesis that iNOS plays an important role in the development of the phenotypic alterations in old SP-D deficient mice.
Small airways dysfunction is associated with poorer control in asthmatics with a preserved FEV1
Authors: Arvind Manoharan, William Anderson, Joseph Lipworth, Ibrahim Ibrahim, Brian Lipworth
Journal: European Respiratory Journal (2014)

Introduction:  There have been no studies investigating the relationship between small airway dysfunction and long-term asthma control in adults.   Aim:  We evaluated whether small airways dysfunction was associated with worse control in asthmatics with a preserved FEV 1 (FEV 1 >80%).   Methods:  Spirometry and impulse oscillometry measurements were linked to a health informatics database for oral corticosteroid and short-acting beta-agonist (SABA) use. We evaluated if small airways dysfunction, defined by a FEF 25-75  1 /FVC 0.07 kPa·L -1 ·s was associated with increased oral corticosteroid and SABA use.   Results:  302 out of 442 (68%) asthmatics had a preserved FEV 1 >80%, mean age:40 years, FEV 1 :97%, median ICS dose:800µg, 42% taking LABA. Comparing FEF 25-75  70% the odds ratio OR(95% CI) for oral corticosteroid and SABA use were 1.67(1.04 -2.68)and 2.00(1.27-3.16) respectively. Comparing R5-R20>0.07 kPa·L -1 ·s vs  -1 ·s; OR were 1.99(1.23-3.19) and 1.83(1.16-2.89) and for FEV 1 /FVC 0.80; OR were 2.06(1.27-3.35) and 1.61(1.02-2.54). The OR increased when patients had more than one abnormal small airway parameter.   Conclusions:  In adult asthmatics with preserved FEV 1 , small airways dysfunction determined by FEF 25-75 , FEV 1 /FVC and R5-R20 was associated with poorer control, suggesting the presence of a defined small airway asthma phenotype.
Baseline Circulating Tumor Cell Counts Significantly Enhance a Prognostic Score for Patients Participating in Phase I Oncology Trials
Authors: David Olmos, Richard D. Baird, Timothy A. Yap, Christophe Massard, Lorna Pope, Shahneen K. Sandhu, Gerhardt Attard, Juliet Dukes, Dionysis Papadatos-Pastos, Philippa Grainger, Stan B. Kaye, Johann S. de Bono
Journal: Clinical Cancer Research (2011)

High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0-1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2-3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials.
Matrix Metalloproteinase-9 Is Upregulated in Nucleophosmin-Anaplastic Lymphoma Kinase–Positive Anaplastic Lymphomas and Activated at the Cell Surface by the Chaperone Heat Shock Protein 90 to Promote Cell Invasion
Authors: Frédéric Lagarrigue, Sophie Dupuis-Coronas, Damien Ramel, Georges Delsol, Hélène Tronchère, Bernard Payrastre, Frédérique Gaits-Iacovoni
Journal: Cancer Research (2010)

Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL.
LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway
Authors: Tze Wei Poh, Shazib Pervaiz
Journal: Cancer Research (2005)

Abstract The phosphoinositide 3-kinase (PI3K)-Akt pathway is constitutively active in many tumors, and inhibitors of this prosurvival network, such as LY294002, have been shown to sensitize tumor cells to death stimuli. Here, we report a novel, PI3K-independent mechanism of LY-mediated sensitization of LNCaP prostate carcinoma cells to drug-induced apoptosis. Preincubation of tumor cells to LY294002 or its inactive analogue LY303511 resulted in a significant increase in intracellular hydrogen peroxide (H2O2) production and enhanced sensitivity to nonapoptotic concentrations of the chemotherapeutic agent vincristine. The critical role of intracellular H2O2 in LY-induced death sensitization is corroborated by transient transfection of cells with a vector containing human catalase gene. Indeed, overexpression of catalase significantly blocked the amplifying effect of LY pretreatment on caspase-2 and caspase-3 activation and cell death triggered by vincristine. Furthermore, the inability of wortmannin, another inhibitor of PI3K, to induce an increase in H2O2 production at doses that effectively blocked Akt phosphorylation provides strong evidence to unlink inhibition of PI3K from intracellular H2O2 production. These data strongly support death-sensitizing effect of LY compounds independent of the PI3K pathway and underscore the critical role of H2O2 in creating a permissive intracellular milieu for efficient drug-induced execution of tumor cells.
Comparison of three preventive methods in order to reduce the incidence of ankle inversion sprains among female volleyball players
Authors: D Stasinopoulos
Journal: British Journal of Sports Medicine (2004)

Background: Ankle sprains are the most common form of acute injury in volleyball. A prevention programme consisting of technical training, proprioceptive training, and external support was previously designed to reduce the rate of ankle sprains in volleyball players. Objective: To investigate which of these three interventions is the most effective in preventing ankle sprain in female volleyball players. Methods: Participants were 52 players who suffered ankle sprains during the season 1998–1999. They were divided randomly into three preventive groups: group 1 (n = 18) followed the technical training programme; group 2 (n = 17) followed the proprioceptive programme; group 3 (n = 17) used orthosis. The players followed their respective programmes for the whole of the 1999–2000 season. Data were collected at the end of the season. Results: The three preventive strategies were all effective in preventive further ankle sprain. Technical training was slightly more effective than the other two methods. Orthosis was not effective in athletes who had suffered ankle sprains more than three times during their careers. Under those circumstances, technical training and proprioceptive training were equally effective at preventive further sprains. Conclusions: Technical training and proprioceptive training are effective methods of preventing ankle sprain in volleyball players who have suffered this injury four or more times during their career. Orthosis appears effective only in players with fewer than four previous sprains.
Role of Estrogen Receptor in the Regulation of Ecto-5′-Nucleotidase and Adenosine in Breast Cancer
Authors: Jozef Spychala, Eduardo Lazarowski, Anna Ostapkowicz, Lanier H. Ayscue, Aiwen Jin, Beverly S. Mitchell
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to understand the expression of ecto-5′-nucleotidase (eN), an adenosine producing enzyme with potential roles in angiogenesis, growth, and immunosuppression, in estrogen receptor (ER)-negative and -positive breast cancer. Experimental Design: We investigated the regulation of eN expression at the mRNA and protein levels by α in a panel of breast cancer cell lines that differ in ER status and invasive and metastatic potential. We also determined rates of adenosine formation in cells with high and low eN expression and in ER+ cells treated with estradiol. Results: ER-negative cells express high eN protein and mRNA levels and produce up to 104-fold more adenosine from AMP and ATP. Estradiol and antiestrogen treatments confirm that eN mRNA and protein expression and adenosine generation are negatively regulated through the ER. Endogenous expression of eN in ER− cells transfected with ERα and phorbol ester-induced eN expression in ER+ cells was strongly suppressed by estradiol, suggesting a dominant function of ER. Finally, an examination of 18 clinical breast cancer samples that were analyzed for both ER status and eN expression by Martin et al. (Cancer Res., 60: 2232–2238, 2000) revealed a significant inverse correlation between ER and eN status. Conclusions: Our results show for the first time that eN is negatively regulated by ERα in dominant fashion and suggests that eN expression and its generation of adenosine may relate to breast cancer progression. Additionally, increased expression of eN in a subset of ER-negative cells may serve as a novel marker for a subset of more aggressive breast carcinoma.
Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.
Authors: J P Valentin, W Z Ying, L A Sechi, K T Ling, C Qiu, W G Couser, M H Humphreys
Journal: Journal of the American Society of Nephrology (1996)

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.
Deficiency of cathepsin S attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice
Authors: Yanwen Qin, Xu Cao, Jun Guo, Yaozhong Zhang, Lili Pan, Hongjia Zhang, Huihua Li, Chaoshu Tang, Jie Du, Guo-Ping Shi
Journal: Cardiovascular Research (2012)

Abdominal aortic aneurysm (AAA) is characterized by extensive aortic wall matrix degradation that contributes to the remodelling and eventual rupture of the arterial wall. Elastinolytic cathepsin S (Cat S) is highly expressed in human aneurysmal lesions, but whether it contributes to the pathogenesis of AAA remains unknown. AAAs were induced in apolipoprotein E (ApoE) and Cat S compound mutant (Apoe–/–Ctss–/–) mice and in ApoE-deficient Cat S wild-type littermates (Apoe–/–Ctss+/+) by chronic angiotensin II infusion, and AAA lesions were analysed after 28 days. We found that Cat S expression increased significantly in mouse AAA lesions. The AAA incidence in Apoe–/–Ctss–/– mice was much lower than that in Apoe–/–Ctss+/+ mice (10 vs. 80%). Cat S deficiency significantly reduced external and luminal abdominal aortic diameters, medial elastin fragmentation, and adventitia collagen content. Cat S deficiency reduced aortic lesion expression and the activity of matrix metalloproteinase (MMP)-2, MMP-9, and Cat K, but not the activity of other major cathepsins, such as Cat B and Cat L. Absence of Cat S significantly reduced AAA lesion media smooth muscle cell (SMC) apoptosis, lesion adventitia microvessel content, and inflammatory cell accumulation and proliferation. In vitro studies proved that Cat S helps promote SMC apoptosis, angiogenesis, monocyte and T-cell transmigration, and T-cell proliferation—all of which are essential to AAA pathogenesis. These data provide direct evidence that Cat S plays an important role in AAA formation and suggest that Cat S is a new therapeutic target for human AAA.
Mesencephalic Astrocyte-Derived Neurotrophic Factor Is an Ischemia-Inducible Secreted Endoplasmic Reticulum Stress Response Protein in the Heart
Authors: Archana Tadimalla, Peter J. Belmont, Donna J. Thuerauf, Matthew S. Glassy, Joshua J. Martindale, Natalie Gude, Mark A. Sussman, Christopher C. Glembotski
Journal: Circulation Research (2008)

The endoplasmic reticulum (ER) stress response (ERSR) is activated when folding of nascent proteins in the ER lumen is impeded. Myocardial ischemia was recently shown to activate the ERSR; however, the role of this complex signaling system in the heart is not well understood. ER stress activates the transcription factor ATF6, which induces expression of proteins targeted to the ER, where they restore protein folding, thus fostering cytoprotection. We previously developed a transgenic mouse line that expresses a conditionally activated form of ATF6 in the heart. In this mouse line, ATF6 activation decreased ischemic damage in an ex vivo model of myocardial ischemia/reperfusion and induced numerous genes, including mesencephalic astrocyte-derived neurotrophic factor (MANF). In the present study, MANF expression was shown to be induced in cardiac myocytes and in other cell types in the hearts of mice subjected to in vivo myocardial infarction. Additionally, simulated ischemia induced MANF in an ATF6-dependent manner in neonatal rat ventricular myocyte cultures. In contrast to many other ER-resident ERSR proteins, MANF lacks a canonical ER-retention sequence, consistent with our finding that MANF was readily secreted from cultured cardiac myocytes. Knockdown of endogenous MANF with micro-RNA increased cell death upon simulated ischemia/reperfusion, whereas addition of recombinant MANF to media protected cultured cardiac myocytes from simulated ischemia/reperfusion-mediated death. Thus, a possible function of the ERSR in the heart is the ischemia-mediated induction of secreted proteins, such as MANF, that can function in an autocrine/paracrine manner to modulate myocardial damage from ER stresses, including ischemia.