tbuckley/cabot-search huggingface dataset:
Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages
Authors: Coralie Fontaine, Elena Rigamonti, Atsushi Nohara, Philippe Gervois, Elisabeth Teissier, Jean-Charles Fruchart, Bart Staels, Giulia Chinetti-Gbaguidi
Journal: Circulation Research (2007)

Macrophages play a central role in host defense against pathogen microbes by recognizing bacterial components, resulting in the activation of an arsenal of anti-microbial effectors. Toll-like receptor (TLR)-4 mediates the recognition of lipopolysaccharide, a pathogen-associated molecular pattern from gram-negative bacteria. Activation of the TLR-4 signaling pathway by lipopolysaccharide increases antibacterial effects by inducing secretion of cytokines that activate an immune inflammatory response and by generating bactericidal reactive oxygen species via the NADPH oxidase system. Liver X Receptors (LXRs) are nuclear receptors controlling cholesterol homeostasis and inflammation in macrophages. In addition, LXRs are critical for macrophage survival and play a role in the innate immune response in the mouse. In this study, we investigated whether LXR activation also regulates host defense mechanisms in human macrophages. In primary human macrophages, oxidized LDL and synthetic LXR ligands increased TLR-4 gene expression. Transient transfection assays, gel shift and chromatin immunoprecipitation analysis indicated that LXRs induce human TLR-4 promoter activity by binding to a DR4-type LXR response element. LXR induction of TLR-4 mRNA was followed by an induction of TLR-4 protein expression. Moreover, although short-term pretreatment with LXR agonists significantly reduced the inflammatory response induced by lipopolysaccharide, pretreatment of macrophages for 48 hours with LXR agonists resulted in an enhanced lipopolysaccharide response. Finally, LXR activation increased reactive oxygen species generation by enhancing the expression of NADPH oxidase subunits. These data provide evidence for an immunomodulatory function of LXRs in human macrophages via mechanisms distinct from those previously identified in mouse macrophages.
Adjuvant Chemotherapy in Completely Resected Gastric Cancer: A Randomized Phase III Trial Conducted by GOIRC
Authors: F. Di Costanzo, S. Gasperoni, L. Manzione, G. Bisagni, R. Labianca, S. Bravi, E. Cortesi, P. Carlini, R. Bracci, S. Tomao, L. Messerini, A. Arcangeli, V. Torri, D. Bilancia, I. Floriani, M. Tonato
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundComplete surgical resection of gastric cancer is potentially curative, but long-term survival is poor.
Chemoprevention of UV Light-Induced Skin Tumorigenesis by Inhibition of the Epidermal Growth Factor Receptor
Authors: Taghrid B. El-Abaseri, Jill Fuhrman, Carol Trempus, Igor Shendrik, Raymond W. Tennant, Laura A. Hansen
Journal: Cancer Research (2005)

Abstract The epidermal growth factor receptor (EGFR) is activated in skin cells following UV irradiation, the primary cause of nonmelanoma skin cancer. The EGFR inhibitor AG1478 prevented the UV-induced activation of EGFR and of downstream signaling pathways through c-Jun NH2-terminal kinases, extracellular signal-regulated kinases, p38 kinase, and phosphatidylinositol 3-kinase in the skin. The extent to which the UV-induced activation of EGFR influences skin tumorigenesis was determined in genetically initiated v-rasHa transgenic Tg.AC mice, which have enhanced susceptibility to skin carcinogenesis. Topical treatment or i.p. injection of AG1478 before UV exposure blocked the UV-induced activation of EGFR in the skin and decreased skin tumorigenesis in Tg.AC mice. AG1478 treatment before each of several UV exposures decreased the number of papillomas arising and the growth of these tumors by ∼50% and 80%, respectively. Inhibition of EGFR suppressed proliferation, increased apoptotic cell death, and delayed the onset of epidermal hyperplasia following UV irradiation. Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure. Thus, the UV-induced activation of EGFR promotes skin tumorigenesis by suppressing cell death, augmenting cell proliferation, and accelerating epidermal hyperplasia in response to UV. These results suggest that EGFR may be an appropriate target for the chemoprevention of UV-induced skin cancer.
Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors
Authors: Alejandro D. Ricart, Jordan D. Berlin, Kyriakos P. Papadopoulos, Samira Syed, Daniel W. Drolet, Charlotte Quaratino-Baker, Julie Horan, Jon Chick, Wendy Vermeulen, Anthony W. Tolcher, Eric K. Rowinsky, Mace L. Rothenberg
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.
Airway Structural Alterations Selectively Associated with Severe Asthma
Authors: Laurent Benayoun, Anne Druilhe, Marie-Christine Dombret, Michel Aubier, Marina Pretolani
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins α-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.
Re: Tandem vs Single Autologous Hematopoietic Cell Transplantation for the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis
Authors: Jayesh Mehta
Journal: JNCI Journal of the National Cancer Institute (2009)

Background Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and metaanalysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM. Methods We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model. Results Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS. Conclusion In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.
False Elevation of Partial Thromboplastin Time and Prothrombin Time
Authors: Robert E. Humphreys
Journal: JAMA (1970)

A partial thromboplastin time (PTT) and a prothrombin time (PT) performed as routine preoperative screening on a young woman hospitalized for preeclampsia were unexpectedly and markedly prolonged. Since there was no clinical suspicion of a bleeding disorder, and since results of numerous repeat tests were normal, an artifact was suspected. The partially evacuated blood drawing (Vacutainer) tubes used on the patient's ward were found to have reduced draw in a range sufficient to produce similar prolongation of the PTT and PT in healthy individuals. False prolongation of the PTT and PT due to inadequate filling of the tubes is likely to be a frequent cause of confusion in patient care, if not appreciated and avoided.
Toxicological assessment of indoor airborne fine particulate matter induced oxidative stress in alveolar epithelial cells
Authors: Yasuo Takano, Tomomi Komura, Kennichi Yagyu, Takeshi Minami
Journal: European Respiratory Journal (2011)

Background: Exposure to airborne particulate matter (PM) has long been associated with adverse health problems. These fine PM particles can penetrate the distal regions of the lung causing severe respiratory problems.

Objectives: As relatively little information of indoor fine PM is available to evaluate the actual risks, we will focus our examination on lung injuries caused by fine indoor PM, by investigating the mechanism of the cell injury using primary culture of alveolar type II cells.

Method: Indoor PM was collected in Nara prefecture, Japan using an Andersen sampler by the impact cascade method. Particle samples of PM were collected on five Teflon filters in accordance with the diameter of particles (diameter: >11μm, 2.1-11 μm, 1.1-2.1 μm, 0.4-1.1 μm, <0.4 μm). Alveolar type II cells from rats were exposed to PM at the concentration of 500 μg/ml for 24 hrs respectively. At the end of the experiment, lactate dehydrogenase (LDH) activity released into the culture medium was determined and the percentage of LDH leakage was then calculated to reflect the cytotoxicity of PM.

Results: In relation to the control cells, the PM-induced LDH leakage was more significant among the smaller fine particles of indoor PM than the larger ones. However this did not occur with the above mentioned 1.1 μm diameter size of PM. Superoxide dismutase (SOD) significantly reduced LDH leakage-induced indoor PM. In the analysis of the elements in indoor PM, the most abundant element was iron (Fe).

Conclusions: Indoor PM causes oxidative cellular damage, which may be closely associated with a transition metal, Fe in rat alveolar epithelial cells.
Viable Group A Streptococci in Macrophages during Acute Soft Tissue Infection
Authors: Pontus Thulin, Linda Johansson, Donald E Low, Bing S Gan, Malak Kotb, Allison McGeer, Anna Norrby-Teglund
Journal: PLoS Medicine (2006)

Group A streptococcal severe soft tissue infections, such as necrotizing fasciitis, are rapidly progressive infections associated with high mortality. Group A streptococcus is typically considered an extracellular pathogen, but has been shown to reside intracellularly in host cells.We characterized in vivo interactions between group A streptococci (GAS) and cells involved in innate immune responses, using human biopsies (n = 70) collected from 17 patients with soft tissue infections. Immunostaining and in situ image analysis revealed high amounts of bacteria in the biopsies, even in those collected after prolonged antibiotic therapy. Viability of the streptococci was assessed by use of a bacterial viability stain, which demonstrated viable bacteria in 74% of the biopsies. GAS were present both extracellularly and intracellularly within phagocytic cells, primarily within macrophages. Intracellular GAS were predominantly noted in biopsies from newly involved tissue characterized by lower inflammation and bacterial load, whereas purely extracellular GAS or a combination of intra- and extracellular GAS dominated in severely inflamed tissue. The latter tissue was also associated with a significantly increased amount of the cysteine protease streptococcal pyrogenic exotoxin SpeB. In vitro studies confirmed that macrophages serve as reservoirs for viable GAS, and infection with a speB-deletion mutant produced significantly lower frequencies of cells with viable GAS following infection as compared to the wild-type bacteria.This is the first study to demonstrate that GAS survive intracellularly in macrophages during acute invasive infections. This intracellular presence may have evolved as a mechanism to avoid antibiotic eradication, which may explain our finding that high bacterial load is present even in tissue collected after prolonged intravenous antibiotic therapy. This new insight into the pathogenesis of streptococcal soft tissue infections highlights a need for alternative therapeutic strategies.
Regulation of Actin Dynamics by Protein Kinase R Control of Gelsolin Enforces Basal Innate Immune Defense
Authors: Aaron T. Irving, Die Wang, Oliver Vasilevski, Olivier Latchoumanin, Noga Kozer, Andrew H.A. Clayton, Anette Szczepny, Hiroyuki Morimoto, Dakang Xu, Bryan R.G. Williams, Anthony J. Sadler
Journal: Immunity (2012)
Unexplained dyspnoea, a matter of posture?
Authors: Eva Bernardi, Luca Pomidori, Gaia Mandolesi, Annalisa Cogo
Journal: European Respiratory Journal (2013)

We present the cases of 3 females (aged 71-78) referred to our outpatient clinic complaining dyspnoea during daily activity, in particular during walking. A careful history has allowed us to understand that dyspnoea was significantly reduced when they walked with a support of the upper limbs.

Methods. Subjects performed respiratory function test (FEV1, FVC, DLCO), chest X-ray, echocardiogram with non invasive measurement of PAPs, blood sample and ventilatory evaluation by means of portable respiratory inductive plethysmography (Lifeshirt System, LS). LS accurately estimates ventilation, ventilatory pattern and the synchrony of rib cage-abdominal motion (phase angle, PhA) at rest and during exercise both in patients and in healthy subjects. Subjects performed 6MWT with and without a rollator at the same exercise intensity while equipped with LS.

Result. Respiratory, cardiac, radiological examination and blood sample was normal. Life shirt evaluation during 6MWT is reported in Table 1 ( values are given as mean). PhA at rest: 13.0, 10.6 and 8.7 for S1, S2, S3 respectively.

View this table:

Table1: 6MWT





Conclusion. During 6MWT without a rollator an evident increase in PhA is shown, which is an index of asynchrony of rib cage-abdominal motion which in turn could induce dyspnoea. We suggest that postural change during walking without upper limbs support can happen in elderly subjects and this could explain the dyspnoea. These cases highlight the importance of thinking outside the usual tests when evaluating patients with dyspnoea.
S70 Non-invasive ventilation (NIV) in Chronic Obstructive Pulmonary Disease (COPD) exacerbations with acute hypercapnic respiratory failure (AHRF) with pH
Authors: A. Thomas, B. Beauchamp, B. Chakraborty, E. Gallagher, A. Ali, R. Mukherjee, D. Banerjee
Journal: Thorax (2010)

<h3>Introduction</h3> Recent British guidelines on NIV suggest patients with AHRF and pH &lt;7.26 on arterial blood gases (ABG) should be managed by critical care (ITU) depending upon local circumstances with a low threshold for intubation, unless NIV is deemed to be the ceiling of treatment. The 7.26 pH cut-off was derived from subgroup analysis of in-hospital mortality assessment from the study by Plant <i>et al</i> (<i>Lancet</i> 2000; 355:1931–5). The use of NIV as an alternative to endotracheal intubation in more severely acidotic COPD patients (pH&lt;7.26) has been controversial but there is increasing evidence that the outcomes in such patients may not be any worse if treated with NIV. <h3>Methods</h3> Analysis of initial ABG (pre-commencement of NIV) for AHRF secondary to COPD between 1 August 2004 and 31 December 2009 was performed. NIV was undertaken in a dedicated unit on a respiratory ward. The admission episodes were stratified by initial pH ranges (predictor variable) and in-hospital mortality was recorded (outcome variable). <h3>Results</h3> Out of 728 (505 unique patients) admissions with COPD requiring NIV for AHRF, 282 admissions had a pH &lt;7.26. Of these, 224 admissions survived to discharge (mortality 20.6%). Stratifying the admissions by pH categories of 0.05, there is no significant difference in the mortality with pH ranges 7.2–7.25 and 7.25–7.30 (p value=0.845). If all COPD admissions requiring NIV (n=728) are stratified into two groups above and below 7.2, the ratio of odds of survival below pH 7.2 drops sharply (p=0.000000088): Abstract S70 Table 1. <h3>Conclusion</h3> Mortality in the group with pH 7.20–7.25 was similar to the group with pH 7.26–7.30, suggesting that NIV on a dedicated respiratory ward can manage COPD patients with AHRF and pH &lt;7.26. Our findings suggest that it is probably justified to recommend that the initial pH cut-off is modified from pH &gt;7.26 to pH &gt;7.20 for ward-based NIV in COPD exacerbations with AHRF. This has important resource implications, given that more patients could be managed in a ward-based dedicated NIV unit rather than the utilising ITU beds in the UK National Health Service.
Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion
Authors: Gina L. Razidlo, Christopher Magnine, Arthur C. Sletten, Rachel M. Hurley, Luciana L. Almada, Martin E. Fernandez-Zapico, Baoan Ji, Mark A. McNiven
Journal: Cancer Research (2015)

Abstract Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48Cre/+, KrasG12D/+, p53F/+ mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors. Cancer Res; 75(14); 2907–15. ©2015 AACR.
Implementation Science and Its Application to Population Health
Authors: Rebecca Lobb, Graham A. Colditz
Journal: Annual Review of Public Health (2013)

Implementation science studies the use of strategies to adapt and use evidence-based interventions in targeted settings (e.g., schools, workplaces, health care facilities, public health departments) to sustain improvements to population health. This nascent field of research is in the early stages of developing theories of implementation and evaluating the properties of measures. Stakeholder engagement, effectiveness studies, research synthesis, and mathematical modeling are some of the methods used by implementation scientists to identify strategies to embed evidence-based interventions in clinical and public health programs. However, for implementation science to reach its full potential to improve population health the existing paradigm for how scientists create evidence, prioritize publications, and synthesize research needs to shift toward greater stakeholder input and improved reporting on external validity. This shift will improve the relevance of the research that is produced and provide information that will help guide decision makers in their selection of research-tested interventions.