tbuckley/cabot-search huggingface dataset:
Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects
Authors: HW de Gouw, K Grunberg, R Schot, AC Kroes, EC Dick, PJ Sterk
Journal: European Respiratory Journal (1998)

Exhaled nitric oxide (NO) is elevated in asthmatics, and varies with disease severity. We postulated that a respiratory virus infection increases exhaled NO levels in asthma, and examined the relationship between the virus-induced changes in exhaled NO and in airway hyperresponsiveness to histamine. In a parallel study, seven patients underwent experimental rhinovirus 16 (RV16) inoculation at days 0 and 1, whilst seven patients received placebo. Exhaled NO was measured at baseline (day 0) and at days 1, 2 and 3 after inoculation. Histamine challenges were performed prior to (day -7) and after inoculation (day 3), and were expressed as provocative concentration causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20). Following RV16 infection there was a significant increase in NO at days 2 and 3 as compared to baseline (median change (range): 4.2 (7.5) parts per billion (ppb), p=0.03, and 3.0 (10.1) ppb, p=0.02, respectively). Furthermore, PC20 decreased significantly following RV16 infection (mean+/-SD change in doubling dose: -0.65+/-0.54, p=0.02), whereas PC20 did not change in the placebo group (p=0.1). There was a significant correlation between the RV16-induced changes in exhaled NO levels at day 2 and the accompanying changes in PC20 at day 3 (rank correlation coefficient (rs): 0.86, p=0.01). Hence, the greater the increase in exhaled NO, the smaller the decrease in PC20. We conclude that rhinovirus infection increases exhaled nitric oxide levels in asthmatics, and that this increase is inversely associated with worsening of airway hyperresponsiveness to histamine. These results suggest that viral induction of nitric oxide synthase within the airways may play a protective role in exacerbations of asthma.
German cockroach proteases regulate matrix metalloproteinase‐9 in human bronchial epithelial cells
Authors: K. Page, V. S. Hughes, G. W. Bennett, H. R. Wong
Journal: Allergy (2006)

Background: Matrix metalloproteinases (MMPs) digest extracellular matrix proteins and may play a role in the pathogenesis of bronchial asthma. MMP‐9 levels are increased in the bronchoalveolar lavage fluid and sputum of asthmatics compared with that of controls. As exposure to cockroaches is an environmental risk factor for asthma, we sought to investigate the role of German cockroach fecal remnants (frass) on MMP‐9 expression. Methods: Human bronchial epithelial cells (16HBE14o‐) and primary normal human bronchial epithelial cells were treated with cockroach frass in the absence or presence of tumor necrosis factor (TNF) α . MMP‐9 mRNA, protein levels and pro‐MMP‐9 activity were determined using real‐time polymerase chain reaction (PCR), enzyme‐linked immunosorbent assay (ELISA) and zymogram assays. Pretreatment of frass with aprotinin abolished protease activity. PD98059, a chemical inhibitor of extracellular signal regulated kinase (ERK), and SLIGKV, an activator of protease‐activated receptor (PAR)‐2 were also used. AP‐1DNA binding was determined by electrophoretic mobility shift assay (EMSA) and ERK phosphorylation by Western blot analysis. Results: Cockroach frass augmented TNF α ‐mediated MMP‐9 mRNA and protein expression by a mechanism dependent on active serine proteases within frass and not on endogenous endotoxin. Frass increased ERK phosphorylation, and chemical inhibition of ERK attenuated cockroaches’ effects on MMP‐9. Serine proteases are known to activate the PAR‐2 receptor. We found that selective activation of PAR‐2 using the peptide SLIGKV augmented TNF α ‐induced MMP‐9 protein levels and increased ERK phosphorylation. Frass and SLIGKV each increased AP‐1 translocation and DNA binding. Conclusions: These data suggest that German cockroach frass contains active serine proteases which augment TNF α ‐induced MMP‐9 expression by a mechanism involving PAR‐2, ERK and AP‐1.
Screening women for intimate partner violence in healthcare settings: abridged Cochrane systematic review and meta-analysis
Authors: L. J. O'Doherty, A. Taft, K. Hegarty, J. Ramsay, L. L. Davidson, G. Feder
Journal: BMJ (2014)

<b>Objective</b> To examine the effectiveness of screening for intimate partner violence conducted within healthcare settings to determine whether or not screening increases identification and referral to support agencies, improves women's wellbeing, decreases further violence, or causes harm. <b>Design</b> Systematic review and meta-analysis of trials assessing effectiveness of screening. Study assessment, data abstraction, and quality assessment were conducted independently by two of the authors. Standardised estimations of the risk ratios and 95% confidence intervals were calculated. <b>Data sources</b> Nine databases searched up to July 2012 (CENTRAL, Medline, Medline(R), Embase, DARE, CINAHL, PsycINFO, Sociological Abstracts, and ASSIA), and five trials registers searched up to 2010. <b>Eligibility criteria for selecting studies</b> Randomised or quasi-randomised trials of screening programmes for intimate partner violence involving all women aged ≥16 attending a healthcare setting. We included only studies in which clinicians in the intervention arm personally conducted the screening, or were informed of the screening result at the time of the consultation, compared with usual care (or no screening). Studies of screening programmes that were followed by structured interventions such as advocacy or therapeutic intervention were excluded. <b>Results</b> 11 eligible trials (n=13 027) were identified. In six pooled studies (n=3564), screening increased the identification of intimate partner violence (risk ratio 2.33, 95% confidence interval 1.39 to 3.89), particularly in antenatal settings (4.26, 1.76 to 10.31). Based on three studies (n=1400), we detected no evidence that screening increases referrals to domestic violence support services (2.67, 0.99 to 7.20). Only two studies measured women's experience of violence after screening (three to 18 months after screening) and found no reduction in intimate partner violence. One study reported that screening does not cause harm. <b>Conclusions</b> Though screening is likely to increase identification of intimate partner violence in healthcare settings, rates of identification from screening interventions were low relative to best estimates of prevalence of such violence. It is uncertain whether screening increases effective referral to supportive agencies. Screening does not seem to cause harm in the short term, but harm was measured in only one study. As the primary studies did not detect improved outcomes for women screened for intimate partner violence, there is insufficient evidence for screening in healthcare settings. Studies comparing screening versus case finding, or screening in combination with therapeutic intervention for women's long term wellbeing, are needed to inform the implementation of identification policies in healthcare settings.
Sedation and Delirium in the Intensive Care Unit
Authors: Michael C. Reade, Simon Finfer
Journal: New England Journal of Medicine (2014)

Patients in intensive care units (ICUs) are treated with many interventions (most notably endotracheal intubation and invasive mechanical ventilation) that are observed or perceived to be distressing.Pain is the most common memory patients have of their ICU stay. 1 Agitation can precipitate accidental removal of endotracheal tubes or of intravascular catheters used for monitoring or administration of life-sustaining medications.Consequently, sedatives and analgesics are among the most commonly administered drugs in ICUs.Early intensive care practice evolved from intraoperative anesthetic care at a time when mechanical ventilation was delivered by rudimentary machines that were not capable of synchronizing with patients' respiratory efforts.As a result, deep sedation was commonly used until a patient was able to breathe without assistance.Developments over the past 30 years, including microprocessor-controlled ventilators that synchronize with patients' own respiratory efforts and new, shorter-acting sedative and analgesic medications, have dramatically changed this approach.Equally important has been the recognition that pain, oversedation, and delirium are issues that if undetected and untreated are distressing to patients and associated with increased morbidity and mortality.Just as the concept of the "triad of anesthesia" underscores the pharmacodynamic interactions among hypnotics, analgesics, and muscle relaxants and the recognition that the simultaneous administration of agents of each class permits the use of lower doses of drugs of all classes, the concept of the "ICU triad" recognizes that pain, agitation, and delirium -and therefore approaches to their management -are inextricably linked (Fig. 1).According to the principle that it is better to treat disease than to mask it, sedatives should be used only when pain and delirium have been addressed with the use of specific pharmacologic and nonpharmacologic strategies.Pa in, A na l gesi a , a nd Sedation in the ICU Prospective studies confirm that the majority of patients who are treated in ICUs have pain, 1 which makes the assessment of pain and provision of adequate analgesia essential components of ICU care.The short-term consequences of untreated pain include higher energy expenditure and immunomodulation. 2,3Longer-term, untreated pain increases the risk of post-traumatic stress disorder. 4Assessing whether a patient in the ICU is in pain may be difficult.The reference standard for the assessment of pain is self-reporting by the patient, but patients in the ICU may not be sufficiently interactive to give valid responses.Physiological indicators such as hypertension and tachycardia correlate poorly with more intuitively valid measures of pain, 5 but pain scales such as the Behavioral Pain Scale 6 and the Critical
Determination of Fetal, Placental and Neonatal Blood Volumes in the Sheep
Authors: Robert K. Creasy, Maarten Drost, Michael V. Green, John A. Morris
Journal: Circulation Research (1970)

A sheep preparation was developed for studying fetoplacental and neonatal blood volumes using isotope dilution techniques. Fetoplacental blood volume was measured in 46 fetal lambs (gestational age 112 to 146 days) using radioactive iodinated human serum albumin ( 125 I-RISA). In 28 of the 46 animals, blood volume was also computed using 125 I-RISA and maternal red cells labeled with radiochromium ( 51 Cr). Blood volume averaged 156.1 ml/kg of fetal weight with the single-label method and 134.7 ml/kg with the double-label method. Blood volumes measured in 17 neonatal lambs with the single-label technique averaged 110.0 ml/kg, and with the double-label technique in 10 animals averaged 104.0 ml/kg. Placental blood volume, determined by subtracting the neonatal blood volume from the fetoplacental blood volume, although varying from animal to animal, was independent of fetal weight and remained relatively constant during the last fourth of gestation.
Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes.
Authors: A M Schmidt, O Hori, J X Chen, J F Li, J Crandall, J Zhang, R Cao, S D Yan, J Brett, D Stern
Journal: Journal of Clinical Investigation (1995)

Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell recognition protein on the endothelial cell surface (EC), has been associated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irreversible advanced glycation endproducts (AGEs), could mediate VCAM-1 expression by interacting with their endothelial cell receptor (receptor for AGE, RAGE). Exposure of cultured human ECs to AGEs induced expression of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, and was associated with increased levels of VCAM-1 transcripts. The inhibitory effect of anti-RAGE IgG, a truncated form of the receptor (soluble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE-RAGE-induced oxidant stress was central to VCAM-1 induction. Electrophoretic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-kB in the VCAM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma. These data are consistent with the hypothesis that AGE-RAGE interaction induces expression of VCAM-1 which can prime diabetic vasculature for enhanced interaction with circulating monocytes.
A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 <i>In vivo</i> and <i>In vitro</i>
Authors: Jing-jing Liu, Hui-ni Zeng, Lian-ru Zhang, Yan-yan Zhan, Yan Chen, Yuan Wang, Juan Wang, Shao-hua Xiang, Wen-jun Liu, Wei-jia Wang, Hang-zi Chen, Yue-mao Shen, Wen-jin Su, Pei-qiang Huang, Hong-kui Zhang, Qiao Wu
Journal: Cancer Research (2010)

Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents.
Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma
Authors: Ramin Massoumi, Silke Kuphal, Claus Hellerbrand, Bodo Haas, Peter Wild, Thilo Spruss, Alexander Pfeifer, Reinhard Fässler, Anja K. Bosserhoff
Journal: The Journal of Experimental Medicine (2009)

High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.
Screening the Cellular Microenvironment: A Role for Microfluidics
Authors: J.W. Warrick, W.L. Murphy, D.J. Beebe
Journal: IEEE Reviews in Biomedical Engineering (2008)

The cellular microenvironment is an increasingly discussed topic in cell biology as it has been implicated in the progression of cancer and the maintenance of stem cells. The microenvironment of a cell is an organized combination of extracellular matrix (ECM), cells, and interstitial fluid that influence cellular phenotype through physical, mechanical, and biochemical mechanisms. Screening can be used to map combinations of cells and microenvironments to phenotypic outcomes in a way that can help develop more predictive in vitro models and to better understand phenotypic mechanisms from a systems biology perspective. This paper examines microenvironmental screening in terms of outcomes and benefits, key elements of the screening process, challenges for implementation, and a possible role for microfluidics as the screening platform. To assess microfluidics for use in microenvironmental screening, examples and categories of micro-scale and microfluidic technology are highlighted. Microfluidic technology shows promise for simultaneous control of multiple parameters of the microenvironment and can provide a base for scaling advanced cell-based experiments into automated high-throughput formats.
Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions – a prospective comparative study
Authors: Y.‐C. Chen, H.‐H. Chiang, Y.‐T. Cho, C.‐Y. Chang, K.‐L. Chen, C.‐W. Yang, Y.‐H. Lee, C.‐Y. Chu
Journal: Allergy (2015)

Abstract Background Sequential human herpes virus ( HHV ) reactivation is well known in drug reaction with eosinophilia and systemic symptom ( DRESS ), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions ( cADR s). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV ‐6, HHV ‐7, Epstein–Barr virus ( EBV ), and cytomegalovirus ( CMV ) in different cADR s and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. Methods A prospective study was conducted to monitor the viral statuses of patients with different cADR s by polymerase chain reaction and serum‐specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. Results Among the various cADR s, HHV ‐6 reactivation was only observed in DRESS , but EBV and CMV could be detected in other cADR s. Many proinflammatory cytokines and chemokines, including interleukin ( IL )‐1β, IL ‐2, IL ‐6, interferon‐γ, tumor necrosis factor‐α, were significantly lower in DRESS patients with HHV ‐6 reactivation when compared to those without HHV ‐6 reactivation. In addition, these mediators were significantly lower before and during HHV ‐6 reactivation, compared to cytokine levels after HHV ‐6 reactivation in the same patient. Conclusion HHV ‐6 reactivation was only observed in DRESS patients, not in any other cADR . In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV ‐6 reactivation.
Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer
Authors: Bruce G. Haffty, Qifeng Yang, Michael Reiss, Thomas Kearney, Susan A. Higgins, Joanne Weidhaas, Lyndsay Harris, Willam Hait, Deborah Toppmeyer
Journal: Journal of Clinical Oncology (2006)

To determine the prognostic significance of triple negative breast cancers with respect to locoregional relapse and distant metastasis in conservatively managed breast cancer patients.A database of conservative managed (conservative surgery followed by radiation) patients, in whom all three markers (estrogen receptor, progesterone receptor, and HER2/neu) were available, was reviewed. Patients were classified as triple negative if they tested negative for all three markers. Of 482 patients with all three markers available, 117 were classified as triple negative.As of September 2005, with a median follow-up time of 7.9 years, of the 482 patients in the study, there have been 53 in-breast relapses, 10 nodal relapses, 77 distant relapses, and 69 deaths. At 5 years, the triple negative cohort had a poorer distant metastasis-free rate compared with the other subtypes (67% v 82%, respectively; P = .002). Triple negative subtype was an independent predictor of distant metastasis (hazard ratio = 2.14; 95% CI, 1.31 to 3.53; P = .002) and cause-specific survival (hazard ratio = 1.79; 95% CI, 1.03 to 3.22; P = .047). There was no significant difference in local control between the triple negative and other subtypes (83% v 83%, respectively). Of 99 BRCA-tested patients in this cohort, 10 had deleterious mutations in BRCA1, and seven had mutations in BRCA2. Of 10 BRCA1 patients, eight were triple negative, whereas only one of seven BRCA2 patients was triple negative (P < .001).Patients classified as triple negative have a poor prognosis. However, there was no evidence that these patients are at higher risk for local relapse after conservative surgery and radiation. Patients with BRCA1 mutations develop predominantly triple negative tumors.
Interferon-α enhances antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma
Authors: Cong-Jun Wang, Chao-Wen Xiao, Tian-Geng You, Ya-Xin Zheng, Wei Gao, Zhu-Qing Zhou, Jun Chen, Xin-Bo Xue, Jia Fan, Hui Zhang
Journal: Molecular Cancer (2012)

Abstract Background Hepatocellular carcinoma (HCC) has a dismal 5-year-survival rate of 10%, so novel strategies are warranted. IL-24 mediates anti-tumor activity reducing STAT3 expression, which suggests that interferon (IFN) alpha may augment tumor cell lysis and reduce angiogenesis. We investigated the antitumor activity of treatment with IFN-α, with the oncolytic adenovirus SG600-IL-24, or the combination of both in HCC in vitro and in vivo . Results RT-PCR, ELISA assay and Western-blot confirmed that the exogenous IL-24 gene was highly expressed in HCC cells infected with SG600-IL-24. Treatment with combined IFN-α and SG600-IL-24 suppressed growth and promoted apoptosis of the HepG2, MHCC97L, and HCCLM3 cell lines compared with the normal cell line L02. The combined therapy increased STAT1 and SOCS1 and apoptosis, but decreased the expression of the metastatic and angiogenic proteins MMP-2, XIAP, OPN, and VEGF, which are regulated by STAT3 in HCC cells in vitro . To assess the effects in vivo , the HCC cell line HCCLM3 was transplanted subcutaneously into the right flanks of nude mice. Mice in the IFN-α group, the SG600-IL-24 group, or the combined therapy group had significantly suppressed growth of the HCC xenografted tumors compared to the PBS control group of mice. Among the mice treated with the combination of IFN-α and SG600-IL-24, three of those eight mice had long-term survival and no evidence of a tumor. These mice also had decreased expression of the metastatic and angiogenic proteins MMP-2, XIAP, OPN, and VEGF. Conclusions The present study demonstrated for the first time the potential antitumor activity of IFN-α combined with the oncolytic adenovirus SG600-IL-24 in HCC both in vitro and in vivo , and suggests its further development as a potential candidate for HCC cancer gene therapy.