tbuckley/cabot-search huggingface dataset:
Phase I Trial of the Matrix Metalloproteinase Inhibitor Marimastat Combined with Carboplatin and Paclitaxel in Patients with Advanced Non–Small Cell Lung Cancer
Authors: John R. Goffin, Ian C. Anderson, Jeffrey G. Supko, Joseph Paul Eder, Geoffrey I. Shapiro, Thomas J. Lynch, Margaret Shipp, Bruce E. Johnson, Arthur T. Skarin
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics. Experimental Design: Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m2 as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week. Results: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non–small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics. Conclusions: The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m2) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.
Activation of p53-Dependent Apoptosis by Acute Ablation of Glycogen Synthase Kinase-3β in Colorectal Cancer Cells
Authors: Jagadish C. Ghosh, Dario C. Altieri
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The restoration of checkpoint mechanisms may provide a rational anticancer approach, but the molecular circuitries of how this can be achieved therapeutically are poorly understood. A pivotal signaling network in colorectal cancer cells involves glycogen synthase kinase-3β (GSK3β), a multifunctional kinase whose role in tumor cell survival is not defined. Experimental Design: We used molecular, genetic, and pharmacologic antagonists of GSK3β in p53+/+ or p53−/− colorectal cancer cells. We monitored kinase activity in immunoprecipitation, protein expression by immunoblotting, and cell death by multiparametric flow cytometry. A xenograft colorectal cancer model was used to study antitumor activity in vivo. Results: Treatment of p53+/+ colorectal cancer cells with pharmacologic inhibitors of GSK3β resulted in sustained elevation of p53, with up-regulation of p21Waf1/Cip1 and loss of survivin levels. Molecular targeting of GSK3β by overexpression of a GSK3β dominant-negative mutant, or acutesilencing of GSK3β by RNA interference, reproduced the induction of transcriptionally active p53 in colorectal cancer cells. This pathway was recapitulated by deregulated Wnt/T-cell factor signaling, with elevation of the tumor suppressor p14ARF, and reduced expression of the p53 antagonist, MDM2. Rather than cell cycle arrest, GSK3β blockade resulted in p53-dependent apoptosis, which was contributed by acute loss of survivin and inhibition of colorectal cancer growth in mice. Conclusions: Acute ablation of GSK3β in colorectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth. This pathway may be exploited for rational treatment of colorectal cancer patients retaining wild-type p53.
Overactive bladder in women with sleep apnoea-hipopnea syndrome
Authors: Núria Grau, Elisabeth Del Amo, Carles Sanjuás, Cristina Estirado, Antonia Ruiz, Encarna Guardiola, Miquel Félez, Ramon Carreras, Joaquim Gea
Journal: European Respiratory Journal (2012)

INTRODUCTION . Overactive Bladder Syndrome (OAB) is characterized by urgency to urinate, which may be accompanied by increased frequency, nocturia and incontinence. Although nocturia is a common symptom in the setting of sleep apnea-hypopnea syndrome (OSA), the association between OAB and OSA is not well known. The aim of this study was to analyze the presence of OAB in female patients diagnosed from OSA.   METHODS . Seventy-two consecutive female patients referred for polysomnography (PSG) for suspected OSA were included. All patients fulfilled the spanish validated version of the “Bladder Control Self-Assessment Questionnarie” (B-SAQ). The B-SAQ consists of 2 subscales: “symptoms”, consisting of 4 items (urgency, frequency, nocturia and incontinence) and “discomfort” in which it is established the degree of distress associated with symptoms (from 0 to 3).   RESULTS . The scores of “Symptoms” and “Discomfort” were significantly higher in patients who were diagnosed OSA.  Patients with OSA scored significantly higher for symptoms of urgency, nocturia and incontinence and 4 items of “Discomfort”. The AHI was significantly correlated with the score of “Symptoms” (r = 0.297, p= 0.013) and that of “Discomfort” (r= 0.258, p= 0.03). There was no significant correlation between the BMI and the B-SAQ.   CONCLUSIONS . Obstructive sleep apnea is associated with overactive bladder syndrome in women. The Bladder Control Self-Assessment Questionnarie is a valid instrument to assess overactive bladder in patients with OSA.
Biliverdin Reductase Mediates Hypoxia-Induced EMT via PI3-Kinase and Akt
Authors: Rui Zeng, Ying Yao, Min Han, Xiaoqin Zhao, Xiao-Cheng Liu, Juncheng Wei, Yun Luo, Juan Zhang, Jianfeng Zhou, Shixuan Wang, Ding Ma, Gang Xu
Journal: Journal of the American Society of Nephrology (2008)

Chronic hypoxia in the renal parenchyma is thought to induce epithelial-to-mesenchymal transition (EMT), leading to fibrogenesis and ultimately end-stage renal failure. Biliverdin reductase, recently identified as a serine/threonine/tyrosine kinase that may activate phosphatidylinositol 3-kinase (PI3K) and Akt, is upregulated in response to reactive oxygen species that may accompany hypoxia. We investigated this potential role of biliverdin reductase in hypoxia-induced renal tubular EMT. Expression of biliverdin reductase was upregulated in a human proximal tubule cell line (HK-2) cultured in hypoxic conditions (1% O2), and this was accompanied by reduced expression of E-cadherin and increased expression of the mesenchymal marker vimentin. Inhibiting PI3K reversed these changes, consistent with EMT. In normoxic conditions, overexpression of biliverdin reductase promoted similar characteristics of EMT, which were also reversed by inhibiting PI3K. Furthermore, using small interfering RNA (siRNA) to knockdown biliverdin reductase, we demonstrated that the enzyme associates with phosphorylated Akt and mediates the hypoxia-induced EMT phenotype. In vivo, expression of biliverdin reductase increased in the tubular epithelia of 5/6-nephrectomized rats, and immunohistochemistry of serial sections demonstrated similar localization of phosphorylated Akt and biliverdin reductase. In conclusion, biliverdin reductase mediates hypoxia-induced EMT through a PI3K/Akt-dependent pathway.
Placement of a Femoral Venous Catheter
Authors: Janet Y Tsui, Adam B Collins, Douglas W White, Jasmine Lai, Jeffrey A Tabas
Journal: New England Journal of Medicine (2008)

Femoral venous catheterization is a rapid way to obtain intravenous access in hospitalized or emergency department patients. In this video, you will learn how to safely place a femoral line. Placement of a femoral line may be indicated in the following situations: to obtain vascular access when peripheral access cannot be accomplished, to administer hemodialysis when access at a preferable site is not an option, to perform cardiac catheterization, or to administer large or caustic infusions. The following situations are relative contraindications: an uncooporative patient; the presence of infection, trauma, or distorted anatomy at the insertion site; . . . .
Alterations in Internal Elastic Lamina Permeability As a Function of Age and Anatomical Site Precede Lesion Development in Apolipoprotein E–Null Mice
Authors: Kwangdeok Lee, Farhad Forudi, Gerald M. Saidel, Marc S. Penn
Journal: Circulation Research (2005)

Early atherosclerosis is characterized by the accumulation of plasma-borne macromolecules (eg, low-density lipoproteins) in the arterial intima, which is bordered by endothelial cells (EC) and the internal elastic lamina (IEL). This accumulation is believed to be secondary to increased EC permeability. We hypothesized that a decrease in IEL permeability may precede lesion development and contribute to macromolecular accumulation. To test this hypothesis, we quantified EC and IEL permeability in lesion-free areas of the thoracic and abdominal aortas of chow-fed C57BL/6 control and atherosclerotic-prone apolipoprotein E (apoE)-null mice at 3 and 5 months of age. Between 3 and 5 months of age, apoE-null mice begin to develop atherosclerotic lesions in the thoracic aorta. No significant differences in EC and IEL permeability were observed at either time in C57BL/6 control mice. In contrast, 78% and 19% decreases in IEL permeability of the thoracic aorta and abdominal aorta, respectively, were observed between 3 to 5 months of age in apoE-null mice (thoracic: 2.05+/-1.33 and 0.44+/-0.15 microm/min, P<0.001; abdominal: 1.13+/-0.58 and 0.93+/-0.44 microm/min, P<0.05). To further determine whether decreased IEL permeability is linked with atherosclerotic lesion development, we quantified IEL permeability in the greater and lesser curvature of the aortic arch. In apoE-null mice, the lesser curvature of the aortic arch develops lesions before the greater curvature. We found a significant and sustained decrease (59%) in IEL permeability in the lesser curvature of the aortic arch compared with the greater curvature. These data suggest that atherogenesis involves the pathological remodeling of the IEL, not the endothelium before lesion development. This remodeling may be attributable to local responses of the endothelium and smooth muscle cells to hyperlipidemia.
Circadian rhythms in peak expiratory flow rate in workers exposed to cotton dust.
Authors: F F Cinkotai, T C Sharpe, A C Gibbs
Journal: Thorax (1984)

One hundred and sixty two people working in various departments of cotton spinning and weaving mills measured and recorded their own peak expiratory flow rate (PEFR) at two hourly intervals during Monday, Wednesday, and Thursday of the same work week, from waking in the morning throughout the day until going to bed and a last time the following morning after waking. The circadian rhythm in PEFR was computed by the Halberg program. The mean amplitude of the rhythm in the group was found to be 3.3% and the acrophase fell approximately in the middle of the waking hours. Older workers and those claiming to suffer from symptoms of chronic bronchitis were found to have an amplitude significantly higher (4.1% and 3.9% respectively) than their younger or symptom free counterparts (2.6% and 2.9% respectively; p less than 0.03). The amplitude of cardroom workers (2.4%), workers with byssinosis (2.7%), and those with much exposure to airborne cotton dust (3.3%) and bacteria (2.9%) tended to be lower than that of less exposed groups such as office staff (3.9%), though the difference was significant only in the case of cardroom workers (p less than 0.04). This may be due to airborne contaminants in the working environment.
Race and Ethnicity
Authors: Andrew John Karter
Journal: Diabetes Care (2003)

Medical researchers are now paying increasing attention to findings of racial or ethnic (“racial/ethnic” hereafter) differences in quality and access to care, health outcomes, risk factors, genetic markers, and therapeutic response. However, this attention has been met with growing controversy and debate. Society’s history of discrimination, racism and eugenics, and continued disparities in access and quality of care make this a particularly sensitive issue. In the past year, the New England Journal of Medicine (1– 4) and the International Journal of Epidemiology (5,6) have published several commentaries and editorials, some criticizing and others arguing in favor of the use of race/ethnicity in medical research. The editorial board of the Archives of Pediatric and Adolescent Medicine recently instructed submitting authors not to detail race/ethnic variation in disease or risk factors unless there is proof of the biologic, scientific, or sociologic bases for these differences
RNA-seq analysis of transforming growth factor-β-induced glucocorticoid resistance in human bronchial epithelial cells
Authors: Christine Keenan, Guillermo Lopez-Campos, Saad Salem, Trudi Harris, Michael Schuliga, Cameron Johnstone, Alastair Stewart
Journal: European Respiratory Journal (2013)

Introduction: Glucocorticoid (GC) resistance limits the successful treatment of chronic inflammatory diseases. We have identified Transforming Growth Factor-β (TGF-β) as a novel inducer of GC insensitivity in the epithelial cell lines A549 and BEAS-2B. This resistance is not prevented by inhibiting known non-canonical TGF-β signalling pathways, but may be partially due to decreased GRα nuclear localisation in A549 cells, but not in BEAS-2B cells.  Aim: To use RNA-seq to facilitate efforts to reveal the mechanism of TGF-β-induced GC resistance.  Methods: BEAS-2B cells pre-treated for 24h with 40pM TGF-β were treated with 30nM dexamethasone (Dex) for 4h then total RNA was extracted. RNA-seq was performed using an Illumina HiSeq™ 2000 sequencer. Changes from control of more than 2.5 fold were analysed as significant changes and a subset of the observed expression changes were confirmed by RT-qPCR.  Results: RNA-seq analysis detected 108 genes with expression up-regulated by Dex. Six of these that were up-regulated by TGF-β alone were removed to prevent confounding analyses. Sixty-six genes were only up-regulated by Dex in the absence of TGF-β, and 36 genes were still up-regulated by Dex in the presence of TGF-β.  Conclusions: TGF-β impairs a subset of GC gene regulatory effects in BEAS-2B cells. RNA-seq analysis identified 2 sets of genes up-regulated by GCs, one of which remains inducible and the other which is rendered insensitive to GC activation in the presence of TGF-β. Understanding the differences in regulation of these two groups of GC-sensitive genes may lead to therapeutic strategies to reactivate their expression in chronic inflammatory and fibrotic disease.
Risk of cerebrovascular disease associated with the use of glucocorticoids in patients with incident rheumatoid arthritis: a population-based study
Authors: J Antonio Aviña-Zubieta, Michal Abrahamowicz, Hyon K Choi, M Mushfiqur Rahman, Marie-Pierre Sylvestre, John M Esdaile, Diane Lacaille
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To determine the effect of glucocorticoids (GC) on the risk of cerebrovascular accidents (CVA) in patients with rheumatoid arthritis (RA). Methods A population-based cohort study was carried out using administrative health data on 7051 individuals with RA onset between 1997 and 2001 and no exposure to GC before RA onset. Follow-up was until 2006. GC exposure was defined in four ways: current use (yes/no), current dose (mg/day), cumulative dose (grams) and cumulative duration of use (years). All were used as time-dependent variables updated monthly. CVA were ascertained using hospitalisation and vital statistics data. Transient ischaemic attacks were not considered as CVA. Cox regression models adjusting for demographics, cardiovascular drug use, propensity scores and RA characteristics were used. Results The mean age of the cohort was 56 years and 66% were women. Over 6 years' mean follow-up (43 355 person-years), 178 incident CVA cases were identified. GC current use was not associated with a significant increase in the risk of CVA (HR=1.41, 95% CI 0.84 to 2.37). Similarly, the models that accounted for daily dose (HR=1.07, 95% CI 0.94 to 1.21 for each 5 mg increase in the daily dose), cumulative duration of use (HR=1.1, 95% CI 0.94 to 1.32 for each year accumulated in the past) and total cumulative dose (HR=1.04, 95% CI 0.99 to 1.08 per gram accumulated in the past) were also not significantly associated with CVA. Conclusions This large population-based study indicates that GC use is not associated with an increased risk of CVA in cases with RA.
Prevention of Transfusion Accidents
Authors: F. Marsh
Journal: BMJ (1953)

Higher vertebrates are capable not only of forward but also backward and sideways locomotion. Also, single steps in different directions are generated for postural corrections. While the networks responsible for the control of forward walking (FW) have been studied in considerable detail, the networks controlling steps in other directions are mostly unknown. Here, to characterize the operation of the spinal locomotor network during FW and backward walking (BW), we recorded the activity of individual spinal interneurons from L4 to L6 during both FW and BW evoked by epidural stimulation (ES) of the spinal cord at L5–L6 in decerebrate cats of either sex. Three groups of neurons were revealed. Group 1 (45%) had a similar phase of modulation during both FW and BW. Group 2 (27%) changed the phase of modulation in the locomotor cycle depending on the direction of locomotion. Group 3 neurons were modulated during FW only (Group 3a, 21%) or during BW only (Group 3b, 7%). We suggest that Group 1 neurons belong to the network generating the vertical component of steps (the limb elevation and lowering) because it should operate similarly during locomotion in any direction, while Groups 2 and 3 neurons belong to the networks controlling the direction of stepping. Results of this study provide new insights into the organization of the spinal locomotor circuits, advance our understanding of ES therapeutic effects, and can potentially be used for the development of novel strategies for recuperation of impaired balance control, which requires the generation of corrective steps in different directions. <b>SIGNIFICANCE STATEMENT</b> Animals and humans can perform locomotion in different directions in relation to the body axis (forward, backward, sideways). While the networks that control forward walking have been studied in considerable detail, the networks controlling steps in other directions are unknown. Here, by recording the activity of the same spinal neurons during forward and backward walking, we revealed three groups of neurons forming, respectively, the network operating similarly during stepping in different directions, the network changing its operation with a change in the direction of stepping, and the network operating only during locomotion in a specific direction. These networks presumably control different aspects of the step. The obtained results provide new insights into the organization of the spinal locomotor networks.
Biliary β2-microglobulin in liver allograft rejection
Authors: David H. Adams, David Burnett, Robert A. Stockley, Stefan G. Hubscher, Paul McMaster, Elwyn Elias
Journal: Hepatology (1988)

β2-Microglobulin, which is associated with HLA class 1 antigens, was assayed in bile and serum from 19 patients following 22 liver transplants. Serum levels were elevated in all posttransplant patients irrespective of the presence of rejection. In contrast, biliary levels were significantly higher during episodes of acute rejection compared with posttransplant cholangitis (p &lt; 0.01), stable graft function (p &lt; 0.0001) and nontrans-plant samples (p &lt; 0.0001). When bile/serum ratios were studied, the difference between the rejection and the other groups was even more significant, and if a ratio of 0.2 was considered diagnostic of rejection, the test had a sensitivity of 96%, a specificity of 87% with an accuracy of 90%. Therefore, these results suggest that the measurement of bile/serum ratios of β2-microglobulin following liver transplantation may be useful in diagnosing acute rejection. When bile/serum ratios of β2-microglobulin were compared with those for other proteins, there was strong evidence to suggest that local release accounted for most of the increased biliary β2-microglobulin during rejection. These results provide further evidence that HLA class 1 antigens on the biliary epithelium may be important in liver allograft rejection.
Distinct features of dendritic cells and anti-Ig activated B cells as stimulators of the primary mixed leukocyte reaction.
Authors: J P Metlay, E Puré, R M Steinman
Journal: The Journal of Experimental Medicine (1989)

Highly enriched populations of B lymphoblasts have been isolated after culture with anti-Ig-Sepharose and compared with dendritic cells as stimulators of CD4+ T cells in the murine MLR. The two populations clearly differed in phenotype; anti-Ig blasts were FcR+, B220+, 33D1-, while dendritic cells were FcR-, B220-, 33D1+. However, as MLR stimulators, they shared many common features. Both cells (a) expressed comparable levels of class II MHC products; (b) independently stimulated the primary MLR and the production of several T derived lymphokines including IL-2 and IL-4; and (c) were comparable in stimulating freshly sensitized T cells. However, the relative potencies of dendritic cells and anti-Ig blasts as primary MLR stimulators varied in a strain-dependent fashion. Only anti-Ig blasts could stimulate across an Mls barrier, being at least 100 times more active in stimulating Mls-mismatched, MHC-matched T cells, relative to syngeneic T cells. In contrast, dendritic cells were 10-30 times more potent than anti-Ig blasts when stimulating across an MHC barrier and were likewise more effective in binding MHC-disparate T cells to form the clusters in which the MLR was generated. Dendritic cell-T cell clustering was resistant to anti-LFA-1 mAb, while B blast-T cell clustering was totally blocked. Thus, anti-Ig B lymphoblasts and dendritic cells, two cell types which differ markedly in phenotype, also differ in efficiency and mechanism for initiating responses in allogeneic T cells.