tbuckley/cabot-search huggingface dataset:
Cell-Cycle Regulator Cks1 Promotes Hepatocellular Carcinoma by Supporting NF-κB–Dependent Expression of Interleukin-8
Authors: Eun-Kyoung Lee, Dae-Ghon Kim, Jang-Seong Kim, Yeup Yoon
Journal: Cancer Research (2011)

The cell-cycle regulator Cks1 has recently been implicated in Skp2-mediated ubiquitination of the tumor suppressor protein p27. In this article, we report that Cks1 exerts a Skp2-independent regulation of NF-κB that promotes interleukin-8 (IL-8) expression, which is critical to hepatocellular carcinoma (HCC) growth. Cks1 was upregulated frequently in human HCC tissues and cell lines. Cks1 knockdown in HCC cells elevated p27 levels and decreased tumorigenicity in a manner that was also associated with a strong downregulation of IL-8 expression. IL-8 downregulation was not phenocopied by either RNAi-mediated knockdown of Skp2 or ectopic overexpression of p27. However, attenuation of IL-8 expression itself was sufficient to blunt HCC growth. Mechanistic investigations revealed that IL-8 was controlled at a transcriptional level by Cks1 targeting of the NF-κB regulator IκBα, which led to NF-κB activation and IL-8 expression, through a p27-independent regulation of IκB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-κB-mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination.
A Novel Role for p73 in the Regulation of Akt-Foxo1a-Bim Signaling and Apoptosis Induced by the Plant Lectin, Concanavalin A
Authors: A.R.M. Ruhul Amin, Rajib K. Paul, Vijay S. Thakur, Munna L. Agarwal
Journal: Cancer Research (2007)

Abstract Virtually all human cancers encounter disruption of the “p53 network.” From a therapeutic point of view, it is important to devise strategies that eliminate cancer cells, which are often defective in functional p53 and protect p53-expressing normal cells. By comparing the response of a pair of isogenic cell lines, we identify a plant-derived compound, Concanavalin A (Con A), which differentially kills p53-null cells. Further, we find that p53 family member, p73, plays a critical role that is unmasked in the absence of p53. Con A treatment leads to induction of p73 and several others that are important mediators of apoptosis and act downstream, such as p21, Bax, Foxo1a, and Bim. Inactivation of p73 reverses the expression of these proteins and apoptosis. Inhibition of Akt activation sensitizes otherwise resistant cells. These observations thus reveal a novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis especially when p53 is absent. [Cancer Res 2007;67(12):5617–21]
In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats.
Authors: L Rossetti, M Hawkins, W Chen, J Gindi, N Barzilai
Journal: Journal of Clinical Investigation (1995)

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.
Molecular Biomarkers of Residual Disease after Surgical Debulking of High-Grade Serous Ovarian Cancer
Authors: Susan L. Tucker, Kshipra Gharpure, Shelley M. Herbrich, Anna K. Unruh, Alpa M. Nick, Erin K. Crane, Robert L. Coleman, Jamie Guenthoer, Heather J. Dalton, Sherry Y. Wu, Rajesha Rupaimoole, Gabriel Lopez-Berestein, Bulent Ozpolat, Cristina Ivan, Wei Hu, Keith A. Baggerly, Anil K. Sood
Journal: Clinical Cancer Research (2014)

Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test.Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5).High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy.
Rosette formation by circulating lymphocytes from rheumatoid and nonrheumatoid subjects.
Authors: D J Lea, D J Ward
Journal: Annals of the Rheumatic Diseases (1972)

In the majority of patients with rheumatoid arthritis the immune response is most readily detected as a production of rheumatoid factors, IgM antibodies, which agglutinate to high titre erythrocytes coated with IgG antibodies from man, rabbit, or sheep, etc.Generally, only low titres of rheumatoid factors are found in nonrheumatoid individuals.Bach, Delrieu, and Delbarre (1970a, b) described circulating human lymphocytes which bear surface receptors with antiglobulin activity.Upon mixing and centrifuging with human erythrocytes coated with rabbit antibody, each lymphocyte was surrounded by adherent erythrocytes to form a rosette; usually fewer than six rosette- forming lymphocytes per thousand were found in control subjects, whereas over 70 per cent of patients with rheumatoid arthritis gave greater numbers.Patients with gout gave increased rosette counts.These authors suggested that the lymphocyte response of the rheumatoid individual precedes the appearance of humoral rheumatoid factors and that the process may correspond to that found in animals after immunization (Brown and Epstein, 1969).In order to examine the properties and occurrence of rosette-forming lymphocytes, we have tested lymphocyte preparations from normal subjects of various ages, patients suffering from rheumatoid arthritis, and patients with orthopaedic conditions not related to rheumatoid arthritis.
Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection.
Authors: H M Malaty, D Y Graham
Journal: Gut (1994)

<h3>Introduction</h3> Research of age-related treatment failure with biologics for inflammatory bowel disease (IBD) is limited. Previous studies have suggested a higher failure risk for Adults &gt;60 years (&gt;60), but focused on anti-TNFα agents. Newer biologics are revolutionising treatment for Adults with IBD, but to date treatment failure or intolerance in the &gt;60 is poorly understood. RAB-IBD (Retrospective analysis of biologic treatment failure in IBD) at Royal Wolverhampton NHS Trust, is a real-life, longitudinal retrospective single-centre study comparing failure rates for biologics/biosimilar agents. These include anti-TNFα's, integrin-inhibitors, interleukins-inhibitors and JAK-inhibitors. The primary outcome was to evaluate whether treatment failure at 12 months was impacted by age (&gt;60s versus &lt;60s). The secondary outcomes were to analyse if failure to complete 12 months of therapy were a result of the; type of biologic used, use of concomitant drugs, or demographic factors. <h3>Methods</h3> 632 patients were identified from the Trust IBD database, who were initiated on biologics from January 2015 to December 2019. 465 matched our inclusion and exclusion criteria. Baseline characteristics, such as gender, biologic, type of IBD and number of biologics used previously, were matched to produce two cohorts, each of 98 participants comprising &gt;60s and &lt;60s. <h3>Results</h3> Adverse effects, hospitalisation and need for emergency surgery was seen in 5.1% of under 60s (n=5) and 13.3% of over 60s (n=13). There was no significant difference in the proportion of patients who failed to complete 12 months of biologic treatment from the &gt;60s (n=20, 20.4%) versus &lt;60s (n=12, 12.2%) (<i>OR 1.838, p=0.126</i>). A larger proportion of biologic failure was seen in those on anti-TNFα vs. non-anti-TNFα biologics, but this was not significant <i>(OR 2.35, p=0.051</i>). IBD type (Crohn's vs. Colitis) was not a predictor of biological failure (<i>OR 1.856, p=0.176</i>), nor was previous biologic use (<i>OR 0.644, p=0.118)</i>; concomitant thiopurines/methotrexate <i>(OR 0.46, p=0.134);</i> co-morbidities<i> (OR 0.834, p&lt;=0.752</i>); smoking status (<i>OR 0.956, p=0.888</i>); severity score (<i>OR 0.939, p=0.420</i>); baseline CRP (<i>OR 1.024, p=0.250</i>); faecal calprotectin <i>(OR 1.00, p=0.746)</i>. Risk of biological failure at 12 months was greater in women than in men <i>(OR 2.5, p=0.023).</i> <h3>Conclusions</h3> Age is not an independent predictor of pooled biological failure at 12 months post-initiation. This finding may be factored in when personalised treatment approaches are sought for &gt;60s who are not respondent to conventional therapy. However, more research is required in a higher-powered study to investigate whether treatment failure is influenced by various demographic factors and by biologic type.
Cells Capable of Bone Production Engraft from Whole Bone Marrow Transplants in Nonablated Mice
Authors: Susan K. Nilsson, Mark S. Dooner, Heinz-Ulrich Weier, Baruch Frenkel, Jane B. Lian, Gary S. Stein, Peter J. Quesenberry
Journal: The Journal of Experimental Medicine (1999)

Allogeneic and autologous marrow transplants are routinely used to correct a wide variety of diseases. In addition, autologous marrow transplants potentially provide opportune means of delivering genes in transfected, engrafting stem cells. However, relatively little is known about the mechanisms of engraftment in transplant recipients, especially in the nonablated setting and with regard to cells not of hemopoietic origin. In particular, this includes stromal cells and progenitors of the osteoblastic lineage. We have demonstrated for the first time that a whole bone marrow transplant contains cells that engraft and become competent osteoblasts capable of producing bone matrix. This was done at the individual cell level in situ, with significant numbers of donor cells being detected by fluorescence in situ hybridization in whole femoral sections. Engrafted cells were functionally active as osteoblasts producing bone before being encapsulated within the bone lacunae and terminally differentiating into osteocytes. Transplanted cells were also detected as flattened bone lining cells on the periosteal bone surface.
The combined effect of nifedipine and sodium cromoglycate on the airway response to inhaled hypertonic saline in patients with bronchial asthma
Authors: S Kivity, R Ganem, J Greif, M Topilsky
Journal: European Respiratory Journal (1989)

The combined effect of oral nifedipine and aerosolized sodium cromoglycate on the airway response to inhaled sodium chloride at increasing concentrations was randomly studied in 10 patients with bronchial asthma. Nifedipine (20 mg) protected the airways in 6 of the 10 patients, and sodium cromoglycate (20 mg) in all the 10 patients. Following both drugs, the airway response to hypertonic saline was further reduced when compared to each drug on its own. It is concluded that the combination of nifedipine with sodium cromoglycate might be of benefit in the treatment of difficult asthmatic patients.
Potential Ionic Mechanism for Repolarization Differences Between Canine Right and Left Atrium
Authors: Danshi Li, Liming Zhang, James Kneller, Stanley Nattel
Journal: Circulation Research (2001)

Abstract —Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current ( I Kr ) was greater in the LA (eg, 1.83±0.10 pA/pF at +20 mV) than in the RA (1.15±0.07 pA/pF, P &lt;0.01; n=16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca 2+ , and transient outward K + currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go–related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD- and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I Kr than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I Kr may participate in the ability of the LA to act as a “driver region” for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy.
Computed tomography of pulmonary sarcoid-like granulomas induced by complete Freund's adjuvant in rats
Authors: A. Bergeron, J-P. Laissy, P. Loiseau, E. Schouman-Claeys, A.J. Hance, A. Tazi
Journal: European Respiratory Journal (2001)

Intravenous injection of complete Freund's adjuvant (CFA) in rats has been proposed as an experimental model for pulmonary sarcoidosis, but only some animals develop granulomas. Because the detection of the presence of granulomas and evaluation of the extent of the reaction has required histological evaluation, this model has been of limited use in following the evolution of the granulomatous process. The present study evaluated the ability of lung computed tomography (CT) scanning to identify in vivo pulmonary granulomas induced by CFA in rats. Wistar rats were injected with CFA to induce pulmonary sarcoid-like granulomas, and the presence and extent of pulmonary abnormalities, as detected by spiral CT and histopathological analysis, were compared. Spiral CT had a high sensitivity and specificity for the detection of sarcoid-like granulomas in rats injected with CFA. The extent of the pulmonary granulomatous reaction as assessed by the two techniques strongly correlated (r=0.93, p<0.01). In contrast, the mean density of lungs containing granulomas was not significantly different from that of lungs with no granulomatous reaction. Thus, lung computed tomography appears to be a valuable tool for the in vivo evaluation of the pulmonary granulomatous reaction induced by complete Freund's adjuvant in rats. With the help of computed tomography, this experimental model should be suitable for the sequential study of pulmonary sarcoid-like granulomas, particularly in response to various therapeutic strategies.
Recurrence of Rift Valley fever in Egypt
Authors: R.R. Arthur, S.E. Cope, B.A. Botros, R.G. Hibbs, I.Z.E. Imam, R.R. Arthur, M.S. El-Sharkawy, S. Oun, J.C. Morrill, R.E. Shope, M.A. Darwish
Journal: The Lancet (1993)
The Effect of Changes in Rate and Rhythm on Supernormal Excitability in the Isolated Purkinje System of the Dog
Authors: JOSEPH F. SPEAR, E. NEIL MOORE
Journal: Circulation (1974)

Microelectrode techniques were used to investigate the effects of rate and rhythm changes upon the period of supernormal excitability during repolarization in isolated canine right and left bundle branch and Purkinje fibers. The same microelectrode was used for both intracellular stimulation and recording. Excitability curves (strength-interval curves) were measured as the minimum depolarizing current required to re-excite the fiber during repolarization of a conducted action potential. During the supernormal period it required an average of 17.0 ± 4.6 SD % less than diastolic current to re-excite the fibers throughout the left and right bundle branch-Purkinje system. The supernormal period of excitability in the bundle branch-Purkinje system was voltage dependent, reaching minimum current requirements at 74.3 ± 5.8 SD mV. Excitability curves of conducted action potentials were determined at basic cycle lengths ranging from 1000 to 300 msec and following single and multiple premature beats. The decrease in action potential durations associated with shorter cycle lengths was not accompanied by a corresponding shortening of the supernormal period of excitability. Therefore, at shorter cycle lengths the supernormal period encompassed a greater proportion of the total action potential; in some cases as much as 50% of the total action potential duration exhibited a period of supernormal excitability. The supernormal period of excitability could be eliminated by perfusing the tissues in elevated potassium (5.0 and 7.5 mM) Tyrode's solution. The possible implications for the generation of re-entrant arrhythmias are discussed.
MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study
Authors: Josephine K Swanton, Alex Rovira, Mar Tintore, Daniel R Altmann, Frederik Barkhof, Massimo Filippi, Elena Huerga, Katherine A Miszkiel, Gordon T Plant, Chris Polman, Marco Rovaris, Alan J Thompson, Xavier Montalban, David H Miller
Journal: The Lancet Neurology (2007)
Right Ventricular Fibrosis and Conduction Delay in a Patient With Clinical Signs of Brugada Syndrome
Authors: Ruben Coronel, Simona Casini, Tamara T. Koopmann, Francien J.G. Wilms-Schopman, Arie O. Verkerk, Joris R. de Groot, Zahurul Bhuiyan, Connie R. Bezzina, Marieke W. Veldkamp, André C. Linnenbank, Allard C. van der Wal, Hanno L. Tan, Pedro Brugada, Arthur A.M. Wilde, Jacques M.T. de Bakker
Journal: Circulation (2005)

The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown.A BS patient without clinically detected cardiac structural abnormalities underwent cardiac transplantation for intolerable numbers of implantable cardioverter/defibrillator discharges. The patient's explanted heart was studied electrophysiologically and histopathologically. Whole-cell currents were measured in HEK293 cells expressing wild-type or mutated sodium channels from the patient. The right ventricular outflow tract (RVOT) endocardium showed activation slowing and was the origin of ventricular fibrillation without a transmural repolarization gradient. Conduction restitution was abnormal in the RVOT but normal in the left ventricle. Right ventricular hypertrophy and fibrosis with epicardial fatty infiltration were present. HEK293 cells expressing a G1935S mutation in the gene encoding the cardiac sodium channel exhibited enhanced slow inactivation compared with wild-type channels. Computer simulations demonstrated that conduction slowing in the RVOT might have been the cause of the ECG changes.In this patient with BS, conduction slowing based on interstitial fibrosis, but not transmural repolarization differences, caused the ECG signs and was the origin of ventricular fibrillation.
Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney Disease
Authors: Michael Zeisberg, Mona Khurana, Velidi H Rao, Dominic Cosgrove, Jean-Philippe Rougier, Michelle C Werner, Charles F Shield, Zena Werb, Raghu Kalluri
Journal: PLoS Medicine (2006)

Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving alpha3(IV), alpha4(IV), or alpha5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)--MMP-2, MMP-3, and MMP-9--which influence the progression of renal dysfunction in alpha3(IV)-/- mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the alpha3(IV)-/- mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of alpha3(IV)-/- mice.These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in alpha3(IV)-/- mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria.
HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations
Authors: V De Re, D Sansonno, M P Simula, L Caggiari, D Gasparotto, M Fabris, F A Tucci, V Racanelli, R Talamini, M Campagnolo, S Geremia, F Dammacco, S De Vita
Journal: Leukemia (2006)