tbuckley/cabot-search huggingface dataset:
Attachment to laminin-111 facilitates transforming growth factor -induced expression of matrix metalloproteinase-3 in synovial fibroblasts
Authors: M. Hoberg, M. Rudert, T. Pap, G. Klein, S. Gay, W. K Aicher
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> In the synovial membrane of patients with rheumatoid arthritis (RA), a strong expression of laminins and matrix degrading proteases was reported. <b>Aim:</b> To investigate the regulation of matrix metalloproteinases (MMPs) in synovial fibroblasts (SFs) of patients with osteoarthritis (OA) and RA by attachment to laminin-1 (LM-111) and in the presence or absence of costimulatory signals provided by transforming growth factor β (TGFβ). <b>Methods:</b> SFs were seeded in laminin-coated flasks and activated by addition of TGFβ. The expression of genes was investigated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunocytochemistry and ELISA, and intracellular signalling pathways by immunoblotting, and by poisoning p38MAPK by SB203580, MEK-ERK by PD98059 and SMAD2 by A-83-01. <b>Results:</b> Attachment of SF to LM-111 did not activate the expression of MMPs, but addition of TGFβ induced a fivefold higher expression of MMP-3. Incubation of SF on LM-111 in the presence of TGFβ induced a significant 12-fold higher expression of MMP-3 mRNA, and secretion of MMP-3 was elevated 20-fold above controls. Functional blocking of LM-111–integrin interaction reduced the laminin-activated MMP-3 expression significantly. Stimulation of SF by LM-111 and TGFβ activated the p38MAPK, ERK and SMAD2 pathways, and inhibition of these pathways by using SB203580, PD98059 or A-83-01 confirmed the involvement of these pathways in the regulation of MMP-3. <b>Conclusion:</b> Attachment of SF to LM-111 by itself has only minor effects on the expression of MMP-1 or MMP-3, but it facilitates the TGFβ-induced expression of MMP-3 significantly. This mode of MMP-3 induction may therefore contribute to inflammatory joint destruction in RA independent of the proinflammatory cytokines interleukin (IL)1β or tumour necrosis factor (TNF)α.
Immune-mediated thrombocytopenia of malaria.
Authors: J G Kelton, J Keystone, J Moore, G Denomme, E Tozman, M Glynn, P B Neame, J Gauldie, J Jensen
Journal: Journal of Clinical Investigation (1983)

Thrombocytopenia frequently complicates malarial infections but the mechanism has not been elucidated. We studied 28 patients with malarial infections and noted that 16 of 17 thrombocytopenic patients had elevated levels of platelet-associated IgG (PAIgG). In all thrombocytopenic patients studied, the level of PAIgG returned to normal as the platelet count rose to normal levels. To study the mechanism of the elevated platelet-bound IgG, IgG and F(ab')2 from patients with recurrent Plasmodium falciparum infections was purified and radiolabeled. Labeled and unlabeled P. falciparum antigen was also prepared. IgG did not nonspecifically bind to malaria-damaged platelets. Binding studies with 3H-malarial antigen demonstrated platelets have saturable binding sites for malarial antigen. Increasing concentrations of malarial antigen displaced the 125I-IgG antimalarial antibody from the platelets. The binding of 125I-IgG and 125I-F(ab')2 was similar and this excluded significant immune complex binding. The thrombocytopenia that complicates at least some malarial infections is caused by immune mechanisms; specific IgG binds to platelet-bound malaria antigen through the Fab portion of the immunoglobulin molecule.
Glucose Transport and NIDDM
Authors: W Timothy Garvey
Journal: Diabetes Care (1992)

Three major metabolic abnormalities contribute to hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) including defective glucose-induced insulin secretion, elevated rates of hepatic glucose output, and insulin's impaired ability to stimulate glucose uptake in peripheral target tissues (insulin resistance). These functions involve cellular glucose transport in β-cells, liver, adipose tissue, and skeletal muscle; and, in some instances, abnormalities in glucose transporter isoforms (GLUT) specifically expressed in these tissues may constitute key biochemical lesions underlying defective glucose homeostasis. In animal models of NIDDM, suppression of GLUT2 in β-cells is correlated with loss of high-Km glucose transport and glucose-sensitive insulin secretion. Although there are no data on humans with NIDDM, GLUT2 loss would constitute an attractive mechanism for defective glucose sensing in β-cells if it can be shown that transport then becomes rate limiting for glucose metabolism. In the liver, however, hepatocyte glucose transport via GLUT2 probably plays only a permissive role in sustaining increased glucose efflux. Peripheral insulin resistance is associated with decreased glucose transport activity, the likely rate-limiting step for glucose uptake in fat and muscle. Accordingly, the insulin-responsive GLUT4 isoform expressed exclusively in insulin target tissues has been studied intensively in NIDDM. In these studies, pretranslational suppression of GLUT4 appears to be the key mechanism of insulin resistance in adipocytes. However, levels of GLUT4 protein and mRNA are normal in vastus lateralis and rectus abdominis, inferring that defects in GLUT4 functional activity or insulin-mediated translocation cause insulin resistance in muscle. Thus, the intensified study of glucose transport has provided important new insights into NIDDM pathogenesis over the past 5 yr and has presented investigators with additional intriguing hypotheses.
The sensory and affective components of pain
Authors: Fabrizio Benedetti
Journal: Behavioral and Brain Sciences (1997)

Both the sensory and the motivational-affective component of pain must be taken into account in studies on sex differences as well as on neuropathic, postoperative, sympathetic, and visceral pain. In all these cases, therapeutic strategies should be aimed at controlling the peripheral, central, and psychological mechanisms underlying the global pain experience. Similarly, it should be recalled that some neuropeptides act on both sensory and affective pain mechanisms. [berkley; mcmahon; dickenson; coderre &amp; katz; wiesenfeld-hallin et al.; blumberg et al.]
PROPERTIES OF ACATALASIC CELLS GROWING IN VITRO
Authors: Robert S. Krooth, R. Rodney Howell, Howard B. Hamilton
Journal: The Journal of Experimental Medicine (1962)

Acatalasia, a disease due to homozygosity for a Mendelian gene, is characterized by the absence of the enzyme catalase from the tissues of the human body. Red cells from heterozygotes have enzyme activities about one-half normal. In this paper, the development of cell lines from skin biopsies on an affected homozygote, a heterozygote, and eight control patients is described. The cell type is the euploid "fibroblast." It was found that acatalasic cells lacked the enzyme, even after growing for many months in a medium rich in catalase. The control lines all had mean catalase activities double or more that of the heterozygous line. Selection experiments, in which the growth of cells exposed for 20 minutes to varying concentrations of hydrogen peroxide was measured, did not provide a system for preferentially eliminating acatalasic cells. Certain other experiments bearing on the enzymatic defect in this disease were performed.
Decreased production of TNF and IL‐6 in whole blood of CLL patients
Authors: E. Oahlke, R. Schlag, I. Langenmayer, M. Frankenberger, E. Käfferlein, T. Subkowski, B. Emmerich, H. W. L. Ziegler‐Heitbrock
Journal: American Journal of Hematology (1995)

Abstract Monocyte derived cytokines, tumor necrosis factor (TNF) and interleukin‐6 (IL‐6), were determined in cell free plasma after stimulation of heparinized whole blood from chronic lymphocytic leukemia (CLL) patients with lipopolysaccharide (LPS) at 1 μg/ml for 6 hr. Compared to control donors (390 U/ml), CLL patients in average had eight‐fold lower levels of TNF bioactivity (50 U/ml). The depressed levels were observed over a wide range of LPS concentrations (0.01 to 10 μg/ml). Furthermore, after stimulation with S. aureus bacteria, CLL samples gave three‐fold lower levels, as well. TNF levels were not decreased because of defective bioactivity of TNF, since strongly reduced levels of TNF protein were also detected in an immunoassay. Finally, interleukin‐6 levels after LPS stimulation were decreased threefold. Flow cytometry analysis with CD14 antibodies demonstrated comparable numbers of monocytes for control donors and CLL patients (698 ± 802 and 427 ± 267, respectively). This suggests that deficient cytokine production was not due to a reduction in monocyte number, but rather to a functional impairment. The deficiency in cytokine production observed after ex vivo stimulation of whole blood from CLL patients suggests that in vivo during bacterial infection, CLL patients will exhibit an inappropriate response as well. © 1995 witey‐Liss, Inc.
Identification of Pathways for Atherosclerosis in Mice
Authors: Susanna S. Wang, Eric E. Schadt, Hui Wang, Xuping Wang, Leslie Ingram-Drake, Weibin Shi, Thomas A. Drake, Aldons J. Lusis
Journal: Circulation Research (2007)

We report a combined genetic and genomic analysis of atherosclerosis in a cross between the strains C3H/HeJ and C57BL/6J on a hyperlipidemic apolipoprotein E-null background. We incorporated sex and sex-by-genotype interactions into our model selection procedure to identify 10 quantitative trait loci for lesion size, revealing a level of complexity greater than previously thought. Of the known risk factors for atherosclerosis, plasma triglyceride levels and plasma glucose to insulin ratios were particularly strongly, but negatively, associated with lesion size. We performed expression array analysis for 23,574 transcripts of the livers and adipose tissues of all 334 F2 mice and identified more than 10,000 expression quantitative trait loci that either mapped to the gene encoding the transcript, implying cis regulation, or to a separate locus, implying trans-regulation. The gene expression data allowed us to identify candidate genes that mapped to the atherosclerosis quantitative trait loci and for which the expression was regulated in cis. Genes highly correlated with lesions were enriched in certain known pathways involved in lesion development, including cholesterol metabolism, mitochondrial oxidative phosphorylation, and inflammation. Thus, global gene expression in peripheral tissues can reflect the systemic perturbations that contribute to atherosclerosis.
Use of cell permeable NBD peptides for suppression of inflammation
Authors: I Strickland, S Ghosh
Journal: Annals of the Rheumatic Diseases (2006)

Nuclear factor (NF)-κB is a ubiquitous and essential transcription factor whose dysregulation has been linked to numerous diseases including arthritis and cancer. It is therefore not surprising that the NF-κB activation pathway has become a major target for development of novel therapies for inflammatory diseases and cancer. However, the indispensable role played by NF-κB in many biological processes has raised concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function. Instead, drugs that selectively target the inflammation induced NF-κB activity, while sparing the protective functions of basal NF-κB activity, would be of greater therapeutic value and would likely display fewer undesired side effects. The recent identification and characterisation of the NF-κB essential modulator (NEMO)-binding domain (NBD) peptide that can block the activation of the IκB kinase (IKK) complex, have provided an opportunity to selectively abrogate the inflammation induced activation of NF-κB by targeting the NBD–NEMO interaction. This peptide is synthesised in tandem with a protein transduction domain sequence from <i>Drosophila antennapedia</i> which facilitates uptake of the inhibitory peptide into the cytosol of target cells.
Scotland's smoking ban means fewer kids in hospital with asthma
Authors: A. Gupta
Journal: Thorax (2010)

peripheral non-segmental basilar infiltrates, mass-like consolidation, cavitation and pleural effusion or pleural thickening. 2 Thoracic actinomycosis is usually the result of aspiration of infected material from the oropharynx.Normal gravitational and anatomical factors result in a predominance of lower-lobe pulmonary disease. 3Given the usual aetiology of thoracic actinomycosis, the likely factor in our patient's history was oesophageal perforation many years earlier.Penicillin is the treatment of choice, in high dose and for a prolonged duration, most usually suggested for several months, but infections could also be polybacterial needing other antibiotics, especially if the recovery is slow.Complications include chronic and progressive sepsis, which may prove fatal.Surgery is reserved as a treatment option where diagnosis is uncertain (suspected neoplasm) or where there is no initial response to antibiotics. 4 conclude, there should be a high level of suspicion for the presence of actinomyces in cases with draining chest wall sinuses or with spontaneous discharge of an empyema.Recognition of these symptoms might avoid the need for surgery as actinomyces is an extremely penicillin-susceptible organism.
Protein-assisted fabrication of nano-reduced graphene oxide for combined in vivo photoacoustic imaging and photothermal therapy
Authors: Zonghai Sheng, Liang Song, Jiaxiang Zheng, Dehong Hu, Meng He, Mingbin Zheng, Guanhui Gao, Ping Gong, Pengfei Zhang, Yifan Ma, Lintao Cai
Journal: Biomaterials (2013)
Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways
Authors: Jian Ma, Yanpeng Wang, Dong Zheng, Meng Wei, Huaxi Xu, Tianqing Peng
Journal: Cardiovascular Research (2012)

Doxorubicin causes damage to the heart, often leading to irreversible cardiomyopathy, which is fatal. Reactive oxygen species (ROS) or oxidative stress is involved in cardiomyocyte death, contributing to doxorubicin-induced cardiotoxicity. This study investigated the role of Rac1, an important subunit of NADPH oxidase, in doxorubicin-induced cardiotoxicity and the underlying mechanisms. In a mouse model of acute doxorubicin-induced cardiotoxicity, cardiomyocyte-specific deletion of Rac1 inhibited NADPH oxidase activation and ROS production, prevented cardiac cell death, and improved myocardial function in Rac1 knockout mice. Therapeutic administration of the specific Rac1 inhibitor NSC23766 achieved similar cardio-protective effects in doxorubicin-stimulated mice. In rat cardiomyoblasts (H9c2 cells) and cultured neonatal mouse cardiomyocytes, Rac1 inhibition attenuated apoptosis as evidenced by decreases in caspase-3 activity and DNA fragmentation in response to doxorubicin, which correlated with a reduction in ROS production and down-regulation of p53 acetylation and histone H2AX phosphorylation. In contrast, overexpression of Rac1 enhanced apoptosis. Doxorubicin also inhibited the activity of classical histone deacetylases (HDAC), which was preserved by Rac1 inhibition and further decreased by Rac1 overexpression. Interestingly, scavenging ROS mitigated apoptosis but did not change HDAC activity and p53 acetylation stimulated by doxorubicin, suggesting both ROS-dependent and -independent pathways are involved in Rac1-mediated cardiotoxicity. Furthermore, the HDAC inhibitor trichostatin A enhanced apoptosis, p53 acetylation and H2AX phosphorylation in doxorubicin-treated cardiomyocytes. Rac1 signalling contributes to doxorubicin-induced cardiotoxicity through both a ROS-dependent mechanism and ROS-independent HDAC/p53 signalling in cardiomyocytes. Thus, inhibition of Rac1 may be a useful therapy for doxorubicin-induced cardiotoxicity.
Treatment of Adrenocortical Deficiency States
Authors: F. D. Hart
Journal: BMJ (1957)

The treatment of adrenocortical deficiency states has been completely revolutionized since the advent of the new adrenocortical steroids.The discovery by Hench, Kendall, and others in 1949 of cortisone a § a therapeutic agent marked an advance into a new therapeutic era.Now that adrenal substitution therapy is a practical measure, adrenalectomy for a variety of disorders has become increasingly popular.Total or subtotal adrenal- ectomy is now orthodox therapy for Cushing's syndrome, and total adrenalectomy has also been extensively used in the treatment of metastatic malignant disease and of malignant hypertension; it has also been empirically performed in the treatment of a number of disorders: diabetes mellitus, schizophrenia, and rheumatoid arthritis, to mention three.Substitution therapy has there- fore become a day-to-day problem in the wards of many hospitals, and, as a natural sequence, the treatment of adrenocortical crisis has become more common than it used to be.
Perioperative CA19-9 Levels Can Predict Stage and Survival in Patients With Resectable Pancreatic Adenocarcinoma
Authors: Cristina R. Ferrone, Dianne M. Finkelstein, Sarah P. Thayer, Alona Muzikansky, Carlos Fernandez-del Castillo, Andrew L. Warshaw
Journal: Journal of Clinical Oncology (2006)

Different prognostic factors stratify patients with pancreatic adenocarcinoma. The purpose of this study was to determine whether preoperative CA19-9 levels can predict stage of disease or survival and whether a change in preoperative to postoperative CA19-9 or the postoperative CA19-9 predicts overall survival.Four hundred twenty-four consecutive patients with pancreatic adenocarcinoma underwent resection between January 1, 1985 and January 1, 2004. Of the patients with a bilirubin less than 2 mg/dL, 176 had preoperative CA19-9 values, and 111 had pre- and postoperative CA19-9 values. Survival was measured from the first postoperative CA19-9 level measured (median, 39 days) until death or last follow-up. A multivariate failure time model was fit using clinical, operative, pathologic, and adjuvant treatment characteristics, and a categorization was defined by the values and changes in CA19-9 before and after surgery.Of the 176 patients, 128 (73%) had T3 lesions, and 99 (56%) had N1 disease; 138 patients (78%) underwent pancreaticoduodenectomy. Median preoperative CA19-9 levels were lower in N0 patients compared with patients with positive nodes (nine v 164 U/mL, respectively; nonparametric P = .06) and in T1/T2 patients versus T3 patients (41 v 162 U/mL, respectively; P = .03). Median follow-up time (n = 111) was 1.8 years (range, 1 to 12.9 years), with overall actuarial 1-, 3-, and 5-year survival rates of 70%, 36%, and 30%, respectively. Significant predictors of survival on multivariate analysis included a decrease in CA19-9 (P = .0005), negative lymph nodes (P = .001), lower T stage (P = .0008), and postoperative CA19-9 less than 200 U/mL (P = .0007).In patients with pancreatic adenocarcinoma, preoperative CA19-9 correlates with stage of disease. Both a postoperative decrease in CA19-9 and a postoperative CA19-9 value of less than 200 U/mL are strong independent predictors of survival, even after adjusting for stage. CA19-9 levels should be included in a patient's perioperative care and should be considered for prognostic nomograms.
Role of Heparanase in Radiation-Enhanced Invasiveness of Pancreatic Carcinoma
Authors: Amichay Meirovitz, Esther Hermano, Immanuel Lerner, Eyal Zcharia, Claudio Pisano, Tamar Peretz, Michael Elkin
Journal: Cancer Research (2011)

Abstract Pancreatic cancer is characterized by very low survival rates because of high intrinsic resistance to conventional therapies. Ionizing radiation (IR)–enhanced tumor invasiveness is emerging as one mechanism responsible for the limited benefit of radiotherapy in pancreatic cancer. In this study, we establish the role of heparanase—the only known mammalian endoglycosidase that cleaves heparan sulfate—in modulating the response of pancreatic cancer to radiotherapy. We found that clinically relevant doses of IR augment the invasive capability of pancreatic carcinoma cells in vitro and in vivo by upregulating heparanase. Changes in the levels of the transcription factor Egr-1 occurred in pancreatic cancer cells following radiation, underlying the stimulatory effect of IR on heparanase expression. Importantly, the specific heparanase inhibitor SST0001 abolished IR-enhanced invasiveness of pancreatic carcinoma cells in vitro, whereas combined treatment with SST0001 and IR, but not IR alone, attenuated the spread of orthotopic pancreatic tumors in vivo. Taken together, our results suggest that combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination, observed in many IR-treated pancreatic cancer patients. Further, the molecular mechanism underlying heparanase upregulation in pancreatic cancer that we identified in response to IR may help identify patients in which radiotherapeutic intervention may confer increased risk of metastatic spread, where antiheparanase therapy may be particularly beneficial. Cancer Res; 71(7); 2772–80. ©2011 AACR.
The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept
Authors: A. Jamnitski, G. M. Bartelds, M. T. Nurmohamed, P. A. van Schouwenburg, D. van Schaardenburg, S. O. Stapel, B. A. C. Dijkmans, L. Aarden, G. J. Wolbink
Journal: Annals of the Rheumatic Diseases (2010)

The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a second TNF inhibitor will be effective.This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab ('switchers'), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28).After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1 ± 1.3 vs ΔDAS28=2.0 ± 1.3; p = 0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.1 ± 1.3; p = 0.001) and switchers with antibodies (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.0 ± 1.3; p = 0.017).Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.
Improvement of abnormal lactulose/rhamnose permeability in active Crohn's disease of the small bowel by an elemental diet.
Authors: I R Sanderson, P Boulton, I Menzies, J A Walker-Smith
Journal: Gut (1987)

Intestinal permeability to sugar has been used as an objective measure of small bowel integrity to assess the efficacy of an elemental diet as the sole treatment or Crohn9s disease of the small bowel. Fourteen children aged 11-17 years with active small bowel Crohn9s disease were given an elemental diet for six weeks. Investigations with iso-osmolar oral test solutions before and after this treatment showed that all 14 children had abnormally raised lactulose/L-rhamnose permeability ratios, which fell significantly after the elemental diet. This change coincided with marked clinical improvement, as assessed by a disease activity index score.