tbuckley/cabot-search huggingface dataset:
Pegylated interferon -2a versus standard interferon -2a for treatment-naive dialysis patients with chronic hepatitis C: a randomised study
Authors: C-H Liu, C-C Liang, J-W Lin, S-I Chen, H-B Tsai, C-S Chang, P-H Hung, J-H Kao, C-J Liu, M-Y Lai, J-H Chen, P-J Chen, J-H Kao, D-S Chen
Journal: Gut (2007)

Chronic hepatitis C virus (HCV) infection is prevalent in dialysis patients, and standard interferon monotherapy is the current standard of care for such patients.To investigate whether pegylated interferon has a better therapeutic efficacy and safety profile than standard interferon in dialysis patients with chronic hepatitis C.50 such patients were randomly assigned to receive either pegylated interferon alpha-2a 135 microg subcutaneously once per week or standard interferon alpha-2a 3 million units subcutaneously thrice per week for 24 weeks. The primary efficacy and safety end points were sustained virological response (SVR) by intention-to-treat analysis and treatment-related withdrawal rate during the study.In univariate analysis, patients receiving pegylated interferon alpha-2a tended to have a higher sustained virological response (SVR) than those receiving standard interferon alpha-2a (48% vs 20%, p = 0.07). By using multivariate analysis, treatment with pegylated interferon alpha-2a (p = 0.02) and pretreatment HCV RNA level <800 000 IU/ml (p = 0.007) were independently predictive of an SVR. All patients failing to achieve a rapid virological response (RVR) could not achieve an SVR. In addition, patients receiving pegylated interferon alpha-2a had a significantly lower treatment-related withdrawal rate than those receiving standard interferon alpha-2a (0% vs 20%, p = 0.04).Pegylated interferon alpha-2a once weekly provides more effective and safer therapy than standard interferon alpha-2a thrice weekly for treatment-naive dialysis patients with chronic hepatitis C.
Mucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy That Can Be Blocked with CTLA4-Ig
Authors: Katherine P. Ponder, Baomei Wang, Ping Wang, Xiucui Ma, Ramin Herati, Bin Wang, Karyn Cullen, Patty O'Donnell, N. Matthew Ellinwood, Anne Traas, Tina M. Primeau, Mark E. Haskins
Journal: Molecular Therapy (2006)

Although gene therapy has reduced manifestations of genetic diseases, immune responses can abrogate the effect. One approach to inducing tolerance is to perform gene transfer in newborns when the immune system is immature. We demonstrate here that the dose of retroviral vector (RV) is important in mice, as mucopolysaccharidosis I (MPS I) mice that received neonatal intravenous gene therapy with a high dose of a canine alpha-L-iduronidase (cIDUA)-expressing RV had stable expression, while those that received a low dose did not. It was unclear, however, if neonatal transfer with any dose could induce tolerance in large animals. Therefore, newborn MPS I cats were injected intravenously with the RV expressing cIDUA. Although this resulted in high serum IDUA activity due to secretion by transduced cells, expression fell due to a CTL response. Cats that transiently received the immunosuppressive agent CTLA4-Ig did not develop a CTL response. In contrast, MPS I dogs, which can respond immunologically to canine IDUA, had stable serum IDUA activity after neonatal gene therapy. We conclude that cats, but not dogs, mount a potent CTL response to canine IDUA after neonatal gene therapy, which can be prevented with transient CTLA4-Ig.
JunB inhibits proliferation and transformation in B-lymphoid cells
Authors: Agnieszka P. Szremska, Lukas Kenner, Eva Weisz, Rene G. Ott, Emmanuelle Passegué, Michaela Artwohl, Michael Freissmuth, Renate Stoxreiter, Hans-Christian Theussl, Sabina Baumgartner Parzer, Richard Moriggl, Erwin F. Wagner, Veronika Sexl
Journal: Blood (2003)
Organ-, inflammation- and cancer specific transcriptional fingerprints of pancreatic and hepatic stellate cells
Authors: Mert Erkan, Nadine Weis, Zheng Pan, Christian Schwager, Tamar Samkharadze, Xiaohua Jiang, Ute Wirkner, Nathalia A. Giese, Wilhelm Ansorge, Jürgen Debus, Peter E. Huber, Helmut Friess, Amir Abdollahi, Jörg Kleeff
Journal: Molecular Cancer (2010)

Abstract Background Tissue fibrosis is an integral component of chronic inflammatory (liver and pancreas) diseases and pancreatic cancer. Activated pancreatic- (PSC) and hepatic- (HSC) stellate cells play a key role in fibrogenesis. To identify organ- and disease-specific stellate cell transcriptional fingerprints, we employed genome-wide transcriptional analysis of primary human PSC and HSC isolated from patients with chronic inflammation or cancer. Methods Stellate cells were isolated from patients with pancreatic ductal adenocarcinoma (n = 5), chronic pancreatitis (n = 6), liver cirrhosis (n = 5) and liver metastasis of pancreatic ductal adenocarcinoma (n = 6). Genome-wide transcriptional profiles of stellate cells were generated using our 51K human cDNA microarray platform. The identified organ- and disease specific genes were validated by quantitative RT-PCR, immunoblot, ELISA, immunocytochemistry and immunohistochemistry. Results Expression profiling identified 160 organ- and 89 disease- specific stellate cell transcripts. Collagen type 11a1 ( COL11A1 ) was discovered as a novel PSC specific marker with up to 65-fold higher expression levels in PSC compared to HSC (p &lt; 0.0001). Likewise, the expression of the cytokine CCL2 and the cell adhesion molecule VCAM1 were confined to HSC. PBX1 expression levels tend to be increased in inflammatory- vs. tumor- stellate cells. Intriguingly, tyrosine kinase JAK2 and a member of cell contact-mediated communication CELSR3 were found to be selectively up-regulated in tumor stellate cells. Conclusions We identified and validated HSC and PSC specific markers. Moreover, novel target genes of tumor- and inflammation associated stellate cells were discovered. Our data may be instrumental in developing new tailored organ- or disease-specific targeted therapies and stellate cell biomarkers.
Erectile dysfunction: an overview
Authors: A Fabbri
Journal: Human Reproduction Update (1997)

Erectile dysfunction is a common (affecting 10-20 million men in the USA) and multifactorial disease due to organic and/or psychological factors that strongly impairs the quality of life in man. During the past decade many advances in the understanding of pathophysiology of erectile dysfunction have been made and new therapeutic strategies have become available. It has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardized approach for the diagnosis, and the treatment of choice, for erectile dysfunction, but is not widely accepted by the patients. The possibility of treating erectile dysfunction with intraurethral administration of prostaglandin-E1 has recently become available in the USA, and is a therapy more acceptable to the patients. Other non-invasive medical therapies are undergoing evaluation.
Treatment of lupus-prone NZB/NZW F<sub>1</sub>mice with recombinant soluble Fcγ receptor II (CD32)
Authors: S Werwitzke, D Trick, P Sondermann, K Kamino, B Schlegelberger, K Kniesch, A Tiede, U Jacob, R E Schmidt, T Witte
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Systemic lupus erythematosus (SLE) is a classical autoimmune disorder characterised by the production of IgG autoantibodies against double-stranded DNA (dsDNA). Activation of FcγR-bearing effector cells by immune complexes (ICs) is a key event in SLE pathogenesis as lupus-prone NZB/NZW F<sub>1</sub> hybrids lacking activating Fcγ receptors (FcγR) are protected against inflammatory kidney damage despite glomerular deposition of ICs. Moreover, soluble FcγRs inhibit IC-caused Arthus reaction <i>in vivo</i>. Therefore, recombinant human soluble FcγRII (CD32) was evaluated as a novel therapeutic strategy in lupus-like disease in NZB/NZW F<sub>1</sub> hybrids. <h3>Methods:</h3> Binding of husCD32 to murine IgG was studied <i>in vitro</i> by binding to IgG-coated erythrocytes and inhibition of phagocytosis of IgG-opsonised murine erythrocytes. In order to examine therapeutic impact of husCD32 <i>in vivo</i>, female NZB/NZW F<sub>1</sub> mice were treated either from week 16 to 20 ("prophylactic", 150 μg/week husCD32) or continuously from week 24 ("therapeutic"; 100 μg/week husCD32) by subcutaneous injections. Controls received buffered saline. <h3>Results:</h3> <i>In vitro</i> investigations of husCD32 revealed binding to murine erythrocytes coated with murine IgG. Moreover, husCD32 substantially diminished phagocytosis of murine IgG-opsonised murine red blood cells by peritoneal macrophages indicating disruption of IgG–FcγR interaction. There was a therapeutic efficacy of husCD32 to attenuate lupus pathology indicated by significantly delayed onset of proteinuria and weight loss, reduced histopathological findings, delayed development of anaemia and improved survival by prophylactical application. Therapeutic treatment did not reverse nephritis but significantly prolonged survival despite apparent kidney damage. B cell count, concentration of IgG anti-dsDNA autoantibodies and deposition of glomerular ICs was not significantly affected by the application of husCD32. <h3>Conclusions:</h3> The results demonstrate binding properties of husCD32 to ICs <i>in vitro</i> and as a proof-of-principle therapeutic efficacy in inhibiting chronic murine lupus pathology <i>in vivo</i>.
A1.86 The influence of TNFα on the expression of genes of the molecular clock in the synovial tissue
Authors: TM Becker, S Humpeler, Lvan Baarsen, D Gerlag, M Tohidast-Akrad, P Zenz, HP Kiener, C Ekmekcioglu, G Steiner
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) show modulated circadian rhythms of inflammatory cytokines and cortisol suggesting potential involvement of clock genes (CG) in the pathophysiology of RA. In our study we aimed to examine the expression and localization of clock genes in synovial tissues of patients with RA compared to the expression in samples of patients with osteoarthritis (OA). Additionally we investigated the expression of certain clock genes in the synovial tissue of RA or psoriatic arthritis (PsA) patients before and after administration of common TNF inhibitors. <h3>Methods</h3> Synovial fibroblasts (SFs) of patients with RA or OA were synchronised by serum shock or treated with TNFα and gene expression profiles of different CG were determined over 24 hours by real time PCR. The expression of CG in RA and PsA patients was determined before and after administration of TNF inhibitors by real time PCR. Additionally, the in situ expression of clock genes in synovial tissues was examined by immunohistochemistry. <h3>Results</h3> Immunohistochemical analysis revealed that CG are expressed in B-cells, macrophages and fibroblasts but not in T-cells of the synovial tissue but the percentage share of expressing cells is comparable between RA and OA patients. Furthermore we could show that cultured human SFs can be synchronised by TNF a and that this synchronization differs from the synchronization under standard conditions (serum shock). The inflammatory condition with TNFa leads to phase shifts in the expression profiles of some CG and therefore differences in the expressional intensity at different time points. However, the application of TNF blockers such as infliximab in RA patients or adalumimab in PsA patients had no effect on the expression patterns of CG in synovial tissue. Remarkably, a dramatic downregulation of most CG was observed 48 hrs after start of therapy, both in the inflimiximab and the placebo group which might be caused by the first biopsy (i.e. mechanical stress) performed immediately before start of therapy or, alternatively, be related to the fact that participation in the study may create a stressful situation for the hospitalised patient. This phenomenon would certainly deserve further investigation. <h3>Conclusion</h3> Although TNFα can modulate CG expression <i>in vitro</i>, expression of CG does not appear to be altered in synovial tissue of RA patients and CG expression is not affected by anti-TNF therapy.
Ly6C<sup>hi</sup>Monocytes Direct Alternatively Activated Profibrotic Macrophage Regulation of Lung Fibrosis
Authors: Michael A. Gibbons, Alison C. MacKinnon, Prakash Ramachandran, Kevin Dhaliwal, Rodger Duffin, Alexander T. Phythian-Adams, Nico van Rooijen, Christopher Haslett, Sarah E. Howie, A. John Simpson, Nikhil Hirani, Jack Gauldie, John P. Iredale, Tariq Sethi, Stuart J. Forbes
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial.To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved.We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice.We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.
The effect of adalimumab on key drivers in the pathogenesis of psoriasis
Authors: A.G.M. Hendriks, H.M.J. van der Velden, E.A.W. Wolberink, M.M.B. Seyger, J. Schalkwijk, P.L.J.M. Zeeuwen, E.M.G.J. de Jong, M.C. Pasch, P.E.J. van Erp, P.C.M. van de Kerkhof
Journal: British Journal of Dermatology (2013)

The use of recently introduced biologics targeting specific immune mechanisms has identified crucial steps in the pathogenesis of psoriasis. Studying the dynamics of changes of these target mechanisms in sequential skin biopsies during treatment with biologics may reveal potential biomarkers. Correlation between clinical parameters and the expression of specific genes during treatments may identify markers indicative of treatment response.This observational open-label study aimed to provide an overview of important cell biological changes in lesional skin during treatment with adalimumab, and their relationship to clinical improvement.Ten patients with moderate-to-severe plaque psoriasis were included and treated with adalimumab for 16 weeks. At baseline, and after 10 days and 16 weeks of treatment clinical scores were assessed and biopsies were taken to examine gene expression at the mRNA and protein level.The expression of marker genes for innate immunity, and epidermal differentiation and proliferation was rapidly restored to normal levels, whereas genes of the adaptive immune system showed a delayed decrease. The static and dynamic course of CD1a+ Langerhans cells and Ki67+ nuclei showed a significant strong correlation to the Psoriasis Area and Severity Index score. No correlation between interleukin-17 expression and clinical scores was found.The innate immune system is affected during adalimumab treatment well before the changes in the adaptive immune system become apparent. We may speculate that the addition of a treatment with an early effect on adaptive immunity to adalimumab may result in superior effectiveness compared with monotherapies.
Ramifications of screening for breast cancer: Overdiagnosis in the Malmö trial was considerably underestimated
Authors: Peter C Gøtzsche
Journal: BMJ (2006)

Ramifications of screening for breast cancerSee Research p 689 in 4 cancers detected by mammography are pseudocancersEditor-In this issue Zackrisson et al report on follow-up data from the Malmö mammographic screening trial and conclude that the rate of overdiagnosis of breast cancer was 10%. 1 They do not, however, calculate the risk we believe is most relevant to women considering mammography: What is the chance that a screen detected cancer represents overdiagnosis?After 15 years of follow-up, there were 1320 diagnosed in the screened group and 1205 in the control group (table 1).The excess detection of 115 cancers associated with screening led to their conclusion of an overdiagnosis rate of 10% (115/1205).However, because the intervention had stopped 15 years earlier and yet breast cancer cases continue to accumulate in both groups, the approach understates the risk of overdiagnosis.A more relevant denominator is the number of cancers found in the screened group at the end of the trial-741 (table 2).This addresses the question: Were I found to have cancer after being randomised to screening, how likely is it to represent overdiagnosis?As shown in the figure, using this denominator the risk of overdiagnosis is 15% (115/741).However, many of the cancers detected in the screened group are not detected by screening.They are instead clinically detected (either during the interval between screening examinations or among nonattenders).The most relevant denominator is the number of screen detected cancers found at the end of the trial.This addresses the question: Were I found to have cancer by a mammogram, how likely is it to represent overdiagnosis?Although this denominator is not reported by Zackrisson et al, the original BMJ article describing Malmö reported that 64% of the cancers detected in the screened group were detected by screening mammography. 2Thus one can deduce that the number of screen detected cancers at the end of the trial was about 475.As shown in the figure, using this denominator the risk of overdiagnosis is 24% (115/475).
Oesophageal function before, during, and after healing of erosive oesophagitis.
Authors: F Baldi, F Ferrarini, A Longanesi, M Angeloni, M Ragazzini, M Miglioli, L Barbara
Journal: Gut (1988)

In order to investigate the relationship between oesophageal motor abnormalities and oesophagitis, we carried out four hour studies of oesophageal motility and 24 hour pH measurements in fasting and fed conditions in eight patients before, during (pH only), and after medical healing of erosive oesophagitis. Gastrooesophageal acid reflux decreased (ns) during the treatment, but tended to return to basal values at the end. Oesophageal body motility was unchanged after healing, while the lower oesophageal sphincter basal tone was significantly increased at the end of the study in the postcibal period. The results suggest that the impairment of the sphincter tone in reflux oesophagitis is secondary to the presence of the oesophageal lesions. Macroscopic healing is not paralleled by improved major pathogenic factors of the disease, however--that is, acid reflux and oesophageal body motility.
Molecular Biology of Digestive Disease
Authors: I D Ansell
Journal: BMJ (1994)

Ed Philip Quirke BMJ/Gut, pounds sterling 12.95, pp 116 ISBN 0-7279-0827-8

Hardly a week goes by these days without an announcement that the gene for such and such a disease has been discovered or that gene therapy is being used for the first time in a certain inherited condition. In the past year or two technological developments have made molecular biology much easier, quicker, and cheaper to use for investigating disease processes and it is becoming widely used …
Toward extending the relational priming model: Six questions
Authors: Eric Dietrich
Journal: Behavioral and Brain Sciences (2008)

Abstract Six questions are posed that are really specific versions of this question: How can Leech et al.'s system be extended to handle adult-level analogies that frequently combine concepts from semantically distant domains sharing few relational labels and that involve the production of abstractions? It is Leech et al. who stress development; finding such an extension would seem to have to be high on their priority list.
Adrian Llewellyn Thomas
Authors: David Thomas
Journal: BMJ (2004)

Former general practitioner Southampton (b Leicester 1933; q Birmingham 1956; DObst RCOG 1958), died from lung cancer on 27 April 2004.​2004.




Figure 1




At Birmingham University Adrian was awarded a rugby blue. With general practice in mind he took an obstetric post in Solihull and obtained the DRCOG. In Witney, Oxfordshire, and from 1970 in Southampton he thoroughly enjoyed general practice. He was medical officer to Hampshire County Cricket Club for several years. Adrian loved sailing, walking, and caravanning with his family. He leaves a wife, Joyce; four children; and nine grandchildren.
Nuclear Localization of Nuclear Factor-κB p65 in Primary Prostate Tumors Is Highly Predictive of Pelvic Lymph Node Metastases
Authors: Laurent Lessard, Pierre I. Karakiewicz, Pascale Bellon-Gagnon, Mona Alam-Fahmy, Hazem A. Ismail, Anne-Marie Mes-Masson, Fred Saad
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Lymph node invasion (LNI) is associated with increased risk of prostate cancer progression. Unfortunately, pelvic lymph node dissections are fraught with a high rate of false-negative findings, emphasizing the need for highly accurate markers of LNI. Because nuclear factor-κB (NF-κB) is a candidate marker of prostate cancer progression, we tested the association between nuclear localization of NF-κB in radical prostatectomy specimens and the presence of LNI. Experimental Design: NF-κB expression in radical prostatectomy specimens was assessed with a monoclonal NF-κB p65 antibody, in 20 patients with LNI and in 31 controls with no LNI and no biochemical relapse 5 years after radical prostatectomy. Univariate and multivariate logistic regression models were used. The accuracy of multivariate predictions with and without NF-κB was quantified with the area under the receiver operating characteristics curve and 200 bootstrap resamples were used to reduce overfit bias. Results: Univariate regression models showed a 7% increase in the odds of observing LNI for each 1% increase in NF-κB nuclear staining (odds ratio, 1.07; P = 0.003). In multivariate models, each 1% increase in NF-κB was associated with an 8% increase in the odds of LNI (odds ratio, 1.08; P = 0.03) and its statistical significance was only surpassed by the presence of seminal vesicle invasion (P = 0.003). Addition of NF-κB to all other predictors increased the accuracy of LNI prediction by 2.3% (from 84.8% to 87.1%; P &amp;lt; 0.001). Conclusion: This is the first study that shows that the extent of nuclear localization of NF-κB in primary prostate tumors is highly accurately capable of predicting the probability of locoregional spread of prostate cancer.