tbuckley/cabot-search huggingface dataset:
Endothelin-1 contributes to maintenance of systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled trial
Authors: D Tripathi
Journal: Gut (2006)

<b>Background and aims:</b> Increased endothelin (ET)-1 activity may contribute to the complications of cirrhosis and portal hypertension. The aim of this study was to assess the systemic and portal haemodynamic effects of selective ET-A and ET-B receptor antagonism in patients with cirrhosis. <b>Methods:</b> Sixteen patients with cirrhosis and portal hypertension (aged 52 (1) years, Pugh score 6.2 (0.3)) underwent 24 studies with infusions of: (A) selective ET-A antagonist, BQ-123 (n = 8), at 1000 and 3000 nmol/min; (B) selective ET-B antagonist, BQ-788 (n = 8), at 100 and 300 nmol/min; or (C) matched saline placebo (n = 8) in a double blind randomised manner. Haemodynamic measurements were performed through pulmonary artery, hepatic venous, and femoral artery catheters. <b>Results:</b> Baseline patient characteristics were well matched. Compared with placebo, BQ-123 decreased mean arterial pressure (MAP −15 (11) mm Hg (−18%); p&lt;0.02) and pulmonary vascular resistance index (PVRI −81 (54) dyn×s×m<sup>2</sup>/cm<sup>5</sup> (−64%); p&lt;0.05), with no effect on hepatic venous pressure gradient (HVPG), cardiac index (CI), or systemic vascular resistance index (SVRI). Compared with placebo, BQ-788 increased MAP (+11 (3) mm Hg (+12%); p&lt;0.03) and SVRI (+1101 (709) dyn×s×m<sup>2</sup>/cm<sup>5</sup> (+50%); p&lt;0.05), reduced CI (−1.0 (0.4) l/min/m<sup>2</sup> (−29%); p = 0.05) with no effect on HVPG or PVRI. <b>Conclusions:</b> ET-1 contributes to maintenance of systemic and pulmonary haemodynamics without acutely affecting HVPG in patients with early cirrhosis. In this group of patients, the use of selective ET-A and ET-B antagonists for the management of variceal haemorrhage is likely to be limited.
<i>CPEB1</i>, a novel gene silenced in gastric cancer: a<i>Drosophila</i>approach
Authors: Joana Caldeira, Joana Simões-Correia, Joana Paredes, Marta T Pinto, Sónia Sousa, Giovanni Corso, Daniele Marrelli, Franco Roviello, Paulo S Pereira, Dominique Weil, Carla Oliveira, Fernando Casares, Raquel Seruca
Journal: Gut (2011)

<h3>Background</h3> Gastric cancer (GC) is a highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer-associated deaths worldwide. Although many genes have been implicated in its development, many cases remain genetically unexplained. Hence, there is an urgent need to find new disease-related genes. <h3>Methods</h3> A transgenic <i>Drosophila</i> model was used to screen for novel genes putatively involved in GC. The authors evaluated the expression of the most interesting candidates in GC cell lines and primary tumours by semi-quantitative reverse transcription PCR, dissected the molecular mechanisms responsible for the deregulation of the most relevant one, and analysed its functional role in vitro and in a chicken embryo model. <h3>Results</h3> Six candidate genes were identified, of which cytoplasmic polyadenylation element binding protein 1 (<i>CPEB1</i>) was downregulated in all GC cell lines and in 11 of 12 primary GC tumours. The pivotal <i>CPEB1</i> promoter CpG site was determined, and it was found that methylation at this 79th CpG site was associated with <i>CPEB1</i> silencing in GC cell lines and primary tumours. It was also discovered that methylation of this site was significantly more prevalent in diffuse type GC (p=0.007) and in cases with lymph node metastases (p=0.042). In vitro, <i>CPEB1</i> impaired invasion. Its antiangiogenic role was also discovered, which was associated with downregulation of <i>MMP14</i> and <i>VEGFA</i>. <h3>Conclusions</h3> The first evidence of <i>CPEB1</i> involvement in GC is presented, along with the molecular mechanism underlying the regulation of its expression and its potential role in invasion and angiogenesis.
The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.
Authors: A Daugherty, E Puré, D Delfel-Butteiger, S Chen, J Leferovich, S E Roselaar, D J Rader
Journal: Journal of Clinical Investigation (1997)

Activated T lymphocytes are present in human atherosclerotic lesions and autoantibodies to antigens within lesions have been detected in serum, but the roles of the cellular and humoral immune systems in atherogenesis have not been determined. The effect of total lymphocyte deficiency on atherogenesis was investigated by crossing apo E-deficient mice (which develop atherosclerosis resembling human disease) with mice deficient in RAG2 (which is required for normal B and T lymphocyte development). Mice were placed on a fat- and cholesterol-enriched diet for 12 wk. RAG2-deficient mice had no serum autoantibodies, in contrast to the high titers in RAG2+/- littermates. There were no T lymphocytes and a markedly reduced number of MHC class II-positive macrophages in atherosclerotic lesions of RAG2-deficient mice. Despite these differences, RAG2-deficient mice developed atherosclerosis similar in extent to that in immunocompetent littermates, based on quantification by two independent methods. In conclusion, the absence of autoantibodies and T lymphocytes did not influence the extent of aortic atherosclerotic lesions in apo E-deficient mice.
LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor
Authors: Xin-Jiang Lu, Jiong Chen, Chao-Hui Yu, Yu-Hong Shi, Yu-Qing He, Rui-Cheng Zhang, Zuo-An Huang, Ji-Neng Lv, Shun Zhang, Lei Xu
Journal: The Journal of Experimental Medicine (2012)

Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional cytokine and reduced plasma levels were found in patients with sepsis. However, precise functions and mechanisms of LECT2 remain unclear. The aim of the present study was to determine the role of LECT2 in modulating immune responses using mouse sepsis models. We found that LECT2 treatment improved outcome in mice with bacterial sepsis. Macrophages (MΦ), but not polymorphonuclear neutrophils, mediated the beneficial effect of LECT2 on bacterial sepsis. LECT2 treatment could alter gene expression and enhance phagocytosis and bacterial killing of MΦ in vitro. CD209a was identified to specifically interact with LECT2 and mediate LECT2-induced MΦ activation. CD209a-expressing MΦ was further confirmed to mediate the effect of LECT2 on sepsis in vivo. Our data demonstrate that LECT2 improves protective immunity in bacterial sepsis, possibly as a result of enhanced MΦ functions via the CD209a receptor. The modulation of MΦ functions by LECT2 may serve as a novel potential treatment for sepsis.
Early phenotypic activation of circulating helper memory T cells in scleroderma: correlation with disease activity.
Authors: U Fiocco, M Rosada, L Cozzi, C Ortolani, G De Silvestro, A Ruffatti, E Cozzi, C Gallo, S Todesco
Journal: Annals of the Rheumatic Diseases (1993)

The differential expression of several accessory/activation molecules (CD26, CD29, CD45RA, CD25, MLR4, HLA-DR) on peripheral blood CD4+ and CD8+ T lymphocytes in patients with scleroderma was compared with that in controls and patients with other connective systemic diseases to look for evidence of the involvement of T cells in the disease process of scleroderma. The two colour expression of surface molecules by circulating T cells was analysed with a panel of monoclonal antibodies and flow cytometry in 17 patients with scleroderma, 10 patients with systemic lupus erythematosus, and five patients with rheumatoid arthritis, and the results compared with those for 10 normal controls. The two colour T CD4+ phenotype was further compared between patients with active and quiescent disease in these patients with scleroderma. The coexpression of surface molecules by CD4+ T cells was also analysed by three colour flow cytometry in eight patients with scleroderma. Patients with scleroderma showed increased CD4+CD26+ and CD4+CD25+ percentages and absolute numbers and decreased CD8+CD29+ percentages compared with controls. Moreover, a significant correlation between the higher CD4+CD26+ T cell percentage and absolute cell numbers with disease activity was observed. Most of the CD4+ peripheral blood T cells from patients with scleroderma showed the CD26+CD45RA- phenotype by three colour flow cytometry analysis. The distinctive pattern of early helper memory T cell activation in these patients with rapidly evolving scleroderma supports the role of a T cell mediated mechanism in the progression of scleroderma.
c-Myb Is an Evolutionary Conserved miR-150 Target and miR-150/c-Myb Interaction Is Important for Embryonic Development
Authors: Y.-C. Lin, M.-W. Kuo, J. Yu, H.-H. Kuo, R.-J. Lin, W.-L. Lo, A. L. Yu
Journal: Molecular Biology and Evolution (2008)

Human c-Myb proto-oncogene is highly expressed in hematopoietic progenitors as well as leukemia and certain solid tumor. However, the regulatory mechanisms of its expression and biological functions remain largely unclear. Recently, c-Myb has been shown to be targeted by microRNA-150 (miR-150) which thereby controls B cell differentiation in mice. In this study, we demonstrated that c-Myb is an evolutionary conserved target of miR-150 in human and zebrafish, using reporter assays. Ectopic expression of miR-150 in breast cancer and leukemic cells repressed endogenous c-Myb at both messenger RNA (mRNA) and protein levels. Among several leukemia cell lines, primary leukemia cells, and normal lymphocytes, expression levels of miR-150 inversely correlated with c-Myb. The miR-150 overexpression or c-Myb silencing in zebrafish zygotes led to similar and serious phenotypic defects in zebrafish, and the phenotypic aberrations induced by miR-150 could be reversed by coinjection of c-Myb mRNA. Our findings suggest that c-Myb is an evolutionally conserved target of miR-150 and miR-150/c-Myb interaction is important for embryonic development and possibly oncogenesis.
Interstitial mononuclear cell populations in renal graft rejection. Identification by monoclonal antibodies in tissue sections
Authors: JL Platt, TW LeBien, AF Michael
Journal: The Journal of Experimental Medicine (1982)

The interstitial mononuclear cell populations of 22 renal grafts with interstitial rejection (IR), 6 grafts with interstitial nephritis without rejection (IN), and 5 kidneys without infiltration (3 donor kidneys, 2 grafts) were identified and quantitated by monoclonal antibodies recognizing T cells (TA-1, OKT3), helper inducer cells (OKT4), cytotoxic/suppressor cells (OKT8), B cells (BA-1), and monocytes and null cells (OKM1). Double-layer fluorochrome enhancement using F(ab')(2) reagents and nuclear counter staining with ethidium bromide enabled quantitation of the number of positive mononuclear cells, interstitial cells, and total cells on each of 30-55 microscopic fields per tissue section. T cells were the most abundant infiltrating cell in tissues with IR (35 +/- 9.8 percent), significantly higher than that seen in IN (21 +/- 16 percent) or in kidneys without infiltration (5.0 +/- 3.9 percent). The percentage of T cells identified by TA-1 or OKT3 was approximately equivalent to the summation of OKT4 plus OKT8. Although no differences were observed in the percentage of OKT4 cells, the percentage of OKT8 was significantly higher in IR (26 +/- 7.7 percent, P {less than} 10(-4)) than in IN (9.3 +/- 6.2 percent) or in kidneys with normal interstitium (3.0 +/- 2.4 percent). The ratio of OKT8/OKT4-positive T cells in 22 graft tissues with IR (3.2 +/- 1.4) was greater (P {less than} 0.0007) than 6 graft tissues with IN without rejection (0.82 +/- 0.39) and the 5 kidney tissues without interstitial infiltration (0.75 +/- 0.25). There was no significant difference between the groups in the relatively low percentage of interstitial cells identified as B cells reacting with BA-1 or containing S(IgD,M). The percentage of interstitial cells recognized by OKM1 was similar in rejection and interstitial nephritis, with both being greater than controls (P {less than} 0.02). The relative numbers of blood mononuclear cells identified by the monoclonal antibodies was generally not predictive of the proportions present in kidney tissue, although OKT4-positive blood cells were less numerous and OKMI+ blood cells were more numerous than in controls (P {less than} 0.002). Quantitative analysis of identifiable interstitial cells in graft rejection reveals that most infiltrating cells are T cells, the greater proportion of which are recognized by OKT8. OKT8-positive cells may play an important role in mediating renal graft rejection.
Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents
Authors: Magdalena Klanova, Lucie Lorkova, Ondrej Vit, Bokang Maswabi, Jan Molinsky, Jana Pospisilova, Petra Vockova, Cory Mavis, Lucie Lateckova, Vojtech Kulvait, Dana Vejmelkova, Radek Jaksa, Francisco Hernandez, Marek Trneny, Martin Vokurka, Jiri Petrak, Pavel Klener
Journal: Molecular Cancer (2014)

Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive. Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies. Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts. Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.
Brief Report: Successful In Vitro Culture of Rheumatoid Arthritis Synovial Tissue Explants at the Air–Liquid Interface
Authors: Koji Sakuraba, Kenjiro Fujimura, Yasuharu Nakashima, Ken Okazaki, Jun‐ichi Fukushi, Masanobu Ohishi, Akiko Oyamada, Yukio Esaki, Hisaaki Miyahara, Yukihide Iwamoto, Yasunobu Yoshikai, Hisakata Yamada
Journal: Arthritis & Rheumatology (2015)

To establish a method to culture synovial tissue explants from patients with rheumatoid arthritis (RA).Synovial tissue explants obtained from 10 patients with RA were cultured at the air-liquid interface or were submerged in culture medium. As a control, synovial explants were engrafted subcutaneously into SCID mice. The synovial explants were harvested at different time points, and histologic or flow cytometric analysis was performed. Cytokine levels in the culture supernatants were measured by enzyme-linked immunosorbent assay. Infliximab was added to the air-liquid interface culture to evaluate the effect of tumor necrosis factor α blockade on inflammatory cytokine production.The histologic features of RA synovitis, including a hyperplastic lining layer and the presence of cellular infiltrate in the sublining layer, were maintained in synovial tissue explants in air-liquid interface culture. In synovial grafts harvested from SCID-HuRAg mice, the cellular infiltrate was well maintained in the sublining, but the lining layer was lost. Viable CD4+ T cells and macrophages were abundant after air-liquid interface culture but were virtually absent after submerged culture. Furthermore, synovial tissue explants in air-liquid interface culture produced interleukin-6 (IL-6) and IL-8 for a prolonged period of time. The addition of infliximab effectively reduced cytokine production.RA synovial explants can be maintained for weeks using an air-liquid interface culture. This simple culture system might be useful for analyzing the pathogenesis of RA synovitis and for developing antirheumatic drugs.
What protection for the unborn child of a psychologically vulnerable adult?
Authors: E A J Beveridge, H Ananth, H J Scurlock
Journal: Journal of the Royal Society of Medicine (2003)

We describe a case that illustrates the difficulties of protecting the unborn children of ‘vulnerable adults’. These people are psychosocially vulnerable, but are not afforded the protection of the Mental Health Act 1983 because they do not have ‘treatable mental illness’.
Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells
Authors: Jie Zou, Peng Li, Fei Lu, Na Liu, Jianjian Dai, Jingjing Ye, Xun Qu, Xiulian Sun, Daoxin Ma, Jino Park, Chunyan Ji
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL). Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α) activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. Methods T-ALL cell lines (Jurkat, Sup-T1) transfected with HIF-1α or Notch1 small interference RNA (siRNA) were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. Results Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2) and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. Conclusions Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation, invasion and chemoresistance in T-ALL. Pharmacological inhibitors of HIF-1α or Notch1 signalling may be attractive interventions for T-ALL treatment.
Comparison of IgE Epitope Mapping By Peptide Microarray and a Novel Luminex-Based Peptide Assay
Authors: Gustavo Gimenez, Cansin Sackesen, Stephanie Schmidt, Robert C. Getts, Jim Kadushin, Jing Lin, George N. Konstantinou, Ebru Arik Yilmaz, Ozlem Cavkaytar, Ozge Soyer, Galina Grishina, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2015)
What to use INSTEAD of inhaled corticosteroids in COPD?
Authors: Peter M.A. Calverley
Journal: European Respiratory Journal (2014)

Inhaled corticosteroids (ICS) have had an important impact on the management of chronic obstructive pulmonary disease (COPD). When combined with an inhaled long-acting β-agonist (LABA), they improve lung function more than is the case with the LABA alone, improve health status and reduce the number of exacerbations patients experience [1]. There are data to suggest that they modify the decline in lung function and improve survival but these effects remain more controversial [1, 2]. There have always been concerns about the risks of developing osteoporosis or cataracts and even diabetes in COPD patients who use ICS drugs, although randomised controlled studies suggest that the impact of such changes are small in patients with more severe COPD [3]. However, there is now consistent evidence from randomised controlled trials that patients using fluticasone-based corticosteroids are more likely to develop pneumonia [4, 5]. The clinical significance of these events remains less certain [6, 7] as does the generalised ability of these findings to all ICS [8]. Nonetheless, concerns about the balance of the risks and benefits of ICS-based treatments has led to renewed interest in defining patients who could be managed as well with other therapies.

One way to establish whether ICS treatment should be continued is to stop it and see what happens. Early observational studies and randomised control trials suggested that acute withdrawal of ICS from the treatment regimen of COPD patients precipitated …
Lack of effect of N-acetylcysteine on the release of oxygen radicals from neutrophils and alveolar macrophages
Authors: E Drost, S Lannan, MM Bridgeman, D Brown, C Selby, K Donaldson, W MacNee
Journal: European Respiratory Journal (1991)

N-acetylcysteine (NAC) is rapidly de-acetylated in vivo to cysteine (CYSH), a precursor of glutathione (GSH) which is an antioxidant in cells and body fluids. We investigated the effect of oral administration of N-acetyl cysteine for 5 days on the spontaneous and stimulated generation of hydrogen peroxide (H2O2) and superoxide anion (O2-) from human and rat phagocytic leucocytes. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (BAL) in control rats and rats given NAC in their drinking water. Neutrophils (PMNL) were harvested from whole blood in normal nonsmoking volunteers before and after NAC was given by mouth. The stimulated release of H2O2 and O2 from both rat AM and human PMN was not changed by administration of NAC. However, a small but significant increase was observed in both the spontaneous generation of O2- from rat AM and the spontaneous generation of H2O2 from human PMNL. Administration of NAC significantly increased cysteine levels in human plasma and rat BAL, but the levels in human PMNL and rat AM after NAC did not differ from control levels. GSH levels were not altered significantly by NAC.