tbuckley/cabot-search huggingface dataset:
Association of C-Reactive Protein With Cardiovascular Disease Mortality According to Diabetes Status
Authors: Andre Pascal Kengne, G. David Batty, Mark Hamer, Emmanuel Stamatakis, Sébastien Czernichow
Journal: Diabetes Care (2011)

OBJECTIVE C-reactive protein (CRP) is associated with the risk of cardiovascular disease (CVD); whether the effects are modified by diabetes status still is unclear. This study investigated these issues and assessed the added value of CRP to predictions. RESEARCH DESIGN AND METHODS Participants were drawn from representative samples of adults living in England and Scotland. Cox proportional hazards regression models were used to relate baseline plasma CRP with all-cause and CVD mortality during follow-up in men and women with and without diabetes. The added value of CRP to the predictions was assessed through c-statistic comparison and relative integrated discrimination improvement. RESULTS A total of 25,979 participants (4.9% with diabetes) were followed for a median of 93 months, during which period there were 2,767 deaths (957 from CVD). CRP (per SD loge) was associated with a 53% (95% CI 43–64) and 43% (38–49) higher risk of cardiovascular and all-cause mortality, respectively. These associations were log linear and did not differ according to diabetes status (both P ≥ 0.08 for interaction), sex, and other risk factors. Adding CRP to conventional risk factors improved predictions overall and separately by diabetes status but not for CVD mortality, although such improvements only were marginal based on several discrimination statistics. CONCLUSIONS The association between CRP and CVD was similar across diabetes status, and the effects are broadly similar across levels of other conventional risk factors.
Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid
Authors: Rüdiger Popp, Ralf P. Brandes, Gregor Ott, Rudi Busse, Ingrid Fleming
Journal: Circulation Research (2002)

Functional gap junctional communication between vascular cells has been implicated in ascending dilatation and the cytochrome P-450 (CYP) inhibitor–sensitive and NO- and prostacyclin-independent dilatation of many vascular beds. Here, we assessed the mechanisms by which the epoxyeicosatrienoic acids (EETs) generated by a CYP 2C enzyme control interendothelial gap junctional communication. In CYP 2C–expressing porcine coronary endothelial cells, bradykinin, which enhances EET formation, elicited a biphasic effect on the electrical coupling and transfer of Lucifer yellow between endothelial cells, consisting of a transient increase in coupling followed by a sustained uncoupling. The initial phase was sensitive to the CYP 2C9 inhibitor sulfaphenazole and the protein kinase A (PKA) inhibitors Rp-cAMPS and KT5720 and could be mimicked by forskolin and caged cAMP as well as by the PKA activators 5,6-dichloro-1-β- d -ribofuranosylbenzimidazole 3′,5′-cyclic monophosphorothioate sodium salt and Sp-cAMPS. Gap junction uncoupling in bradykinin-stimulated porcine coronary endothelial cells was prevented by inhibiting the activation of extracellular signal–regulated kinase (ERK)1/2. In human endothelial cells, which express little CYP 2C, bradykinin elicited only an ERK1/2-mediated inhibition of intercellular communication. The CYP 2C9 product, 11,12-EET, also exerted a dual effect on the electrical and dye coupling of human endothelial cells, which was sensitive to PKA inhibition. These results demonstrate that an agonist-activated CYP-dependent pathway as well as 11,12-EET can positively regulate interendothelial gap junctional communication, most probably via the activation of PKA, an effect that is curtailed by the subsequent activation of ERK1/2.
Homeoprotein Six2 Promotes Breast Cancer Metastasis via Transcriptional and Epigenetic Control of E-Cadherin Expression
Authors: Chu-An Wang, David Drasin, Catherine Pham, Paul Jedlicka, Vadym Zaberezhnyy, Michelle Guney, Howard Li, Raphael Nemenoff, James C. Costello, Aik-Choon Tan, Heide L. Ford
Journal: Cancer Research (2014)

Abstract Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin. Cancer Res; 74(24); 7357–70. ©2014 AACR.
Defining race/ethnicity and explaining difference in research studies on lung function
Authors: Lundy Braun, Melanie Wolfgang, Kay Dickersin
Journal: European Respiratory Journal (2012)

The 2005 guidelines of the American Thoracic Society/European Respiratory Society recommend the use of race- and/or ethnic-specific reference standards for spirometry. Yet definitions of the key variables of race and ethnicity vary worldwide. The purpose of this study was to determine whether researchers defined race and/or ethnicity in studies of lung function and how they explained any observed differences. Using the methodology of the systematic review, we searched PubMed in July 2008 and screened 10 471 titles and abstracts to identify potentially eligible articles that compared "white" to "other racial and ethnic groups". Of the 226 eligible articles published between 1922 and 2008, race and/or ethnicity was defined in 17.3%, with the proportion increasing to 70% in the 2000s for those using parallel controls. Most articles (83.6%) reported that "other racial and ethnic groups" have a lower lung capacity compared to "white"; 94% of articles failed to examine socioeconomic status. In the 189 studies that reported lower lung function in "other racial and ethnic groups", 21.8% and 29.4% of explanations cited inherent factors and anthropometric differences, respectively, whereas 23.1% of explanations cited environmental and social factors. Even though researchers sought to determine differences in lung function by race/ethnicity, they typically failed to define their terms and frequently assumed inherent (or genetic) differences.
Eosinophilia in transgenic mice expressing interleukin 5.
Authors: L A Dent, M Strath, A L Mellor, C J Sanderson
Journal: The Journal of Experimental Medicine (1990)

Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.
A Novel Cytoplasmic Protein with RNA-binding Motifs Is an Autoantigen in Human Hepatocellular Carcinoma
Authors: Jian-Ying Zhang, Edward K.L. Chan, Xuan-Xian Peng, Eng M. Tan
Journal: The Journal of Experimental Medicine (1999)

In hepatocellular carcinoma (HCC), autoantibodies to intracellular antigens are detected in 30–40% of patients. Patients with chronic hepatitis or liver cirrhosis develop HCC, and when this occurs, some patients exhibit autoantibodies of new specificities. It has been suggested that these novel autoantibody responses may be immune system reactions to proteins involved in transformation-associated cellular events. One HCC serum shown to contain antibodies to unidentified cellular antigens was used to immunoscreen a cDNA expression library, and a full length cDNA clone was isolated with an open reading frame encoding 556 amino acids with a predicted molecular mass of 62 kD. The 62-kD protein contained two types of RNA-binding motifs, the consensus sequence RNA–binding domain (CS-RBD) and four hnRNP K homology (KH) domains. This protein, provisionally called p62, has close identity (66–70%) to three other proteins at the amino acid sequence level, and all four proteins may belong to a family having CS-RBD in the NH2-terminal region and four KH domains in the mid-to-COOH– terminal region. The homologous proteins are: KH domain–containing protein overexpressed in cancer (Koc); zipcode binding protein, a protein which binds to a conserved nucleotide element in chicken β-actin mRNA (ZBP1); and a protein which binds to a promoter cis element in Xenopus laevis TFIIIA gene (B3). p62 protein is cytoplasmic in location, and autoantibodies were found in 21% of a cohort of HCC patients. Patients with chronic hepatitis and liver cirrhosis, conditions which are frequent precursors to HCC, were negative for these autoantibodies, suggesting that the immune response might be related to cellular events leading to transformation. However, the possible involvement of p62 autoantigen as a factor in the transformation process remains to be elucidated.
Persistent activation of dermal fibroblasts from patients with gadolinium-associated nephrogenic systemic fibrosis
Authors: Sonsoles Piera-Velazquez, Natalia Louneva, Jolanta Fertala, Peter J Wermuth, Francesco Del Galdo, Sergio A Jimenez
Journal: Annals of the Rheumatic Diseases (2010)

Background Nephrogenic systemic fibrosis (NSF) is a systemic fibrotic disorder occurring in some patients with renal insufficiency after exposure to gadolinium-based contrast agents (GdBCA). Objectives To examine cultured NSF dermal fibroblast production and expression of collagens I and III, fibronectin, hyaluronic acid and α-smooth muscle actin (α-SMA) during serial passages and the effects of two GdBCA on collagen gene expression and production by normal dermal fibroblasts. Methods NSF fibroblasts were analysed for expression and production of types I and III collagen, fibronectin, hyaluronic acid and α-SMA. Collagen, type I, α1 (COL1A1) promoter transcription was examined in transient transfections. Nuclear extracts were assayed for binding activity of 108 transcription factors, and specific transcription factor binding was examined by electrophoretic gel mobility assays. Normal fibroblasts were cultured with GdBCA, and collagen expression assessed by real-time PCR and western blots. Results NSF fibroblasts displayed a marked increase in collagens I and III, fibronectin and hyaluronic acid production, which was maintained for 9–11 subpassages in vitro. NSF fibroblasts also showed a marked increase in α-SMA expression, twofold higher transcriptional activity of the COL1A1 promoter and increased cREL binding in nuclear extracts compared with normal fibroblasts. GdBCA induced a dose-dependent stimulation of COL1A1 expression and production of type I collagen in normal fibroblasts. Conclusions Fibroblasts from patients with NSF displayed a markedly profibrotic phenotype, which was maintained for several passages in culture. Elevated COL1A1 expression was mediated by transcriptional activation of its promoter associated with increased cREL binding activity. GdBCA stimulated cultured normal fibroblasts to produce increased amounts of collagen.
A8.4 IL4–10 synerkine: a novel anti-inflammatory drug to inhibit immunopathology in inflammatory rheumatic diseases
Authors: SAY Hartgring, C Steen-Louws, M De Smet, CE Hack, JAG van Roon
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> A considerable percentage of patients shows a limited response to biologics targeting one specific inflammatory mediator, largely because of redundancy of these mediators. An attractive alternative is inhibition of multiple proinflammatory mediators and induction of immunoregulatory activity by regulatory cytokines such as IL4 and IL10. Many studies demonstrated the strong capacity of IL4 and IL10 as stand-alone drugs to inhibit inflammation and tissue-destructive responses in animal and human <i>in vitro</i> models. Clinical results of these cytokines, however, have been modest, possibly because of poor bioavailability that is mainly due to low molecular weight and rapid renal clearance. <h3>Objectives</h3> To execute a feasibility study to develop IL4 and IL10 as one biologic (called IL4–10 synerkine), preserving distinct characteristics of each molecule plus improving bioavailablity by increasing the molecular size. <h3>Materials and methods</h3> Biochemical properties of IL4–10 synerkine were determined by western blot, size exclusion chromatography, and ELISA. Functional properties were studied by measuring the capacity of IL4–10 synerkine to regulate production of pro-inflammatory cytokines and their inhibitors, as well as proinflammatory and regulatory T-cell activity, and expression of Fc receptors. In addition, blockade of IL4 and IL10 receptor was performed to confirm the specific activities of IL4 and IL10. <h3>Results</h3> IL4–10 synerkine appeared as a glycosylated dimeric protein with a molecular size of ˜70 kDa, consisted of intact IL10 and IL4 subunits. In whole blood assays IL4–10 synerkine robustly and dose-dependently inhibited multiple pro-inflammatory cytokines, which was almost complete at 20 ng/ml (IL1β, TNFα, IL6 and IL8, all p &lt; 0.001). This effect was dependent on interaction with IL10R and IL4R. Oppositely, the synerkine significantly induced production of IL1RA and preserved sTNFR levels. IL4–10 synerkine strongly inhibited Th1 and Th17 cytokine secretion (P &lt; 0.01), while maintaining FoxP3 expression. Finally, while IL4 upregulated FcεR expression and IL10 upregulated expression of activating FcγRs on monocytes (all p &lt; 0.001), both Fcε and FcγR expression were largely preserved at control levels in the presence of IL4–10 synerkine (all at least p &lt; 0.01). <h3>Conclusions</h3> IL4–10 synerkine is a novel anti-inflammatory drug that shifts multiple proinflammatory pathways towards immunoregulation. The increased molecular mass predicts better bioavailabilty in humans than the wild-type molecules, which potentially enhances its clinical efficacy. The strong and improved inhibitory activities of IL4–10 synerkine (as compared to IL4 and IL-10 monotherapy) that we observed in several animal models for inflammatory pain underscores the potential for treatment of inflammatory and possibly degenerative rheumatic diseases.
Re: Orazio Caffo, Ugo De Giorgi, Lucia Fratino, et al. Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. Eur Urol 2015;68:147–53
Authors: Kevin Lu
Journal: European Urology (2015)
Inspiratory muscle relaxation rate assessed from sniff nasal pressure.
Authors: D Kyroussis, G Mills, C H Hamnegard, S Wragg, J Road, M Green, J Moxham
Journal: Thorax (1994)

Slowing of the maximum relaxation rate (MRR) of inspiratory muscles measured from oesophageal pressure (POES) during sniffs has been used as an index of the onset and recovery of respiratory muscle fatigue. The purpose of this study was to measure MRR at the nose (PNASAL MRR), to investigate its relationship with POES MRR, and to establish whether PNASAL MRR slows with respiratory loading.Five normal subjects were studied. Each performed sniffs before and after two minutes of maximal isocapnic ventilation (MIV). In a separate session the subjects performed submaximal sniffs. POES and PNASAL were recorded during sniffs and the MRR (% pressure fall/10 ms) for each sniff was determined.Before MIV mean POES MRR was 8.9 and PNASAL MRR was 9.3. The mean (SD) difference between PNASAL MRR and POES MRR during a maximal sniff was 0.48 (0.34) (n = 64) and during submaximal sniffs was 0.28 (0.46) (n = 526). The subjects showed a mean decrease in sniff POES MRR of 27.4% (range 22.5-36%) after MIV and a similar reduction in sniff PNASAL MRR of 28.5% (range 24.1-41.3%). Both returned to control values within 5-10 minutes.PNASAL MRR reflects POES MRR over a wide range of sniff pressures, PNASAL MRR of maximal sniffs reflects POES MRR in normal subjects at rest and following MIV, so measurement of PNASAL MRR may be a useful non-invasive method for measuring inspiratory muscle MRR, thereby providing an index of respiratory muscle fatigue.
Temporal changes in magnetic resonance imaging characteristics of Gliadel wafers and of the adjacent brain parenchyma
Authors: S. Ulmer, K. Spalek, A. Nabavi, S. Schultka, H. M. Mehdorn, S. Kesari, L. Dorner
Journal: Neuro-Oncology (2012)

Carmustine is used in the treatment of glioblastomas as locally applied chemotherapy in the form of biodegradable wafers, which are lined on the walls of the resection cavity at the end of the resection, to increase local concentrations and decrease systemic toxicity. A total of 44 patients with glioblastoma with gross macroscopic tumor removal were included. MRIs were performed at various times postoperatively (within 24 hours, 1 week, 1 month, 2 months, 3 months, 6 months, 9 months, and 1 year). MR protocols included a T2-, diffusion-weighted, and T1-weighted sequences with and without intravenous administration of gadolinium. On T1, the wafers change from their initial hypointense to an isointense appearance after a period during which they appear to be hypointense, with a hyperintense rim most prominent less than 1 month postoperatively. On T2 they change from a hypointense to an isointense appearance. Restricted diffusivity reshaping the silhouette of the wafer's surface at the rim of the resection cavity can be found as early as day 1 postoperatively; however, 1 month after implantation, they all show areas of restricted diffusion, which may remain up to 1 year. Contrast enhancement at the rim of the resection cavity can already be found at day 1 postoperatively, with a peak shortly after 1 month after surgery. These changes can easily be mistaken for an abscess and hamper the early differentiation between residual tumor tissue and normal postoperative changes. However, early changes in either appearance do not predict overall survival or the progression free interval.
Enhanced inhibition of lymphocyte activation by Mycobacterium avium complex in human T lymphotrophic virus type I carriers
Authors: W Matsuyama
Journal: Thorax (2001)

<h3>BACKGROUND</h3> We have previously reported that disseminated pulmonary<i>Mycobacterium avium </i>complex (MAC) infection is more common in human T lymphotrophic virus type I (HTLV-I) carriers than in non-carriers. However, the reason for this remains unclear. It has been shown that glycopeptidelipid (GPL), one of the lipid components of the cell envelope of MAC, is able to reduce the lymphocyte blastogenic response to mitogens. The purpose of this study was to clarify whether or not the inhibitory effect of GPL differs between HTLV-I carriers and non-carriers. <h3>METHODS</h3> Peripheral blood lymphocytes were obtained from 29 patients who had recovered from pulmonary MAC infection (10 of whom also had HTLV-I infection) and the lymphocyte counts and T cell subpopulations of the peripheral blood lymphocytes in HTLV-I carriers and non-carriers were compared. The inhibitory effect of GPL on the lymphocyte blastogenic response to phytohaemagglutinin (PHA) was tested in these 29 cases and in 15 healthy controls who had never suffered from MAC (seven of whom also had HTLV-I infection). All HTLV-I positive cases were carriers. <h3>RESULTS</h3> There was no significant difference in the numbers or subset proportions of T cells between HTLV-I carriers and non-carriers. Lymphocyte activation by PHA was significantly inhibited by GPL in MAC positive and negative HTLV-I carriers compared with MAC negative non-carriers and MAC negative healthy controls (p&lt;0.001). <h3>CONCLUSIONS</h3> We suggest that MAC infection leads to strong inhibition of lymphocyte activation in HTLV-I carriers. This may account, in part, for the severity of pulmonary MAC infection in HTLV-I carriers.
Preferential induction of polyclonal IgA secretion by murine Peyer's patch dendritic cell-T cell mixtures.
Authors: D M Spalding, S I Williamson, W J Koopman, J R McGhee
Journal: The Journal of Experimental Medicine (1984)

Polyclonal IgA secretion is inducible in murine B cells when DC-T from Peyer's patches (PP) provide the inducing stimulus. PP DC-T, which are composed predominantly of dendritic cells and Lyt-1+ T cells, are capable of dramatic augmentation of IgA secretion by PP or spleen B cells with minimal induction of IgM secretion. DC-T from spleen, however, are incapable of augmenting IgA secretion by either PP or spleen B cells. The level of IgA secretion is dependent upon the dose of DC-T providing the inducing stimulus and reaches a plateau with DC-T:B ratios of less than 1:1. This system for preferential induction of IgA responses should permit elucidation of cellular mechanisms involved in regulation of IgA secretion.