tbuckley/cabot-search huggingface dataset:
Traffic-related air pollution in relation to respiratory symptoms, allergic sensitisation and lung function in schoolchildren
Authors: M Rosenlund, F Forastiere, D Porta, M De Sario, C Badaloni, C A Perucci
Journal: Thorax (2008)

Urban air pollution can trigger asthma exacerbations, but the effects of long-term exposure to traffic-related air pollution on lung function or onset of airway disease and allergic sensitisation in children is less clear.All 2107 children aged 9-14 years from 40 schools in Rome in 2000-1 were included in a cross-sectional survey. Respiratory symptoms were assessed on 1760 children by parental questionnaires (response rate 83.5%). Allergic sensitisation was measured by skin prick tests and lung function was measured by spirometry on 1359 children (77.2%). Three indicators of traffic-related air pollution exposure were assessed: self-reported heavy traffic outside the child's home; the measured distance between the child's home and busy roads; and the residential nitrogen dioxide (NO2) levels estimated by a land use regression model (R2 = 0.69).There was a strong association between estimated NO2 exposure per 10 microg/m3 and lung function, especially expiratory flows, in linear regression models adjusted for age, gender, height and weight: -0.62% (95% CI -1.05 to -0.19) for forced expiratory volume in 1 s as a percentage of forced vital capacity, -62 ml/s (95% CI -102 to -21) for forced expiratory flow between 25% and 75% of forced vital capacity and -85 ml/s (95% CI -135 to -35) for peak expiratory flow. The other two exposure indicators showed similar but weaker associations. The associations appeared stronger in girls, older children, in children of high socioeconomic status and in those exposed to parental smoking. Although lifetime asthma was not an effect modifier, there was a suggestion of a larger effect on lung function in subjects with a positive prick test. Multiple logistic regression models did not suggest a consistent association between traffic-related air pollution exposure and prevalence of respiratory symptoms or allergic sensitisation.The results of this study suggest that residential traffic-related air pollution exposure is associated with reduced expiratory flows in schoolchildren.
Molecular detection and monitoring of cancer using tumor-derived DNA in plasma
Authors: Yuk Ming Dennis Lo
Journal: Clinical Cancer Research (2006)

KN-02   Recently, much interest has been focused on the use of nucleic acids that are released by tumor cells into the plasma of cancer patients. My group has focused on the use of this approach for cancers which are particularly common in South China, especially nasopharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC). NPC is a particularly attractive target for this approach because virtually all cases of NPC in South China are associated with Epstein-Barr virus (EBV) infection. We have demonstrated that EBV DNA is present in high concentrations in the plasma of most NPC patients. Furthermore, the concentration of plasma EBV DNA is a powerful prognosticator, both at presentation and following treatment. With regard to the biophysical characterization of circulating EBV DNA, we have shown that these molecules consist of short DNA fragments instead of complete virions. This observation might be related to the mode of release of EBV DNA into the plasma, for example, as a result of tumoral cell death. For HCC, we have focused on the use of aberrant DNA methylation as a tumor marker in plasma.In addition to plasma DNA, my group has also demonstrated that RNA is readily detectable in human plasma. Furthermore, such plasma RNA molecules are surprisingly stable, possibly protected from plasma RNase digestion through association with particulate matter. As a consequence, tumor-derived RNA molecules have been reported by a number of groups in the plasma of cancer patients. Tumor-associated targets which have been reported to date include EBV RNA, tyrosinase mRNA, beta-catenin mRNA, etc. My group has also demonstrated that such plasma RNA molecules are partially degraded, with a predominance of the 59 ends of the molecules. This latter observation is probably a consequence of the fact that most mammalian RNases work from the 39 direction. A measurement of the ratio of concentrations of the 59 and 39 sequences of mRNA in plasma is therefore an indication of plasma RNA integrity. Furthermore, plasma RNA integrity has been found to be decreased in NPC patients and to be normalized following radiotherapy. This latter observation suggests that plasma RNA integrity may be a new tumor marker.The potential functionality of circulating nucleic acids is one area which has been debated, but where no definite empirical answer has emerged to date.
RECOMBINATION OF ANTIBODY POLYPEPTIDE CHAINS IN THE PRESENCE OF ANTIGEN
Authors: Henry Metzger, Mart Mannik
Journal: The Journal of Experimental Medicine (1964)

Conditions were developed by which the separated H and L chains of gamma2 globulins recombined to form four-chained molecules in good yields. In the absence of antigen, anti-2,4-dinitrophenyl (anti-DNP) H chains randomly reassociated with a mixture of antibody and non-specific gamma2 globulin L chains. In the presence of a specific hapten, however, the antibody H chains preferentially interacted with the anti-DNP L chains. Antibody H chain-antibody L chain recombinants formed in the presence of hapten were more active than the corresponding recombinants formed in the absence of hapten. Speculations are made regarding the possible mechanisms and biological significance of these effects.
Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action
Authors: T. M. Penning
Journal: Human Reproduction Update (2003)

Steroid target tissues regulate the local level of steroid hormone that can bind and trans‐activate nuclear receptors (a process known as intracrine modulation). This pre‐receptor regulation can be achieved by hydroxysteroid dehydrogenases (HSDs). For each sex hormone there is a pair of HSD isoforms which act either as reductases or oxidases to convert potent steroid hormones into their cognate inactive metabolites, or vice‐versa. In this manner, HSDs can function as molecular switches to regulate steroid hormone action. Because these HSDs show tissue‐specific expression, inhibitors of these enzymes are predicted to cause tissue‐specific responses to steroid hormones. These inhibitors would represent a new class of therapeutics called 'selective intracrine modulators' (SIMs). SIMs are expected to have the same tissue‐specific effects as selective steroid receptor modulators but a different mode of action as their effects are enzyme‐ and not receptor‐mediated. HSDs responsible for these interconversions belong to two protein superfamilies: the short‐chain dehydrogenases/reductases; and the aldo‐keto reductases. Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad‐based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target.
Pulmonary hypertension in Portugal: First data from a nationwide registry
Authors: Rui Baptista, José Meireles, Ana Agapito, Graça Castro, António Marinho da Silva, Teresa Shiang, Ana Oliveira, Daniela Ferreira, Fabienne Gonçalves, Susana Robalo-Martins, António Nunes Diogo, Abilio Reis
Journal: European Respiratory Journal (2012)

Pulmonary arterial hypertension (PAH) is a rare disease that must be managed in specialized centers integrated in a national network. Availability of epidemiological national data is critical for planning and regulation of healthcare in this field.  We conducted a prospective, observational and multicenter registry in 5 portuguese centers. Adults with PAH and chronic thromboembolic PH (CTEPH) confirmed by right heart cath (RHC) were included.  79 patients were enrolled; 46 (58.2%) classified as PAH and 33 (41.8%) as CTEPH. PAH patients had a mean age of 43.4±16.4 years and the f/m ratio 1.9:1. Idiopathic PAH was present in 17 (37%) patients, followed by connective tissue disease (n=12, 26%), congenital heart disease (n=10, 22%), portopulmonary (n=5, 11%), heritable (n=1, 2%) and other etiologies (n=1, 2%). At baseline most patients were WHO class III or IV (71%). Baseline RHC: elevated RAP (7.7±5.9 mmHg), mPAP (50.6±17.9 mmHg) and mean PVR (11.4±6.5 Wood U), with a low CI (2.7±1.1 L.min-1.m-2).  At baseline patients were medicated with conventional therapies; at follow-up, most were on single (50%), double (28%) or triple (9%) combination of specific therapy. 1-year survival was 93.5%.  CTEPH patients were older (60.0±12.5 years) and had higher RAP (11.0±5.2 mmHg, p = 0.015), but 1-year survival (93.9%) was similar to PAH patients. Five CTEPH patients underwent pulmonary endarterectomy.  We estimated an annual incidence of 1.5 and 1.1 per million in PAH and CTEPH, respectively.  Our report describes nationwide data on the diagnosis, management and clinical course of groups 1 and 4 PH patients. Clinical presentation, hemodynamics and survival are comparable with those reported on other national registries.
Unculturable bacteria--the uncharacterized organisms that cause oral infections
Authors: W. Wade
Journal: Journal of the Royal Society of Medicine (2002)

The first bacterial culture media were broths made either by infusion or by enzymatic digestion of meat from various sources. Originally developed by Spallanzani in the 18th century and then refined by Pasteur in the 19th century, these allowed the recovery of bacteria from human disease sites1,2. However, it was quickly realized that such broths would be likely to contain mixtures of micro-organisms, and Robert Koch saw the need for development of solid culture media that would allow the physical separation of bacterial colonies. He first tried aseptically divided potatoes. Material taken from infected lesions was spread across the potato and then incubated at body temperature. Following incubation, bacterial colonies were seen which could be subcultured to further potatoes to give pure cultures. Although successful, Koch observed that only a limited number of the micro-organisms present in the sample grew on the potato. This was probably the first recognition of the phenomenon of unculturability in vitro. Nevertheless, the success of the technique led to the use of solidifying agents such as gelatin and agar to create solid media from the broths developed by Pasteur and others. This advance led to the golden age of medical microbiology, in the last quarter of the 19th century, when many of the bacteria causing serious infections in man were identified. This tremendous success, however, probably led microbiologists to become complacent simply because so many important pathogenic bacteria could be cultured in vitro in this way.
2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells
Authors: Dharminder Chauhan, Laurence Catley, Teru Hideshima, Guilan Li, Richard Leblanc, Deepak Gupta, Martin Sattler, Paul Richardson, Robert L. Schlossman, Klaus Podar, Edie Weller, Nikhil Munshi, Kenneth C. Anderson
Journal: Blood (2002)
Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells
Authors: Atsushi Naganuma, Hiromichi Dansako, Takashi Nakamura, Akito Nozaki, Nobuyuki Kato
Journal: Cancer Research (2004)

Abstract Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)17 dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to non-neoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.
MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1
Authors: Claudia R. Ruprecht, Anders Krarup, Lucy Reynell, Axel M. Mann, Oliver F. Brandenberg, Livia Berlinger, Irene A. Abela, Roland R. Regoes, Huldrych F. Günthard, Peter Rusert, Alexandra Trkola
Journal: The Journal of Experimental Medicine (2011)

Interference with virus entry is known to be the principle mechanism of HIV neutralization by antibodies, including 2F5 and 4E10, which bind to the membrane-proximal external region (MPER) of the gp41 envelope protein. However, to date, the precise molecular events underlying neutralization by MPER-specific antibodies remain incompletely understood. In this study, we investigated the capacity of these antibodies to irrevocably sterilize HIV virions. Long-term effects of antibodies on virions can differ, rendering neutralization either reversible or irreversible. MPER-specific antibodies irreversibly neutralize virions, and this capacity is associated with induction of gp120 shedding. Both processes have similar thermodynamic properties and slow kinetics requiring several hours. Antibodies directed to the CD4 binding site, V3 loop, and the MPER can induce gp120 shedding, and shedding activity is detected with high frequency in plasma from patients infected with divergent genetic HIV-1 subtypes. Importantly, as we show in this study, induction of gp120 shedding is closely associated with MPER antibody inhibition, constituting either a primary event leading to virion neutralization or representing an immediate consequence thereof, and thus needs to be factored into the mechanistic processes underlying their activity.
Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man.
Authors: M Rowe, L S Young, J Crocker, H Stokes, S Henderson, A B Rickinson
Journal: The Journal of Experimental Medicine (1991)

When human peripheral blood lymphocytes (PBLs) from Epstein-Barr virus (EBV)-seropositive donors are injected intraperitoneally into SCID mice, EBV+ B cell tumors develop within weeks. A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma. The present work shows that generally the human (hu) PBL-SCID tumors are distinct from Burkitt's lymphoma and instead resemble lymphoblastoid cell lines (LCLs) generated by EBV-infection of normal B cells in vitro in terms of: (a) their cell surface phenotype, with expression of B cell activation antigens and adhesion molecules, (b) normal karyotype, and (c) viral phenotype, with expression of all the transformation-associated EBV latent proteins and, in a minority of cells, productive cycle antigens. Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype of the LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PBL-derived hu-SCID tumors resemble the EBV+ large cell lymphomas that develop in immuno-suppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency of tumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBV-transformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV+ large cell lymphoma of the immunosuppressed may arise in a similar way.
The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells.
Authors: S D Miller, R P Wetzig, H N Claman
Journal: The Journal of Experimental Medicine (1979)

A mouse model of cell-mediated immunity (CMI) and tolerance to protein antigens horse gamma globulin (HoGG) and cytochrome (Cyt C) was investigated. A reliable CMI response as measured in vivo by ear swelling or by an in vitro T-cell proliferation assay could be induced by one of two methods: (a) sensitization by antigen-complete Freund's adjuvant in the base of the tail, or (b) sensitization by s.c. injection of antigen coupled to syngeneic lymphoid cells. The in vivo response exhibited characteristic CMI parameters, delayed kinetics, and transfer by viable T cells. Prior i.v. injection of HoGG-modified lymphoid cells (HoGG-LC) or Cyt C-LC before sensitization resulted in a rapidly induced, dose-dependent, antigen-specific suppression of both in vivo and in vitro manifestations of the CMI response. In addition, tolerance in this system was transferrable by an antigen-specific suppressor T cell (Ts). The Ts were found to diminish the in vivo ear swelling reaction in recipient animals, but had no effect on the in vitro T-cell proliferative response of the recipients. In contrast to the rapid development of tolerance in donor mice (phenotypic tolerance), transferrable Ts were first demonstrable 4--7 d posttolerization. This latter result indicates that at least two mechanisms of tolerance are operative in this system: the rapid induction of clone inhibition of reactive T cells and the slower induction of Ts. These results indicate again that the mode of antigen presentation is crucial in determining the immunologic outcome. In these experiments, cell-bound proteins injected subcutaneously led to delayed hypersensitivity while the same antigens injected intravenously led to tolerance. These results are considered in the light of recent experiments which show that T cells recognize antigens on cells in association with major histocompatibility complex products. We believe the following pathways are involved. In sensitization via subcutaneous injection of HoGG-LC, antigen reaches the lymph node via lymphatic pathways which lead to immunogenic macrophage-associated presentation and the activation of delayed hypersensitivity T cells (TDH). In tolerization via intravenous injection of HoGG-LC, antigen (a) reaches the lymph node via the blood, probably directly meeting the TDH, preventing its subsequent activation by immunogenic HoGG (clone inhibition) and (b) reaches the spleen, also via the blood, activating suppressor T cells.
Time Dependency of Factors Affecting Renal Allograft Survival
Authors: SURAZEE PROMMOOL, GIAN S. JHANGRI, SANDRA M. COCKFIELD, PHILIP F. HALLORAN
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age ≥55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: ≤6 mo, 6 mo to 5 yr, and &gt;5 yr. Of the 135 graft failures, 53 occurred ≤6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis, the risks for graft failure in interval ≤6 mo were AR (hazard ratio (HR) = 4.86, P &lt; 0.001); delayed graft function (HR = 1.47, P = 0.06); and high panel-reactive antibodies (HR = 2.04, P = 0.03). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P &lt; 0.001) and serum creatinine at 6 mo ≥150 μmol/L (HR = 3.69, P &lt; 0.001). Beyond 5 yr the risk factors were donor age ≥55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.
Non-cysteine linked MUC1 cytoplasmic dimers are required for Src recruitment and ICAM-1 binding induced cell invasion
Authors: Ashlyn J Bernier, Jing Zhang, Erik Lillehoj, Andrew RE Shaw, Nirosha Gunasekara, Judith C Hugh
Journal: Molecular Cancer (2011)

Abstract Background The mucin MUC1, a type I transmembrane glycoprotein, is overexpressed in breast cancer and has been correlated with increased metastasis. We were the first to report binding between MUC1 and Intercellular adhesion molecule-1 (ICAM-1), which is expressed on stromal and endothelial cells throughout the migratory tract of a metastasizing breast cancer cell. Subsequently, we found that MUC1/ICAM-1 binding results in pro-migratory calcium oscillations, cytoskeletal reorganization, and simulated transendothelial migration. These events were found to involve Src kinase, a non-receptor tyrosine kinase also implicated in breast cancer initiation and progression. Here, we further investigated the mechanism of MUC1/ICAM-1 signalling, focusing on the role of MUC1 dimerization in Src recruitment and pro-metastatic signalling. Methods To assay MUC1 dimerization, we used a chemical crosslinker which allowed for the detection of dimers on SDS-PAGE. We then generated MUC1 constructs containing an engineered domain which allowed for manipulation of dimerization status through the addition of ligands to the engineered domain. Following manipulation of dimerization, we immunoprecipitated MUC1 to investigate recruitment of Src, or assayed for our previously observed ICAM-1 binding induced events. To investigate the nature of MUC1 dimers, we used both non-reducing SDS-PAGE and generated a mutant construct lacking cysteine residues. Results We first demonstrate that the previously observed MUC1/ICAM-1signalling events are dependent on the activity of Src kinase. We then report that MUC1 forms constitutive cytoplasmic domain dimers which are necessary for Src recruitment, ICAM-1 induced calcium oscillations and simulated transendothelial migration. The dimers are not covalently linked constitutively or following ICAM-1 binding. In contrast to previously published reports, we found that membrane proximal cysteine residues were not involved in dimerization or ICAM-1 induced signalling. Conclusions Our data implicates non-cysteine linked MUC1 dimerization in cell signalling pathways required for cancer cell migration.