tbuckley/cabot-search huggingface dataset:
Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine
Authors: Lichen Jing, Jürgen Haas, Tiana M. Chong, Joseph J. Bruckner, Greg C. Dann, Lichun Dong, Joshua O. Marshak, Christopher L. McClurkan, Tori N. Yamamoto, Susanne M. Bailer, Kerry J. Laing, Anna Wald, Georges M.G.M. Verjans, David M. Koelle
Journal: Journal of Clinical Investigation (2012)

Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens.
Intratumor Heterogeneity and Precision of Microarray-Based Predictors of Breast Cancer Biology and Clinical Outcome
Authors: William T. Barry, Dawn N. Kernagis, Holly K. Dressman, Ryan J. Griffis, J'Vonne D. Hunter, John A. Olson, Jeff R. Marks, Geoffrey S. Ginsburg, Paul K. Marcom, Joseph R. Nevins, Joseph Geradts, Michael B. Datto
Journal: Journal of Clinical Oncology (2010)

Purpose Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. Patients and Methods Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. Results Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). Conclusion Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.
Plague in San Francisco in 1900
Authors: LOREN GEORGE LIPSON
Journal: Annals of Internal Medicine (1972)

Bubonic plague, the feared Black Death of the Middle Ages, probably came to the United States in 1900 by way of the port of San Francisco. The controversy that ensued concerning the actual existence of this disease led to one of the most scandalous episodes in the history of American public health and involved everyone from the President of the United States to the individual resident of San Francisco. The incident necessitated the formation of a special commission to ascertain if plague existed and brought out racial prejudice in high government office. It placed the state governor and special interest groups against the public health authorities. The initial failure to take action against the plague may have led to dissemination of this disease in the West. Out of this episode came a strong state department of public health and an increased public awareness of the dangers of communicable diseases.
Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes
Authors: Salim Yusuf, Shamir R Mehta, Susan Chrolavicius, Rizwan Afzal, Janice Pogue, Christopher B Granger, Andrzej Budaj, Ron J G Peters, Jean-Pierre Bassand, Lars Wallentin, Campbell Joyner, Keith A A Fox
Journal: New England Journal of Medicine (2006)

The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding.
β <sub>2</sub> -Adrenergic Receptor Actions in Neonatal and Adult Rat Ventricular Myocytes
Authors: Valiery Kuznetsov, Elena Pak, Richard B. Robinson, Susan F. Steinberg
Journal: Circulation Research (1995)

Abstract The physiological function of β 2 -adrenergic receptors in the neonatal and adult heart is incompletely understood, and possible age-dependent differences in β 2 -receptor actions have not been considered. We used isoproterenol (mixed β 1 - and β 2 -receptor agonist) and zinterol (β 2 -selective agonist) to compare β-receptor subtype actions in neonatal and adult rat ventricular myocytes. When delivered as a bolus at a final concentration of 10 −7 mol/L, both isoproterenol and zinterol increased the amplitude and hastened the kinetics of the calcium and cell-shortening transients in neonatal myocytes. Under identical experimental conditions, isoproterenol increased the amplitude and accelerated the kinetics of the calcium transient and the twitch in adult myocytes, whereas zinterol did not. In the presence of CGP 20712A (β 1 -receptor blocker), a 100-fold higher concentration of zinterol increased the amplitude but prolonged the duration of the twitch in adult myocytes. To probe the mechanism for this age-dependent difference in β 2 -receptor responsiveness, we compared β-receptor expression and stimulation of cAMP accumulation in neonatal and adult myocytes. β-Receptor density was 44 339±5178 sites per cell in neonatal myocytes and 186 346±13 356 sites per cell in adult myocytes; the relative proportion of β 2 -receptors was comparable in each (16.7±2.3% and 16.9±0.9%, respectively). Isoproterenol induced a large increase in cAMP accumulation in neonatal and adult myocytes (20.0±1.0- and 20.6±2.6-fold over basal). In contrast, zinterol evoked a substantial increase in cAMP accumulation in neonatal myocytes but only a minor increase in adult myocytes. These studies provide evidence that at low agonist concentrations, β 2 -receptor activation contributes to the positive inotropic response by increasing cAMP and increasing the amplitude and hastening the kinetics of the twitch in neonatal, but not adult, myocytes. Moreover, these results suggest that age-dependent differences in β 2 -receptor coupling to more distal elements in the signaling cascade can influence myocyte β 2 -receptor responsiveness.
Tight Junction Protein Claudin-1 Enhances the Invasive Activity of Oral Squamous Cell Carcinoma Cells by Promoting Cleavage of Laminin-5 γ2 Chain via Matrix Metalloproteinase (MMP)-2 and Membrane-Type MMP-1
Authors: Naohisa Oku, Eri Sasabe, Eisaku Ueta, Tetsuya Yamamoto, Tokio Osaki
Journal: Cancer Research (2006)

Abstract Although adherent junctions have been extensively studied, the role of tight junctions in cancer cell invasion is not sufficiently explored. We investigated whether claudin-1, a component of tight junctions, regulated invasion activity in oral squamous cell carcinoma (OSC) cells. The expression of claudin-1, activity of matrix metalloproteinase (MMP)-2, and cleavage of laminin-5 γ2 chains were assessed by Western blot analysis, immunohistochemistry, and zymography in OSC cell lines (OSC-4 and NOS-2, highly invasive; OSC-7, weakly invasive) and their xenografts in severe combined immunodeficient (SCID) mice. The influence of claudin-1 small interfering RNA (siRNA) on the invasion activity of the cell lines was also investigated. Compared with OSC-7, both OSC-4 and NOS-2 more strongly expressed claudin-1 and possessed high activities of MMP-2 and MMP-9. Tumors formed in the tongues of SCID mice xenografted with OSC-4, NOS-2, and OSC-7 immunohistochemically revealed strong, moderate, and weak expression of laminin-5 γ2 chains, respectively, and laminin-5 γ2 chains were secreted in the conditioned medium of the cancer cells in parallel with the in vivo results. Claudin-1 siRNA largely suppressed the invasion of OSC-4 and decreased the activation of MMP-2, the expression of membrane-type MMP-1 (MT1-MMP), and the cleavage of laminin-5 γ2. In addition, not only antibodies against MT1-MMP and epidermal growth factor receptor (EGFR) but also MMP-2 and EGFR inhibitors strongly suppressed the invasion activity of OSC-4. These results suggest that claudin-1 up-regulates cancer cell invasion activity through activation of MT1-MMP and MMP-2, which results in enhanced cleavage of laminin-5 γ2 chains. (Cancer Res 2006; 66(10): 5271-7)
C. elegans DAF-12, Nuclear Hormone Receptors and human longevity and disease at old age
Authors: S.P. Mooijaart, B.W. Brandt, E.A. Baldal, J. Pijpe, M. Kuningas, M. Beekman, B.J. Zwaan, P.E. Slagboom, R.G.J. Westendorp, D. van Heemst
Journal: Ageing Research Reviews (2005)
In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.
Authors: J Jacob, R Kassir, G Kelsoe
Journal: The Journal of Experimental Medicine (1991)

After primary immunization with an immunogenic conjugate of (4-hydroxy-3-nitrophenyl)acetyl, two anatomically and phenotypically distinct populations of antibody-forming cells arise in the spleen. As early as 2 d after immunization, foci of antigen-binding B cells are observed along the periphery of the periarteriolar lymphoid sheaths. These foci expand, occupying as much as 1% of the splenic volume by day 8 of the response. Later, foci grow smaller and are virtually absent from the spleen by day 14. A second responding population, germinal center B cells, appear on day 8-10 and persist at least until day 16 post-immunization. Individual foci and germinal centers represent discrete pauciclonal populations that apparently undergo somatic evolution in the course of the primary response. We suggest that foci may represent regions of predominantly interclonal competition for antigen among unmutated B cells, while germinal centers are sites of intraclonal clonal competition between mutated sister lymphocytes.
I<scp>NTERRELATIONSHIPS OF</scp>K<scp>EY</scp>V<scp>ARIABLES OF</scp>H<scp>UMAN</scp>Z<scp>INC</scp>H<scp>OMEOSTASIS</scp>: Relevance to Dietary Zinc Requirements
Authors: Michael Hambidge, Nancy F Krebs
Journal: Annual Review of Nutrition (2001)

▪ Abstract Currently, estimates of human zinc requirements depend primarily on a factorial approach. The availability of tracer techniques employing zinc stable isotopes has facilitated the acquisition of data on major variables of zinc homeostasis in addition to those that can be measured with careful metabolic balance techniques. These data have promising potential to facilitate and improve the factorial approach. The thesis proposed in this paper is that realistic estimations of dietary zinc requirements by a factorial approach require attention to the dynamic interrelationships between major variables of zinc homeostasis. This applies especially to the positive relationship between endogenous fecal zinc and total absorbed zinc, which is the essential starting point in estimating physiologic and, from there, dietary requirements.
Development of an ELISA for Digestion-Resistant Ara h 2 Peptide: Monitoring the Peptide in Body Fluids of Healthy Volunteers Who Consumed Peanut
Authors: J.L. Baumert, K.A. Peeters, A.C. Knulst, S.J. Koppelman, S.J. Maleki, E. Knol, S.L. Hefle
Journal: Journal of Allergy and Clinical Immunology (2006)
Mononuclear cells from patients with the hyperimmunoglobulin E-recurrent infection syndrome produce an inhibitor of leukocyte chemotaxis.
Authors: H Donabedian, J I Gallin
Journal: Journal of Clinical Investigation (1982)

The chemotactic responsiveness of the neutrophils of 10 patients with the hyperimmunoglobulin E-recurrent infection syndrome (HIE) were compared with neutrophils from normal volunteers over a 10-mo period. HIE neutrophils as a group displayed significantly less chemotactic motility than control neutrophils. The data from individual patients were variable, being normal or abnormal on different days. Mononuclear cells from HIE patients, when cultured for 24 h in the absence of serum or a mitogen, produced a factor that inhibited normal neutrophil and monocyte chemotaxis. Mononuclear cells from normal volunteers with and without atopy or from patients with parasites or bacterial infections did not produce such an inhibitory factor. The production of this chemotactic inhibitory factor in vitro was variable over time, but it correlated with the presence of an in vitro neutrophil chemotactic defect. The chemotactic inhibitory factor was partially purified and was found to contain protein, to be stable at 56 degrees C, and to have a molecular weight of approximately 61,000. Irreversible inhibitors of serine esterases do not inactivate the factor. The factor is produced by esterase-negative mononuclear cells and is not toxic to neutrophils. This chemotactic inhibitory factor may be the basis of the variable chemotactic defect in HIE neutrophils.
Accuracy of diagnostic coding of hospital admissions for cryptogenic fibrosing alveolitis.
Authors: I D Johnston, C Bleasdale, C R Hind, A A Woodcock
Journal: Thorax (1991)

To determine the accuracy of diagnostic coding of cryptogenic fibrosing alveolitis, the case notes of 166 admissions to four hospitals were reviewed. These consisted of all admissions that had been coded as "idiopathic fibrosing alveolitis" (ICD code 516.3: 97 admissions) or as "postinflammatory pulmonary fibrosis" (ICD code 515.9: 69 admissions). Of 88 available records of admissions coded as idiopathic fibrosing alveolitis, 70 (80%) patients had definite cryptogenic fibrosing alveolitis, and six (7%) possible cryptogenic fibrosing alveolitis according to predetermined conventional clinical criteria. Only seven (8%) admissions were clearly coded wrongly. Sixty four records were available for patients coded as having postinflammatory pulmonary fibrosis; 16 (25%) of these patients had definite cryptogenic fibrosing alveolitis, a further 12 (19%) had possible cryptogenic fibrosing alveolitis or fibrosing alveolitis with a connective tissue disorder, and the remainder had a very wide range of diagnoses. In this study the idiopathic fibrosing alveolitis (ICD 516.3) code was relatively reliable, but a substantial proportion of admissions coded under postinflammatory pulmonary fibrosis (ICD 515.9) also had cryptogenic fibrosing alveolitis and code 515.9 was of little diagnostic value. The data are inadequate for case finding, though in respect of cryptogenic fibrosing alveolitis may be adequate for planning purposes. There continues to be a need for more medical input into the process of diagnostic coding.
Preferential expression of NF- B-inducing kinase in blood vessels of rheumatoid arthritis synovial tissue containing ectopic lymphoid neogenesis
Authors: A. R. Noort, K. P. M. van Zoest, P. P. Tak, S. W. Tas
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Approximately 30% of rheumatoid arthritis (RA) synovial tissues (ST) is characterised by ectopic lymphoid neogenesis (ELN). This results in structures that may resemble germinal centres. Nuclear factor-κB (NF-κB) transcription factors are essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. The non-canonical NF-κB pathway, with its key mediator NF-κB inducing kinase (NIK), may play an important role in ELN as this pathway can be triggered by stimuli like CD40L and lymphotoxin that are abundantly present in ELN. <h3>Objectives</h3> To investigate the expression and distribution of NIK in RA ST in relation to ELN and to study the role of non-canonical NF-κB signalling in RA. <h3>Materials and methods</h3> ST was obtained via mini-arthroscopy from inflamed knee or ankle joints of RA patients with active disease. RA ST samples were analysed by microarray analysis. Expression of NIK was evaluated using immunohistochemistry (IHC) and immunofluorescence (IF) microscopy. NIK expression was also studied in Grawitz tumour and breast cancer tissues. In vitro angiogenesis/tube formation assays were performed with human umbilical vein endothelial cells (HUVEC). <h3>Results</h3> Microarray analysis revealed increased relative expression of non-canonical NF-κB pathway associated genes in ST containing ELN compared to ST without ELN (p&lt;0.05). The authors confirmed these findings by IHC: NIK expression was significantly higher in ST with ELN and more abundantly present within lymphocyte aggregates (1.53±0.32 vs 0.62±0.19; p&lt;0.05). Of interest, in the tissue away from the lymphocyte aggregates, NIK was also expressed by vascular structures. NIK positive cells were negative for the lymphatic vessel markers lymphatic vessel endothelial hyaluronan receptor 1 and podoplanin, but IF microscopy demonstrated that NIK co-localised with the endothelial cell (EC) marker von Willebrand Factor in the smaller vessels. Furthermore, NIK was also expressed in EC in Grawitz tumour and breast cancer tissues. In vitro, HUVEC treated with stimuli that activate non-canonical NF-κB signalling exhibited increased angiogenic potential and increased vascular cell adhesion molecule 1 expression. <h3>Conclusion</h3> NIK is preferentially expressed in RA ST containing ELN. NIK was also expressed by small EC in RA ST and tumour tissues. In vitro, non-canonical NF-κB signalling inducing stimuli resulted in EC activation and increased angiogenesis. These findings point towards an important role of the non-canonical NF-κB pathway in either angiogenesis, the activation of EC or both. This could be exploited for the development of new therapies, which would not only be applicable for RA but also for other diseases.
Transforming Growth Factor-β Receptor Mutations and Pulmonary Arterial Hypertension in Childhood
Authors: Rachel E. Harrison, Rolf Berger, Sheila G. Haworth, Robert Tulloh, Christoph J. Mache, Nicholas W. Morrell, Micheala A. Aldred, Richard C. Trembath
Journal: Circulation (2005)

Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.
Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon.
Authors: J S Pober, M A Gimbrone, R S Cotran, C S Reiss, S J Burakoff, W Fiers, K A Ault
Journal: The Journal of Experimental Medicine (1983)

We have used monoclonal antibody binding, measured by radioimmunoassay, fluorescence flow cytometry, and ultrastructural immunocytochemistry, to measure expression of Ia antigens on cultured human umbilical vein endothelial (HUVE) cells. Under standard culture conditions, HUVE cells do not express Ia antigens. However, treatment of primary HUVE cultures with phytohemagglutinin induces the expression of Ia antigens. Every endothelial cell in the culture becomes Ia-positive and endothelial cells appear to synthesize Ia. HLA-A,B is concomitantly increased. The expression of Ia appears to be mediated by T cells because (a) pretreatment of primary HUVE cultures with OKT3 plus complement blocks the action of the lectins but not of medium conditioned by lectin-activated peripheral blood mononuclear cells; (b) co-culture of endothelial cells with allogeneic T cells, in the absence of lectin, also induces endothelial Ia; and (c) human immune (gamma) interferon, produced by Chinese hamster ovary cells transfected with the human gamma interferon gene, directly induces endothelial Ia. During co-culture with lymphocytes, about one-third of the endothelial cells are Ia-positive after 24 h and all of the endothelial cells are Ia-positive by 72 h. Proliferation of allogeneic T cells starts by 96 h and peaks at 144 h. Thus, endothelial Ia appears sufficiently early to be a determinant for the proliferation of allogeneic T cells. Inducible expression of Ia by endothelium may be important both for allograft rejection and for recruitment of circulating T cells into the site of an immune response.