tbuckley/cabot-search huggingface dataset:
Oral but Not Parenteral Interleukin (IL)-12 Redirects T Helper 2 (Th2)-type Responses to an Oral Vaccine Without Altering Mucosal IgA Responses
Authors: Mariarosaria Marinaro, Prosper N. Boyaka, Fred D. Finkelman, Hiroshi Kiyono, Raymond J. Jackson, Emilio Jirillo, Jerry R. McGhee
Journal: The Journal of Experimental Medicine (1997)

Our past studies have shown that the mucosal adjuvant cholera toxin (CT) induces T helper type 2 (Th2) responses with systemic IgG1, IgE and mucosal secretory IgA (S-IgA) antibodies (Abs). In this study, recombinant murine IL-12 (rmIL-12) was given either parenterally or orally to mice orally immunized with tetanus toxoid (TT) and CT to determine whether this cytokine could redirect the CT-induced Th2-type responses and what effect this shift would have on S-IgA Ab responses. Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines. This cytokine profile was accompanied by increased delayed-type hypersensitivity (DTH) and shifts in serum IgG1 to IgG2a and IgG3 anti-TT Ab responses. Further, serum IgE and S-IgA Ab responses were markedly reduced by parenteral IL-12. When IL-12 complexed to liposomes was given orally both shifts to IgG2a and IgG3 and low IgE Abs again occurred concomitant with enhanced serum IFN-gamma and DTH responses. Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12. Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.
Flanking sequences influence the presentation of an endogenously synthesized peptide to cytotoxic T lymphocytes.
Authors: L C Eisenlohr, J W Yewdell, J R Bennink
Journal: The Journal of Experimental Medicine (1992)

Cytotoxic T lymphocytes (CTL) recognize class I major histocompatibility complex molecules complexed to peptides of eight to nine residues generated from cytosolic proteins. We find that CTL recognize, in vitro and in vivo, cells synthesizing a 10-residue peptide consisting of an initiating methionine followed by nine residues corresponding to a naturally processed determinant from influenza virus nucleoprotein (NP) (residues 147-155). Addition of two COOH-terminal residues corresponding to NP residues 157 and 158 severely reduced presentation of the endogenously produced peptide to CTL in vitro and in vivo. Extension of NH2 and COOH terminal flanking residues to include residues corresponding to NP residues 137-146 and 159-168 failed to increase the antigenicity of this peptide. Its presentation was greatly enhanced, however, by further extending the NH2 and COOH termini to include all of the additional residues of NP. These findings indicate first, that a naturally processed viral ligand (with an NH2-terminal Met) of a class I molecule contains sufficient information to access intracellular class I molecules, and second, that flanking residues can influence the processing and presentation of antigens to CTL.
Unipolar Potential Measurements in the Electric Field Produced by an Arbitrary Dipole in a Circular Homogeneous Lamina
Authors: ROBERT H. BAYLEY
Journal: Circulation Research (1959)

Unipolar potential measurements are carried out on a circular homogeneous conducting lamina. One set of potential measurements is made using an averaging net work for the zero potential reference. A second set of potential measurements is made with reference to the Frank-Kay "zero" potential reference on the outside ground of the dipole generating circuit. Both sets of unipolar potential measurements are then compared with the theoretically predicted values. The first set is found to be highly accurate. The second set is found to contain errors which make this method unacceptable.
Evolution of Outer Membrane β-Barrels from an Ancestral ββ Hairpin
Authors: M. Remmert, A. Biegert, D. Linke, A. N. Lupas, J. Söding
Journal: Molecular Biology and Evolution (2010)

Outer membrane β-barrels (OMBBs) are the major class of outer membrane proteins from Gram-negative bacteria, mitochondria, and plastids. Their transmembrane domains consist of 8–24 β-strands forming a closed, barrel-shaped β-sheet around a central pore. Despite their obvious structural regularity, evidence for an origin by duplication or for a common ancestry has not been found. We use three complementary approaches to show that all OMBBs from Gram-negative bacteria evolved from a single, ancestral ββ hairpin. First, we link almost all families of known single-chain bacterial OMBBs with each other through transitive profile searches. Second, we identify a clear repeat signature in the sequences of many OMBBs in which the repeating sequence unit coincides with the structural ββ hairpin repeat. Third, we show that the observed sequence similarity between OMBB hairpins cannot be explained by structural or membrane constraints on their sequences. The third approach addresses a longstanding problem in protein evolution: how to distinguish between a very remotely homologous relationship and the opposing scenario of “sequence convergence.” The origin of a diverse group of proteins from a single hairpin module supports the hypothesis that, around the time of transition from the RNA to the protein world, proteins arose by amplification and recombination of short peptide modules that had previously evolved as cofactors of RNAs.
Combinatorial therapy with an IL-15 superagonist (ALT-803) and anti-PD-L1 mAb augment T cell mediated anti-tumor immunity in mice
Authors: Christopher B Johnson, Brian Riesenberg, Dan Neitzke, Emily K Jeng, Warren D Marcus, David Cole, Hing C Wong, Mark P Rubinstein
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts The adoptive transfer of tumor-reactive T cells has shown great promise in treating patients with metastatic cancer. However, effective T cell responses are limited by the availability of T cell growth factors such as IL-2 and tumor-induced suppressive pathways. As tumor-induced
New Regulatory Regions of Drosophila 412 Retrotransposable Element Generated by Recombination
Authors: Nathalie Mugnier, Christian Biémont, Cristina Vieira
Journal: Molecular Biology and Evolution (2004)

There are no doubts that transposable elements (TEs) have greatly influenced genomes evolution. They have, however, evolved in different ways throughout mammals, plants, and invertebrates. In mammals they have been shown to be widely present but with low transposition activity; in plants they are responsible for large increases in genome size. In Drosophila, despite their low amount, transposition seems to be higher. Therefore, to understand how these elements have evolved in different genomes and how host genomes have proposed to go around them, are major questions on genome evolution. We analyzed sequences of the retrotransposable elements 412 in natural populations of the Drosophila simulans and D. melanogaster species that greatly differ in their amount of TEs. We identified new subfamilies of this element that were the result of mutation or insertion-deletion process, but also of interfamily recombinations. These new elements were well conserved in the D. simulans natural populations. The new regulatory regions produced by recombination could give rise to new elements able to overcome host control of transposition and, thus, become potential genome invaders.
Controversies in management: Should doctors perform an elective caesarean section on request? Yes, as long as the woman is fully informed Maternal choice alone should not determine method of delivery
Authors: S Paterson-Brown
Journal: BMJ (1998)

# Should doctors perform an elective caesarean section on request? {#article-title-2} Rates of caesarean section are rising, and mothers' requests for elective caesarean section in an uncomplicated pregnancy are not uncommon. Performing a caesarean section when it is not clinically indicated has traditionally been considered inappropriate, but views may be changing. Sara Paterson-Brown and Olubusola Amu and colleagues debate the issue # Yes, as long as the woman is fully informed {#article-title-3} Surgery is performed by doctors when they believe it is clinically justified and in accordance with accepted medical practice. In obstetrics an elective caesarean section in an uncomplicated pregnancy has traditionally been considered inappropriate, and any request for such a procedure has been refused.1 However, the view that this procedure is clinically unjustifiable has been challenged,2 and over the past decade or so prophylactic caesarean section has been gaining credence. 3 4 The balance of benefit versus harm between caesarean section and vaginal delivery is crucial to this debate; although the evidence is incomplete, it challenges the dogma that vaginal delivery is almost always better. The strongest argument against caesarean section relates to maternal complications. However, evidence supporting this for elective operations under regional blockade with antibiotic cover and thromboprophylaxis is poor. Data on mortality from caesarean section relate to procedures performed for medical or obstetric reasons, often emergencies and often under general anaesthesia. 5 6 These are not comparable to the elective procedure, which most practising obstetricians consider safe. Recent evidence of maternal morbidity after caesarean section and normal and instrumental vaginal delivery challenges some deep rooted obstetric and midwifery teachings: normal vaginal deliveries can cause damage to the pelvic floor,7 and instrumental vaginal deliveries are associated with slower recovery8 and greater pelvic floor damage and incontinence9 than normal delivery and caesarean section. Previous caesarean section does compromise future obstetric performance, 10 11 but evidence is limited and, with reduced family size, this has … Correspondence to: Dr Bolaji
Effects of the Irish Smoking Ban on Respiratory Health of Bar Workers and Air Quality in Dublin Pubs
Authors: Patrick Goodman, Michelle Agnew, Marie McCaffrey, Gillian Paul, Luke Clancy
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Environmental tobacco smoke (ETS) causes disease in nonsmokers. Workplace bans on smoking are interventions to reduce exposure to ETS to try to prevent harmful health effects. On March 29, 2004, the Irish government introduced the first national comprehensive legislation banning smoking in all workplaces, including bars and restaurants. This study examines the impact of this legislation on air quality in pubs and on respiratory health effects in bar workers in Dublin.Exposure study. Concentrations of particulate matter 2.5 microm or smaller (PM(2.5)) and particulate matter 10 microm or smaller (PM(10)) in 42 pubs were measured and compared before and after the ban. Benzene concentrations were also measured in 26 of the pubs. Health effects study. Eighty-one barmen volunteered to have full pulmonary function studies, exhaled breath carbon monoxide, and salivary cotinine levels performed before the ban and repeated 1 year after the ban. They also completed questionnaires on exposure to ETS and respiratory symptoms on both occasions.Exposure study. There was an 83% reduction in PM(2.5) and an 80.2% reduction in benzene concentration in the bars. Health effects study. There was a 79% reduction in exhaled breath carbon monoxide and an 81% reduction in salivary cotinine. There were statistically significant improvements in measured pulmonary function tests and significant reductions in self-reported symptoms and exposure levels in nonsmoking barmen volunteers after the ban.A total workplace smoking ban results in a significant reduction in air pollution in pubs and an improvement in respiratory health in barmen.
Keratins: Guardians of the liver
Authors: Bishr M. Omary, Nam-On Ku, Diana M. Toivola
Journal: Hepatology (2002)

The Cytoskeleton Plays an Important Role in Human Disease T he three major filament cytoskeletal protein networks that maintain cellular structure and integrity in eukaryotic cells are actin microfilaments, tubulin microtubules, and the large family of tissue-specific intermediate filament (IF) proteins.These cytoskeletal proteins participate in a wide range of important cellular functions including cell division, motility, maintenance of cellular mechanical integrity, stress responses, and vesicle transport. 1Accumulating evidence indicates that these 3 cytoskeletal families and/or their associated proteins play an important role in human disease.For example, actin mutations cause cardiac and noncardiac myopathies 2 and although tubulin mutations have not been described, the microtubule-associated protein tau is involved in Parkinson's disease. 3In functional terms, IF proteins are the least understood of the 3 cytoskeletal families, yet they are associated with a broad range of human diseases that reflect their diversity and tissue distribution.5][6][7] This review will focus on keratins, the major IF proteins of the liver, and other epithelial tissues and address recent insights pertaining to keratin function and disease association in the liver.[10]
EFFECTS OF UK 69 578: A NOVEL ATRIOPEPTIDASE INHIBITOR
Authors: DavidB. Northridge, ColinT. Alabaster, JohnM.C. Connell, StephenG. Dilly, AnthonyF. Lever, AlanG. Jardine, PaulL. Barclay, HenryJ. Dargie, IainN. Findlay, GillianM.R. Samuels
Journal: The Lancet (1989)
A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation
Authors: David L. Porter, Bruce L. Levine, Nancy Bunin, Edward A. Stadtmauer, Selina M. Luger, Steven Goldstein, Alison Loren, Julie Phillips, Sunita Nasta, Alexander Perl, Steven Schuster, Donald Tsai, Ambika Sohal, Elizabeth Veloso, Stephen Emerson, Carl H. June
Journal: Blood (2005)
Choosing Phase II Endpoints and Designs: Evaluating the Possibilities
Authors: Michael LeBlanc, Catherine Tangen
Journal: Clinical Cancer Research (2012)

Abstract Selecting the phase II design and endpoint to achieve the best possible chance of success for a confirmatory phase III study in a particular disease and treatment setting is challenging but critical. Simulating from existing clinical trial data sets and from mathematical models can be useful tools for evaluating statistical properties. Clin Cancer Res; 18(8); 2130–2. ©2012 AACR.
Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques
Authors: Bart L Haagmans, Thijs Kuiken, Byron E Martina, Ron A M Fouchier, Guus F Rimmelzwaan, Geert van Amerongen, Debby van Riel, Ton de Jong, Shigeyuki Itamura, Kwok-Hung Chan, Masato Tashiro, Albert D M E Osterhaus
Journal: Nature Medicine (2004)
Effects of progestins on cardiovascular diseases: the haemostatic system
Authors: U. Winkler
Journal: Human Reproduction Update (1999)

The effect of progestin-only therapy on the haemostatic system has mainly been studied in premenopausal women. Although these studies are difficult to compare, most authors agree that there is no consistent pattern of effects on haemostasis. Oestrogen-progestin combinations have been extensively studied in pre- (combined oral contraceptives) and postmenopausal women (sequential and continuous combined hormone replacement therapy), but mostly with emphasis on the effects of oestrogens. Comparative studies into the differential effects of progestins in combined preparations are scarce. Based on these studies, there is evidence for modifying effects of progestins on oestrogen-induced changes, particularly on fibrinogen, factor VII and the fibrinolytic system. The modifying effects appear to vary among certain progestins, the variation being most likely due to differential effects on lipid metabolism. The clinical interpretation of steroid-induced effects on the haemostatic system is difficult. Retrospective analyses linking certain patterns of haemostatic regulation to the risk of venous or arterial vascular diseases are subject to bias, and no interventional studies are yet available. In the absence of such prospective studies and well-designed comparative studies, the available data do not support the notion of a superiority of certain progestins with regard to cardiovascular risks of combined preparations.
Perfluoroalkyl Acids in Maternal Serum and Indices of Fetal Growth: The Aarhus Birth Cohort
Authors: Cathrine Carlsen Bach, Bodil Hammer Bech, Ellen Aagaard Nohr, Jørn Olsen, Niels Bjerregård Matthiesen, Eva Cecilie Bonefeld-Jørgensen, Rossana Bossi, Tine Brink Henriksen
Journal: Environmental Health Perspectives (2015)

Previous studies indicated an association between intrauterine exposure to perfluorooctane sulfonate (PFOS) or perfluorooctanoate (PFOA) and lower birth weight. However, these perfluoroalkyl acids (PFAAs) have to some extent been substituted by other compounds on which little is known.We investigated the association between specific PFAAs and birth weight, birth length, and head circumference at birth.We studied 1,507 mothers and their children from the Aarhus Birth Cohort (2008-2013). Nulliparous women were included during pregnancy, and serum levels of 16 PFAAs were measured between 9 and 20 completed gestational weeks (96% within 13 weeks). For compounds with quantifiable values in > 50% of samples (7 compounds), we report the associations with birth weight, birth length, and head circumference at birth determined by multivariable linear regression.Estimated mean birth weights were lower among women with serum perfluorohexane sulfonate, perfluoroheptane sulfonate, and PFOS concentrations above the lowest exposure quartile, but we found no consistent monotonic dose-response patterns. These associations were stronger when the population was restricted to term births (n = 1,426). For PFOS, the birth weight estimates for the highest versus lowest quartile were -50 g (95% CI: -123, 23 g) in all births and -62 g (95% CI: -126, 3 g) in term births. For the other PFAAs, the direction of the associations was inconsistent, and no overall association with birth weight was apparent. No PFAAs were associated with birth length or head circumference at birth.Overall, we did not find strong or consistent associations between PFAAs and birth weight or other indices of fetal growth, though estimated mean birth weights were lower among those with exposures above the lowest quartile for some compounds.Bach CC, Bech BH, Nohr EA, Olsen J, Matthiesen NB, Bonefeld-Jørgensen EC, Bossi R, Henriksen TB. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal growth: the Aarhus Birth Cohort. Environ Health Perspect 124:848-854; http://dx.doi.org/10.1289/ehp.1510046.
The Impact of Glycosylation on the Biological Function and Structure of Human Immunoglobulins
Authors: James N. Arnold, Mark R. Wormald, Robert B. Sim, Pauline M. Rudd, Raymond A. Dwek
Journal: Annual Review of Immunology (2006)

Immunoglobulins are the major secretory products of the adaptive immune system. Each is characterized by a distinctive set of glycoforms that reflects the wide variation in the number, type, and location of their oligosaccharides. In a given physiological state, glycoform populations are reproducible; therefore, disease-associated alterations provide diagnostic biomarkers (e.g., for rheumatoid arthritis) and contribute to disease pathogenesis. The oligosaccharides provide important recognition epitopes that engage with lectins, endowing the immunoglobulins with an expanded functional repertoire. The sugars play specific structural roles, maintaining and modulating effector functions that are physiologically relevant and can be manipulated to optimize the properties of therapeutic antibodies. New molecular models of all the immunoglobulins are included to provide a basis for informed and critical discussion. The models were constructed by combining glycan sequencing data with oligosaccharide linkage and dynamics information from the Glycobiology Institute experimental database and protein structural data from “The Protein Data Bank.”
Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion
Authors: Carolyn E. Clark, Sunil R. Hingorani, Rosemarie Mick, Chelsea Combs, David A. Tuveson, Robert H. Vonderheide
Journal: Cancer Research (2007)

Abstract The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early “elimination phase” of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer. [Cancer Res 2007;67(19):9518–27]
Increased platelet activation in patients with stable and acute exacerbation of COPD
Authors: J. D. Maclay, D. A. McAllister, S. Johnston, J. Raftis, C. McGuinnes, A. Deans, D. E. Newby, N. L. Mills, W. MacNee
Journal: Thorax (2011)

<h3>Rationale</h3> Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and cardiovascular disease. Interaction between inflammatory cells and activated platelets is important in the pathogenesis of atherothrombosis and may contribute to cardiovascular risk in patients with COPD. <h3>Objectives</h3> To assess platelet-monocyte aggregation in patients with COPD and matched controls, and in patients with an acute exacerbation of COPD. <h3>Methods</h3> 18 men with COPD and 16 male controls matched for age and cigarette smoke exposure were recruited. A further 12 patients were investigated during and at least 2 weeks after hospitalisation for an acute exacerbation. Platelet-monocyte aggregation and platelet P-selectin expression were determined using flow cytometry. <h3>Results</h3> Patients with COPD had increased circulating platelet-monocyte aggregates compared with controls (mean (SD) 25.3 (8.3)% vs 19.5 (4.0)%, p=0.01). Platelet-monocyte aggregation was further increased during an acute exacerbation compared with convalescence (32.0 (11.0)% vs 25.5 (6.4)%, p=0.03). Platelet P-selectin expression and soluble P-selectin did not differ between groups. <h3>Conclusions</h3> Patients with stable COPD have increased circulating platelet-monocyte aggregates compared with well-matched controls. Platelet activation is further increased in patients with COPD during an acute exacerbation. These findings identify a novel mechanism to explain the increased cardiovascular risk in COPD and suggest platelet inhibition as a plausible therapeutic target.