tbuckley/cabot-search huggingface dataset:
Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta-converting enzyme-mediated apoptosis.
Authors: R M Friedlander, V Gagliardini, R J Rotello, J Yuan
Journal: The Journal of Experimental Medicine (1996)

Prointerleukin-1 beta (pro-IL-1 beta) is the only known physiologic substrate of the interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), the founding member of the ICE/ced-3 cell death gene family. Since secreted mature IL-1 beta has been detected after apoptosis, we investigated whether this cytokine, when produced endogenously, plays a role in cell death. We found that hypoxia-induced apoptosis can be inhibited by either the IL-1 receptor antagonist (IL-1Ra) or by neutralizing antibodies to IL-1 or to its type 1 receptor. IL-1Ra also inhibits apoptosis induced by trophic factor deprivation in primary neurons, as well as by tumor necrosis factor alpha in fibroblasts. In addition, during the G1/S phase arrest, mature IL-1 beta induces apoptosis through a pathway independent of CrmA-sensitive gene activity. We also demonstrate that Ice, when expressed in COS cells, requires the coexpression of pro-IL-1 beta for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1 beta has antiapoptotic activity when added exogenously before the onset of hypoxia, which we found is caused in part by its ability to downregulate the IL-1 receptor. Our findings demonstrate that pro-IL-1 beta is a substrate of ICE relevant to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1 beta may function as a positive or negative mediator of cell death.
PPAR and human metabolic disease
Authors: R. K. Semple
Journal: Journal of Clinical Investigation (2006)

The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARα, PPARδ, and PPARγ) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARα and PPARδ appear primarily to stimulate oxidative lipid metabolism, while PPARγ is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARγ in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARγ in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.
B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-<i>O</i>-acetyl sialic acid esterase
Authors: Annaiah Cariappa, Hiromu Takematsu, Haoyuan Liu, Sandra Diaz, Khaleda Haider, Cristian Boboila, Geetika Kalloo, Michelle Connole, Hai Ning Shi, Nissi Varki, Ajit Varki, Shiv Pillai
Journal: The Journal of Experimental Medicine (2008)

We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of α2–6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.
Decreased NK Cells in Patients with Head and Neck Cancer Determined in Archival DNA
Authors: William P. Accomando, John K. Wiencke, E. Andres Houseman, Rondi A. Butler, Shichun Zheng, Heather H. Nelson, Karl T. Kelsey
Journal: Clinical Cancer Research (2012)

Natural killer (NK) cells are a key element of the innate immune system implicated in human cancer. To examine NK cell levels in archived bloods from a study of human head and neck squamous cell carcinoma (HNSCC), a new DNA-based quantification method was developed.NK cell-specific DNA methylation was identified by analyzing DNA methylation and mRNA array data from purified blood leukocyte subtypes (NK, T, B, monocytes, granulocytes), and confirmed via pyrosequencing and quantitative methylation specific PCR (qMSP). NK cell levels in archived whole blood DNA from 122 HNSCC patients and 122 controls were assessed by qMSP.Pyrosequencing and qMSP confirmed that a demethylated DNA region in NKp46 distinguishes NK cells from other leukocytes, and serves as a quantitative NK cell marker. Demethylation of NKp46 was significantly lower in HNSCC patient bloods compared with controls (P < 0.001). Individuals in the lowest NK tertile had over 5-fold risk of being a HNSCC case, controlling for age, gender, HPV16 status, cigarette smoking, alcohol consumption, and BMI (OR = 5.6, 95% CI, 2.0 to 17.4). Cases did not show differences in NKp46 demethylation based on tumor site or stage.The results of this study indicate a significant depression in NK cells in HNSCC patients that is unrelated to exposures associated with the disease. DNA methylation biomarkers of NK cells represent an alternative to conventional flow cytometry that can be applied in a wide variety of clinical and epidemiologic settings including archival blood specimens.
On Inconsistency of the Neighbor-Joining, Least Squares, and Minimum Evolution Estimation When Substitution Processes Are Incorrectly Modeled
Authors: E. Susko
Journal: Molecular Biology and Evolution (2004)

Using analytical methods, we show that under a variety of model misspecifications, Neighbor-Joining, minimum evolution, and least squares estimation procedures are statistically inconsistent. Failure to correctly account for differing rates-across-sites processes, failure to correctly model rate matrix parameters, and failure to adjust for parallel rates-across-sites changes (a rates-across-subtrees process) are all shown to lead to a "long branch attraction" form of inconsistency. In addition, failure to account for rates-across-sites processes is also shown to result in underestimation of evolutionary distances for a wide variety of substitution models, generalizing an earlier analytical result for the Jukes-Cantor model reported in Golding (Mol. Biol. Evol. 1:125–142, 1983) and a similar bias result for the GTR or REV model in Kelly and Rice (1996). Although standard rates-across-sites models can be employed in many of these cases to restore consistency, current models cannot account for other kinds of misspecification. We examine an idealized but biologically relevant case, where parallel changes in rates at sites across subtrees is shown to give rise to inconsistency. This changing rates-across-subtrees type model misspecification cannot be adjusted for with conventional methods or without carefully considering the rate variation in the larger tree. The results are presented for four-taxon trees, but the expectation is that they have implications for larger trees as well. To illustrate this, a simulated 42-taxon example is given in which the microsporidia, an enigmatic group of eukaryotes, are incorrectly placed at the archaebacteria-eukaryotes split because of incorrectly specified pairwise distances. The analytical nature of the results lend insight into the reasons that long branch attraction tends to be a common form of inconsistency and reasons that other forms of inconsistency like "long branches repel" can arise in some settings. In many of the cases of inconsistency presented, a particular incorrect topology is estimated with probability converging to one, the implication being that measures of uncertainty like bootstrap support will be unable to detect that there is a problem with the estimation. The focus is on distance methods, but previous simulation results suggest that the zones of inconsistency for distance methods contain the zones of inconsistency for maximum likelihood methods as well.
The impact of plasma levels of C-reactive protein, lipoprotein (a) and homocysteine on the long-term prognosis after successful coronary stenting
Authors: Michael N Zairis, John A Ambrose, Stavros J Manousakis, Alexander S Stefanidis, Olga A Papadaki, Helen I Bilianou, Mary C DeVoe, Constantine N Fakiolas, Evangelos G Pissimissis, Christopher D Olympios, Stefanos G Foussas
Journal: Journal of the American College of Cardiology (2002)
Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention
Authors: Pim A.L. Tonino, Bernard De Bruyne, Nico H.J. Pijls, Uwe Siebert, Fumiaki Ikeno, Marcel van `t Veer, Volker Klauss, Ganesh Manoharan, Thomas Engstrøm, Keith G. Oldroyd, Peter N. Ver Lee, Philip A. MacCarthy, William F. Fearon
Journal: New England Journal of Medicine (2009)

In patients with multivessel coronary artery disease who are undergoing percutaneous coronary intervention (PCI), coronary angiography is the standard method for guiding the placement of the stent. It is unclear whether routine measurement of fractional flow reserve (FFR; the ratio of maximal blood flow in a stenotic artery to normal maximal flow), in addition to angiography, improves outcomes.In 20 medical centers in the United States and Europe, we randomly assigned 1005 patients with multivessel coronary artery disease to undergo PCI with implantation of drug-eluting stents guided by angiography alone or guided by FFR measurements in addition to angiography. Before randomization, lesions requiring PCI were identified on the basis of their angiographic appearance. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions, whereas those assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was 0.80 or less. The primary end point was the rate of death, nonfatal myocardial infarction, and repeat revascularization at 1 year.The mean (+/-SD) number of indicated lesions per patient was 2.7+/-0.9 in the angiography group and 2.8+/-1.0 in the FFR group (P=0.34). The number of stents used per patient was 2.7+/-1.2 and 1.9+/-1.3, respectively (P<0.001). The 1-year event rate was 18.3% (91 patients) in the angiography group and 13.2% (67 patients) in the FFR group (P=0.02). Seventy-eight percent of the patients in the angiography group were free from angina at 1 year, as compared with 81% of patients in the FFR group (P=0.20).Routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year. (ClinicalTrials.gov number, NCT00267774.)
Concurrent Cetuximab, Cisplatin, and Concomitant Boost Radiotherapy for Locoregionally Advanced, Squamous Cell Head and Neck Cancer: A Pilot Phase II Study of a New Combined-Modality Paradigm
Authors: David G. Pfister, Yungpo Bernard Su, Dennis H. Kraus, Suzanne L. Wolden, Eric Lis, Timothy B. Aliff, Andrew J. Zahalsky, Simone Lake, Michael N. Needle, Ashok R. Shaha, Jatin P. Shah, Michael J. Zelefsky
Journal: Journal of Clinical Oncology (2006)

Purpose Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy. Patients and Methods Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m 2 intravenously weeks 1 and 4), and cetuximab (400 mg/m 2 intravenously week 1, followed by 250 mg/m 2 weeks 2 to 10). Results Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%. Conclusion This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.
ECM1 controls TH2 cell egress from lymph nodes through re-expression of S1P1
Authors: Zhenhu Li, Yuan Zhang, Zhiduo Liu, Xiaodong Wu, Yuhan Zheng, Zhiyun Tao, Kairui Mao, Jie Wang, Guomei Lin, Lin Tian, Yongyong Ji, Meiling Qin, Shuhui Sun, Xueliang Zhu, Bing Sun
Journal: Nature Immunology (2011)
Early Thymocyte Development Is Regulated by Modulation of E2a Protein Activity
Authors: Isaac Engel, Carol Johns, Gretchen Bain, Richard R. Rivera, Cornelis Murre
Journal: The Journal of Experimental Medicine (2001)

The E2A gene encodes the E47 and E12 basic helix-loop-helix (bHLH) transcription factors. T cell development in E2A-deficient mice is partially arrested before lineage commitment. Here we demonstrate that E47 expression becomes uniformly high at the point at which thymocytes begin to commit towards the T cell lineage. E47 protein levels remain high until the double positive developmental stage, at which point they drop to relatively moderate levels, and are further downregulated upon transition to the single positive stage. However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway. Consistent with these observations, a deficiency in E2A proteins completely abrogates the developmental block observed in mice with defects in TCR rearrangement. Thus E2A proteins are necessary for both initiating T cell differentiation and inhibiting development in the absence of pre-TCR expression. Mechanistically, these data link pre-TCR mediated signaling and E2A downstream target genes into a common pathway.
The Efficacy and Safety Of The Short Ragweed Sublingual Immunotherapy Tablet MK-3641 Is Similar In Asthmatic and Nonasthmatic Subjects Treated For Allergic Rhinitis With/Without Conjunctivitis (AR/C)
Authors: Jennifer Maloney, David I. Bernstein, Jacques Hébert, Martha White, Robert Fisher, Thomas B. Casale, Amarjot Kaur, Hendrik Nolte
Journal: Journal of Allergy and Clinical Immunology (2014)
Characterization of Chemokines and Adhesion Molecules Associated with T cell Presence in Tertiary Lymphoid Structures in Human Lung Cancer
Authors: Luc de Chaisemartin, Jérémy Goc, Diane Damotte, Pierre Validire, Pierre Magdeleinat, Marco Alifano, Isabelle Cremer, Wolf-Herman Fridman, Catherine Sautès-Fridman, Marie-Caroline Dieu-Nosjean
Journal: Cancer Research (2011)

De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies.
MDA-7 negatively regulates the β-catenin and PI3K signaling pathways in breast and lung tumor cells
Authors: Abner M Mhashilkar, Alexis L Stewart, Kerry Sieger, Heng-Yin Yang, Anis H Khimani, Isao Ito, Yuji Saito, Kelly K Hunt, Elizabeth A Grimm, Jack A Roth, Raymond E Meyn, Rajagopal Ramesh, Sunil Chada
Journal: Molecular Therapy (2003)

mda-7 is a novel tumor suppressor with cytokine properties. Adenoviral mda-7 (Ad-mda7) induces apoptosis and cell death selectively in tumor cells. The molecular mechanisms underlying the anti-tumor activity of Ad-mda7 in breast and lung cancer lines were investigated. Microarray analyses implicated both the β-catenin and the PI3K signaling pathways. Ad-mda7 treatment increased protein expression from tumor suppressor genes, including E-cadherin, APC, GSK-3β, and PTEN, and decreased expression of proto-oncogenes involved in β-catenin and PI3K signaling. Ad-mda7 caused a redistribution of cellular β-catenin from the nucleus to the plasma membrane, resulting in reduced TCF/LEF transcriptional activity, and upregulated the E-cadherin–β-catenin adhesion complex in a tumor cell-specific manner. Expression of the PI3K pathway members (p85 PI3K, FAK, ILK-1, Akt, and PLC-γ) was downregulated and expression of the PI3K antagonist PTEN was increased. Consistent with this result, pharmacological inhibition of PI3K by wortmannin did not abrogate killing by Ad-mda7. Killing of breast cancer cells by Ad-mda7 required both MAPK and MEK1/2 signaling pathways, whereas these pathways were not essential for MDA-7-mediated killing in lung cancer cells. Thus, in breast and lung tumor cells MDA-7 protein expression modulates cell–cell adhesion and intracellular signaling via coordinate regulation of the β-catenin and PI3K pathways.
The CD3-γδε and CD3-ζ/η Modules Are Each Essential for Allelic Exclusion at the T Cell Receptor β Locus but Are Both Dispensable for the Initiation of V to (D)J Recombination at the T Cell Receptor–β, –γ, and –δ Loci
Authors: Laurence Ardouin, Jamila Ismaili, Bernard Malissen, Marie Malissen
Journal: The Journal of Experimental Medicine (1998)

The pre–T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-β chain. Recent experiments in pre-Tα chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-β locus. Using CD3-ε– and CD3-ζ/η–deficient mice harboring a productively rearranged TCR-β transgene, we showed that the CD3-γδε and CD3-ζ/η modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-β locus. Furthermore, using mutant mice lacking both the CD3-ε and CD3-ζ/η genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-β, TCR-γ, and TCR-δ loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-β locus first accessible to, and later insulated from, the action of the V(D)J recombinase.
Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins
Authors: Aase Haj Hensvold, Patrik K E Magnusson, Vijay Joshua, Monika Hansson, Lena Israelsson, Ricardo Ferreira, Per-Johan Jakobsson, Rikard Holmdahl, Lennart Hammarström, Vivianne Malmström, Johan Askling, Lars Klareskog, Anca Irinel Catrina
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To investigate the role of genetic and environmental factors in the development of anticitrullinated protein antibodies (ACPA) and ACPA-positive rheumatoid arthritis (RA) in a twin cohort. <h3>Methods</h3> A total of 12 590 twins were analysed for the presence of ACPAs (CCP2 ELISA), HLA-DRB1 shared epitope (SE) gene alleles, and exposure to smoking. Twins with established RA were identified in national public care registers. Antibody reactivities against citrullinated and native forms of α-enolase, vimentin, fibrinogen and type II collagen peptides were tested by ELISA in anti-CCP2-positive subjects and their cotwins. Structural equation models and ORs for the development of ACPA and ACPA-positive RA were computed for smokers and SE carriers. <h3>Results</h3> A total of 2.8% (350/12 590) of the twins were ACPA positive, and 1.0% (124/12 590) had ACPA-positive RA. Most of the variability in the ACPA status was accounted for by non-shared environmental or stochastic factors (78%, 95% CI 55% to 100%) rather than shared environmental and genetic factors. Analysis of specific risk factors revealed an association between smoking and SE and the presence of ACPAs. Twins with ACPA-positive RA were more frequently SE positive than twins with ACPAs without RA. Reactivities against multiple citrullinated peptides were present in most twins with ACPA-positive RA but in fewer twins with ACPAs without RA. <h3>Conclusions</h3> Environment, lifestyle and stochastic factors may be more important than genetics in determining which individuals develop ACPAs. Genetic factors (particularly SE) may have a relatively larger role in determining which ACPA-positive individuals will ultimately develop arthritis.