tbuckley/cabot-search huggingface dataset:
T-cell receptor γ gene rearrangement in cutaneous T-cell lymphoma: comparative study of polymerase chain reaction with denaturing gradient gel electrophoresis and GeneScan analysis
Authors: A.L. Goeldel, P. Cornillet-Lefebvre, A. Durlach, P. Birembaut, P. Bernard, P. Nguyen, F. Grange
Journal: British Journal of Dermatology (2009)

Background The usefulness of T-cell receptor gene rearrangement (TCR-GR) analyses for differentiating cutaneous T-cell lymphoma (CTCL) from benign inflammatory disorders (BID) has been insufficiently studied to date. Objectives To evaluate the diagnostic value of TCR-GR analyses, comparing polymerase chain reaction (PCR) with denaturing gradient gel electrophoresis (DGGE) analysis and BIOMED-2 standardized protocol PCR with GeneScan analysis (BIOMED-2-GS). Methods Both types of PCR were performed in 157 patients evaluated for initial features suggestive of CTCL between 1996 and 2007. After clinical and histological review, the final diagnosis was CTCL in 77 cases and BID in 80 cases. Results DGGE and BIOMED-2-GS had a similar diagnostic value for distinguishing CTCL from BID, with a sensitivity of 74% and 77%, respectively, and a specificity of 86%. The observed concordance between both methods was 90% and the kappa coefficient was 0·79. Positivity rates did not depend on the PCR method but varied according to the type of CTCL (73–75% in mycosis fungoides, 90–100% in Sézary syndrome, 40–60% in lymphomatoid papulosis and 100% in other types). The positivity rate in BID was 14% with both methods. The most frequent BID with a monoclonal pattern were drug-induced cutaneous lymphoid hyperplasia, erythrodermic psoriasis and pityriasis lichenoides chronica. Conclusions BIOMED-2-GS analysis of the TCRγ gene is as sensitive and specific as DGGE for CTCL diagnosis. In addition, BIOMED-2-GS is less time-consuming and gives more information concerning the size and nature of TCR-GR.
Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib
Authors: Ralf Weichsel, Carolin Dix, Linda Wooldridge, Matthew Clement, Angharad Fenton-May, Andrew K. Sewell, Josef Zezula, Elisabeth Greiner, Emma Gostick, David A. Price, Hermann Einsele, Ruth Seggewiss
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator. Experimental Design: Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNγ, and tumor necrosis factor α), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction. Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations. Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell–driven autoimmune diseases.
CYTOMETRIC ASSAY OF TOXICITY OF BRUCELLA ANTIGENS FOR SENSITIZED AND NON-SENSITIZED CELLS FROM THE GUINEA PIG
Authors: Charles M. Carpenter, Morimichi Fukuda, Charles L. Heiskell
Journal: The Journal of Experimental Medicine (1962)

1. A significant cytotoxic effect of trypsinized, sensitized cell cultures was observed when re-exposed to Brucella antigens in vitro. 2. The cytometric assay of the toxic effects of Brucella antigens using trypsinized cells from sensitized animals provides an objective measure of induced cellular hypersensitivity.
Stimulation of acetylcholine receptors impairs host defence during pneumococcal pneumonia
Authors: I. A. J. Giebelen, M. Leendertse, S. Florquin, T. van der Poll
Journal: European Respiratory Journal (2008)

The cholinergic nervous system can inhibit the systemic inflammation accompanying sepsis by virtue of a specific action of acetylcholine on alpha7 cholinergic receptors. The current authors sought to determine the effect of nicotine, an alpha7 cholinergic receptor agonist, on the host response to pneumonia caused by Streptococcus pneumoniae. Mice were intranasally infected with S. pneumoniae and treated with nicotine or saline intraperitoneally using a treatment schedule shown to improve host defence against abdominal sepsis. Nicotine treatment was associated with a transiently enhanced growth of S. pneumoniae, as indicated by higher bacterial loads in both lungs and blood at 24 h after infection. At 48 h after infection, bacterial burdens had increased in both treatment groups and differences were no longer present. Remarkably, mice treated with nicotine showed enhanced lung inflammation at 24 h after infection. Moreover, both lung and plasma concentrations of the pro-inflammatory cytokines tumour necrosis factor-alpha and interferon-gamma were higher in nicotine-treated animals at this time-point. Additional studies examining the effect of nicotine on the immediate (4-h) inflammatory response to S. pneumoniae did not reveal an anti-inflammatory effect of nicotine either. The present data suggest that nicotine transiently impairs host defence in pneumococcal pneumonia.
T Cell Anergy
Authors: Ronald H. Schwartz
Journal: Annual Review of Immunology (2003)

T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4 + and CD8 + cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naïve T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.
The Diagnostic Accuracy of Reverse Transcription-PCR Quantification of Cytokeratin mRNA in the Detection of Sentinel Lymph Node Invasion in Oral and Oropharyngeal Squamous Cell Carcinoma: A Comparison with Immunohistochemistry
Authors: Renaud Garrel, Mathilde Dromard, Valérie Costes, Eric Barbotte, Frédéric Comte, Quentin Gardiner, César Cartier, Marc Makeieff, Louis Crampette, Bernard Guerrier, Nathalie Boulle
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The main goal of sentinel lymph node (SLN) detection in head and neck squamous cell carcinomas is to limit neck dissections to pN+ cases only. However, intraoperative + diagnosis cannot be routinely done using the current gold standard, serial step sectioning with immunohistochemistry. Real-time quantitative reverse transcription-PCR (RT-PCR) is potentially compatible with intraoperative use, proving highly sensitive in detecting molecular markers. This study postoperatively assessed the accuracy of quantitative RT-PCR in staging patients from their SLN. Experimental Design: A combined analysis on the same SLN by serial step sectioning with immunohistochemistry and quantitative RT-PCR targeting cytokeratins 5, 14, and 17 was done in 18 consecutive patients with oral or oropharyngeal squamous cell carcinoma and 10 control subjects. Results: From 71 lymph nodes examined, mRNA levels (KRT) were linked to metastasis size for the three cytokeratins studied (Pearson correlation coefficient, r = 0.89, 0.73, and 0.77 for KRT 5, 14, and 17 respectively; P &amp;lt; 0.05). Histopathology-positive SLNs (macro- and micrometastases) showed higher mRNA values than negative SLNs for KRT 17 (P &amp;lt; 10−4) and KRT 14 (P &amp;lt; 10−2). KRT 5 showed nonsignificant results. KRT 17 seemed to be the most accurate marker for the diagnosis of micrometastases of a size &amp;gt;450 μm. Smaller micrometastases and isolated tumor cells did not provide results above the background level. Receiver operating characteristic curve analysis for KRT 17 identified a cutoff value where patient staging reached 100% specificity and sensitivity for macro- and micrometastases. Conclusion: Quantitative RT-PCR for SLN staging in cN0 patients with oral and oropharyngeal squamous cell carcinoma seems to be a promising approach.
Screening for bone metastases. Are only scans necessary?
Authors: I. R. McDougall
Journal: JAMA (1975)

The results of total skeletal scintigraphy with technetium 99m-labeled diphosphonate in 200 patients with biopsy-proven primary cancer demonstrated abnormalities in 114; 57 had normal roentgenograms. In 32 of the 57 patients, the abnormalities were ascribed to malignant lesions. This is a false-negative rate of 17% for the roentgenographic examinations. Only three patients had abnormal roentgenograms but normal scans, a yield of 1.6% false-negative scans. In a comparison of scan and roentgenographic findings with the skeleton divided into 12 regions, 119 of 160 abnormalities seen on scans but not on roentgenograms were attributed to tumor. Only five of 17 regions that were abnormal on roentgenogram but not on scans were unexplained false-negative findings. Thus, on a regional basis, the yields of false-negative roentgenograms and scans were 9.1% and 0.4%, respectively. (<i>JAMA</i>231:46-50, 1975)
Modular expression analysis reveals functional conservation between human Langerhans cells and mouse cross-priming dendritic cells
Authors: Maxim N. Artyomov, Adiel Munk, Laurent Gorvel, Daniel Korenfeld, Marina Cella, Thomas Tung, Eynav Klechevsky
Journal: The Journal of Experimental Medicine (2015)

Characterization of functionally distinct dendritic cell (DC) subsets in mice has fueled interest in whether analogous counterparts exist in humans. Transcriptional modules of coordinately expressed genes were used for defining shared functions between the species. Comparing modules derived from four human skin DC subsets and modules derived from the Immunological Genome Project database for all mouse DC subsets revealed that human Langerhans cells (LCs) and the mouse XCR1+CD8α+CD103+ DCs shared the class I–mediated antigen processing and cross-presentation transcriptional modules that were not seen in mouse LCs. Furthermore, human LCs were enriched in a transcriptional signature specific to the blood cross-presenting CD141/BDCA-3+ DCs, the proposed equivalent to mouse CD8α+ DCs. Consistent with our analysis, LCs were highly adept at inducing primary CTL responses. Thus, our study suggests that the function of LCs may not be conserved between mouse and human and supports human LCs as an especially relevant therapeutic target.
Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells
Authors: Daniel R. Neill, William R. Coward, Jenna F. Gritzfeld, Luke Richards, Francesc J. Garcia-Garcia, Javier Dotor, Stephen B. Gordon, Aras Kadioglu
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization.We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage.Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage.We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-β1 by S. pneumoniae in human host cells and highlight the key role for TGF-β1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-β1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-β1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-β1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx.These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage.
Health-Related Quality of Life Predicts Major Amputation and Death, but Not Healing, in People With Diabetes Presenting With Foot Ulcers: The Eurodiale Study
Authors: Volkert Siersma, Hanne Thorsen, Per E. Holstein, Marleen Kars, Jan Apelqvist, Edward B. Jude, Alberto Piaggesi, Karel Bakker, Michael Edmonds, Alexandra Jirkovská, Didac Mauricio, Gunnel Ragnarson Tennvall, Heinrich Reike, Maximilian Spraul, Luigi Uccioli, Vilma Urbancic, Kristien van Acker, Jeff van Baal, Nicolaas C. Schaper
Journal: Diabetes Care (2013)

OBJECTIVE Low health-related quality of life (HRQoL) has been consistently reported to be associated with poor prognosis for a variety of health outcomes in various settings. We aimed to evaluate whether HRQoL in patients presenting with new diabetic foot ulcers (DFUs) has prognostic significance for ulcer healing, major amputation, and death. RESEARCH DESIGN AND METHODS We followed 1,088 patients with new DFUs presenting for treatment at one of the 14 centers in 10 European countries participating in the Eurodiale (European Study Group on Diabetes and the Lower Extremity) study, prospectively until healing (76.9%), major amputation (4.6%), or death (6.4%) up to a maximum of 1 year. At baseline, patient and ulcer characteristics were recorded as well as EQ-5D, a standardized instrument consisting of five domains and a visual analog scale for use as a measure of HRQoL. The prognostic influence of the EQ-5D domains was evaluated in multivariable Cox regression analyses on the time-to-event data, adjusting for baseline clinical characteristics of the ulcer and comorbidities. RESULTS While predictive effects of HRQoL, adjusted for possible confounders, were absent for healing, decreased HRQoL, especially in the physical domains, was statistically significant for major amputation (mobility, self-care, usual activities) and death (self-care, usual activities, pain/discomfort). CONCLUSIONS Low HRQoL appears to be predictive for major amputation and death, but high HRQoL does not increase healing. Future studies into the influence of HRQoL on ulcer outcome are important in attempts to decrease treatment failure and mortality.
Closed-Loop Artificial Pancreas Systems: Physiological Input to Enhance Next-Generation Devices
Authors: Yogish C. Kudva, Rickey E. Carter, Claudio Cobelli, Rita Basu, Ananda Basu
Journal: Diabetes Care (2014)

To provide an understanding of both the preclinical and clinical aspects of closed-loop artificial pancreas systems, we provide a discussion of this topic as part of this two-part Bench to Clinic narrative. Here, the Bench narrative provides an in-depth understanding of insulin-glucose-glucagon physiology in conditions that mimic the free-living situation to the extent possible in type 1 diabetes that will help refine and improve future closed-loop system algorithms. In the Clinic narrative, Doyle and colleagues compare and evaluate technology used in current closed-loop studies to gain further momentum toward outpatient trials and eventual approval for widespread use.
PURIFIED PROTEIN DERIVATIVE OF TUBERCULIN INDUCES IMMUNOGLOBULIN PRODUCTION IN NORMAL MOUSE SPLEEN CELLS
Authors: Bengt S. Nilsson, Barnet M. Sultzer, Wesley W. Bullock
Journal: The Journal of Experimental Medicine (1973)

Purified protein derivative (PPD) tuberculin induced immunoglobulin production in cultures of nonimmune mouse spleen cells, as measured by plaque-forming cells (PFC) against sheep erythrocytes (SRBC), horse erythrocytes, and 4-hydroxy-3,5-dinitrophenacetyl-SRBC. The increase started between 15 and 20 h of culture and reached a peak at 48–72 h. Higher PPD concentrations resulted in earlier peak responses than low concentrations. The Ig produced was mainly 19S and of very low avidity. The response elicited by PPD was of the same type as that caused by lipopolysaccharide of bacterial origin. Mitomycin treatment of cells before culture did not change the numbers of PFC/106 recovered cells but the cell recovery was considerably lower. Also injection of PPD in vivo resulted in increased numbers of PFC. On the basis of these results it is suggested that PPD nonspecifically activates a majority of the B cell population to proliferation and immunoglobulin synthesis.
Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery
Authors: I.H. Heijink, S.M. Brandenburg, D.S. Postma, A.J.M. van Oosterhout
Journal: European Respiratory Journal (2011)

Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far. We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) from COPD patients, nonsmokers and healthy smokers. We demonstrate that CSE rapidly and transiently impairs 16HBE barrier function, largely due to disruption of cell-cell contacts. CSE induced a similar, but stronger and more sustained, defect in PBECs. Application of the specific epidermal growth factor receptor (EGFR) inhibitor AG1478 showed that EGFR activation contributes to the CSE-induced defects in both 16HBE cells and PBECs. Furthermore, our data indicate that the endogenous protease calpain mediates these defects through tight junction protein degradation. CSE also delayed the reconstitution of 16HBE intercellular contacts during wound healing and attenuated PBEC barrier function upon wound regeneration. These findings were comparable between PBECs from smokers, healthy smokers and COPD patients. In conclusion, we demonstrate for the first time that CSE reduces epithelial integrity, probably by EGFR and calpain-dependent disruption of intercellular contacts. This may increase susceptibility to environmental insults, e.g. inhaled pathogens. Thus, EGFR may be a promising target for therapeutic strategies to improve mucosal barrier function in cigarette smoking-related disease.
Levels of Expression of <b> <i>CYR61</i> </b> and <b> <i>CTGF</i> </b> Are Prognostic for Tumor Progression and Survival of Individuals with Gliomas
Authors: Dong Xie, Dong Yin, He-Jing Wang, Gen-Tao Liu, Robert Elashoff, Keith Black, H. Phillip Koeffler
Journal: Clinical Cancer Research (2004)

Abstract The biological properties of CCN proteins include stimulation of cell proliferation, migration, and adhesion, as well as angiogenesis and tumorigenesis. We quantified CYR61, CTGF, WISP-1, and NOV mRNA expression levels in samples from sixty-six primary gliomas and five normal brain samples using quantitative real-time PCR assay. Statistical analysis was performed to explore the links between expression of the CCN genes and clinical and pathological parameters. Overexpression of CYR61, CTGF, WISP-1, and NOV occurred in 48% (32 of 66), 58% (38 of 66), 36% (24 of 66), and 15% (10 of 66) of primary gliomas, respectively. Interestingly, significant associations were found between CYR61 expression versus tumor grade, pathology, gender, and age at diagnosis. Also, a significant correlation existed between CTGF mRNA levels versus tumor grade, gender, and pathology. In contrast to CYR61 and CTGF, no significant association was found between expression of either WISP-1 or NOV versus any of the pathological features. Furthermore, Cox regression analysis showed that CYR61 and CTGF expression had a significant correlation with patient survival. These results suggest that CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance; and these proteins might serve as valuable targets for therapeutic intervention.
Relationship Between Glycosylated Hemoglobin Assessment and Glucose Therapy Intensification in Patients With Diabetes Hospitalized for Acute Myocardial Infarction
Authors: Joshua M. Stolker, John A. Spertus, Darren K. McGuire, Marcus Lind, Fengming Tang, Philip G. Jones, Silvio E. Inzucchi, Saif S. Rathore, Thomas M. Maddox, Frederick A. Masoudi, Mikhail Kosiborod
Journal: Diabetes Care (2012)

To evaluate the relationship between A1C and glucose therapy intensification (GTI) in patients with diabetes mellitus (DM) hospitalized for acute myocardial infarction (AMI).A1C was measured as part of routine care (clinical A1C) or in the core laboratory (laboratory A1C, results unavailable to clinicians). GTI predictors were identified using hierarchical Poisson regression.Of 1,274 patients, 886 (70%) had clinical A1C and an additional 263 had laboratory A1C measured. Overall, A1C was <7% in 419 (37%), 7-9% in 415 (36%), and >9% in 315 patients (27%). GTI occurred in 31% of patients and was more frequent in those with clinical A1C both before (34 vs. 24%, P < 0.001) and after multivariable adjustment (relative risk 1.34 [95% CI 1.12-1.62] vs. no clinical A1C).Long-term glucose control is poor in most AMI patients with DM, but only a minority of patients undergo GTI at discharge. Inpatient A1C assessment is strongly associated with intensification of glucose-lowering therapy.