tbuckley/cabot-search huggingface dataset:
Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort
Authors: D A Lomas, E K Silverman, L D Edwards, B E Miller, H O Coxson, R Tal-Singer
Journal: Thorax (2008)

<h3>Background:</h3> Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to Clara cell toxicity. It has therefore been suggested that this protein may be a useful marker of chronic obstructive pulmonary disease (COPD). <h3>Methods:</h3> Serum CC-16 levels were measured in 2083 individuals aged 40–75 years with COPD and a smoking history of ⩾10 pack-years, 332 controls with a smoking history of ⩾10 pack-years and normal lung function and 237 non-smoking controls. <h3>Results:</h3> Serum CC-16 had a coefficient of repeatability of 2.90 over 3 months in a pilot study of 267 individuals. The median serum CC-16 level was significantly reduced in a replication group of 1888 current and former smokers with COPD compared with 296 current and former smokers without airflow obstruction (4.9 and 5.6 ng/ml, respectively; p&lt;0.001) and 201 non-smokers (6.4 ng/ml; p&lt;0.001). Serum levels of CC-16 were lower in current than in former smokers with GOLD stage II and III COPD but were not different in individuals with stage IV disease. Former, but not current smokers, with COPD had lower serum CC-16 levels with increasing severity of COPD (GOLD II vs GOLD IV COPD: 5.5 and 5.0 ng/ml, p = 0.006; r = 0.11 with forced expiratory volume in 1 s, p&lt;0.001) and had significantly higher levels if they also had reversible airflow obstruction (p = 0.034). Serum CC-16 was affected by gender and age (r = 0.35; p&lt;0.001) in subjects with COPD but not by body mass index or the presence of either chronic bronchitis or emphysema. <h3>Conclusions:</h3> Serum CC-16 levels are reduced in individuals with COPD and there is a weak correlation with disease severity in former smokers. <h3>Trial registration number:</h3> SCO104960, NCT00292552.
The alpha 3 domain of the Qa-2 molecule is defective for CD8 binding and cytotoxic T lymphocyte activation.
Authors: M Teitell, H Holcombe, H Cheroutre, C J Aldrich, I Stroynowski, J Forman, M Kronenberg
Journal: The Journal of Experimental Medicine (1993)

Qa-2 is a nonclassical class I molecule encoded by the Q7 gene within the mouse major histocompatibility complex (MHC). Results from previous experiments on Qa-2, and on a chimeric Ld molecule (LQ3) in which the alpha 3 domain is encoded by Q7b, suggested that the alpha 3 domain of Qa-2 does not carry out the functions typical of the alpha 3 domains in other classical and nonclassical class I antigens. Class I molecules that contain the Qa-2 alpha 3 domain are poorly recognized by primary cytotoxic T lymphocytes (CTLs), and do not function normally in either positive or negative selection in vivo. By employing a cell-cell adhesion assay we demonstrate directly that the Qa-2 alpha 3 domain in the context of the LQ3 hybrid molecule cannot bind to human CD8, although other mouse class I alpha 3 domains bind efficiently. In addition, CD8-dependent CTL-mediated lysis of target cells, in a system which requires mouse CD8-class I alpha 3 domain interactions, is deficient in cells that express the Qa-2 alpha 3 domain. When combined with our earlier work on LQ3 transgenic mice, these results provide additional molecular support for the hypothesis that interaction with CD8 is required for both positive and negative selection of class I restricted T cells in the thymus. As the Qa-2 alpha 3 domain sequence does not differ from the previously defined minimal CD8 binding sequence of other class I molecules, these results also suggest that additional amino acids in the alpha 3 domain must be critical for CD8 binding and CTL activation.
Tired surgical trainees: unfit to drive but fit to operate?
Authors: R. Jeffers
Journal: BMJ (2002)

EDITOR—Last week Mr Gary Hart was sentenced to five years' imprisonment for causing the Selby rail crash and the deaths of 10 people by dangerous driving after falling asleep at the wheel. A tragic chain of events led to the deaths of 10 people and injury of more than 70 people when Mr Hart fell asleep while driving his Land Rover, causing it to veer off the M62 and on to a railway. The …
Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma
Authors: H. Pels, A. Juergens, I. Schirgens, A. Glasmacher, H. Schulz, A. Engert, G. Schackert, H. Reichmann, F. Kroschinsky, M. Vogt-Schaden, G. Egerer, U. Bode, M. Deckert, R. Fimmers, H. Urbach, I. G. H. Schmidt-Wolf, U. Schlegel
Journal: Neuro-Oncology (2010)

In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain "prognostic groups". However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0–124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.
Fibroblast Growth Factor Homologous Factor 13 Regulates Na <sup>+</sup> Channels and Conduction Velocity in Murine Hearts
Authors: Chuan Wang, Jessica A. Hennessey, Robert D. Kirkton, Chaojian Wang, Victoria Graham, Ram S. Puranam, Paul B. Rosenberg, Nenad Bursac, Geoffrey S. Pitt
Journal: Circulation Research (2011)

Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na(+) channels and have been linked to neurodegenerative diseases. Although certain FHFs have been found in embryonic heart, they have not been reported in adult heart, and they have not been shown to regulate endogenous cardiac Na(+) channels or to participate in cardiac pathophysiology.We tested whether FHFs regulate Na(+) channels in murine heart.We demonstrated that isoforms of FGF13 are the predominant FHFs in adult mouse ventricular myocytes. FGF13 binds directly to, and colocalizes with, the Na(V)1.5 Na(+) channel in the sarcolemma of adult mouse ventricular myocytes. Knockdown of FGF13 in adult mouse ventricular myocytes revealed a loss of function of Na(V)1.5-reduced Na(+) current density, decreased Na(+) channel availability, and slowed Na(V)1.5-reduced Na(+) current recovery from inactivation. Cell surface biotinylation experiments showed ≈45% reduction in Na(V)1.5 protein at the sarcolemma after FGF13 knockdown, whereas no changes in whole-cell Na(V)1.5 protein or in mRNA level were observed. Optical imaging in neonatal rat ventricular myocyte monolayers demonstrated slowed conduction velocity and a reduced maximum capture rate after FGF13 knockdown.These findings show that FHFs are potent regulators of Na(+) channels in adult ventricular myocytes and suggest that loss-of-function mutations in FHFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from Na(V)1.5 loss-of-function mutations.
Arsenic Trioxide and the Phosphoinositide 3-Kinase/Akt Pathway in Chronic Lymphocytic Leukemia
Authors: Dennis J. Goussetis, Leonidas C. Platanias
Journal: Clinical Cancer Research (2010)

Abstract Simultaneous targeting of the phosphoinositide 3-kinase (PI3K)/Akt pathway increases arsenic trioxide (ATO)–dependent cytotoxicity of chronic lymphocytic leukemia (CLL) cells, whereas it has no significant effects on normal lymphocytes. Combinations of ATO with small molecules that target PI3K and/or Akt may provide a novel approach for the treatment of CLL. Clin Cancer Res; 16(17); 4311–2. ©2010 AACR.
Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO)
Authors: J. Vansteenkiste, F. Barlesi, C.F. Waller, J. Bennouna, C. Gridelli, E. Goekkurt, D. Verhoeven, A. Szczesna, M. Feurer, J. Milanowski, P. Germonpre, H. Lena, D. Atanackovic, M. Krzakowski, C. Hicking, J. Straub, M. Picard, W. Schuette, K. O'Byrne
Journal: Annals of Oncology (2015)
Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4
Authors: Y. Cheng, P. Zhu, J. Yang, X. Liu, S. Dong, X. Wang, B. Chun, J. Zhuang, C. Zhang
Journal: Cardiovascular Research (2010)

The aims of the present study are to determine the miRNA expression signature in rat hearts after ischaemic preconditioning (IP) and to identify an IP-regulated miRNA, miR-21, in IP-mediated cardiac protection, and the potential cellular and molecular mechanisms involved. The miRNA expression signature was investigated in rat hearts. Among the 341 arrayed miRNAs, 40 miRNAs were differentially expressed (21 up and 19 down) in rat hearts with IP, compared with their controls. Some of these differentially expressed miRNAs were further verified by quantitative reverse transcriptase–polymerase chain reaction. Remarkably, miR-21 was one of most upregulated miRNAs in hearts after IP. In vivo, IP-mediated cardiac protection against ischaemia/reperfusion injury was inhibited by knockdown of cardiac miR-21. In cultured cardiac myocytes, we identified that miR-21 also had a protective effect on hypoxia/reoxygenation-induced cell apoptosis that was associated with its target gene, programmed cell death 4. The protective effect of miR-21 on cardiac cell apoptosis was further confirmed in rat hearts after ischaemia/reperfusion injury in vivo. The results suggest that miRNAs are involved in IP-mediated cardiac protection. Identifying the roles of IP-regulated miRNAs in cardiac protection may provide novel therapeutic and preventive targets for ischaemic heart disease.
Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma
Authors: Nicolaus Kröger, Rainer Schwerdtfeger, Michael Kiehl, Herbert Gottfried Sayer, Helmut Renges, Tatjana Zabelina, Boris Fehse, Florian Tögel, Georg Wittkowsky, Rolf Kuse, Axel Rolf Zander
Journal: Blood (2002)
Abstract 3221: Covalent inhibitors of S100B (SBiXs) in malignant melanoma
Authors: Michael C. Cavalier
Journal: Cancer Research (2014)

Abstract Summary: The calcium binding protein, S100B, has been directly linked to malignant melanoma (MM) and has long been used as a prognostic indicator. Studies have proven S100B to not only be a clinical marker within MM, but that it binds to the tumor suppressor p53, and promotes its degradation. p53 is typically found as wild-type in MM, and inhibition of S100B expression restores both p53 protein levels and normal transcriptional activation/apoptosis activities. Subsequently, we have made it our long-term goal to discover S100B inhibitors (SBiXs) in order to restore the p53 tumor suppression function in patients with MM, and have already identified many SBiXs. Purpose: It is our purpose to discover/synthesize and/or to improve existing inhibitors of S100B to restore p53 activity in human malignant melanoma. Amongst these SBiXs are compounds which covalently modify S100B. The effects of covalent SBiXs on S100B in Malignant Melanoma are to be investigated. Results and conclusions: The development of S100B inhibitors (SBiXs) is ongoing at the University of Maryland Schools of Pharmacy and Medicine with the goal of improving affinity and specificity towards inhibiting S100B. Fluorescent Polarization Completion Assays have identified compounds that bind S100B and inhibit melanoma cell growth. S100B binding by these SBiXs was confirmed using NMR spectroscopy. The crystallographic structures of the SBiX:S100B complexes were solved revealing covalent modifiers occupying persistent binding site 2. The compounds offer potential bridging scaffolds between sites 1 and 3. All five SBiXs demonstrated the ability to kill malignant melanoma with some killing in a S100B dependent manner. TheS100B-SBiX complexes presented will act as the basis for the design of improved SBiXs. SBiXs may also have therapeutic value for treating other cancers with elevated S100B and wt p53 such as astrocytoma, renal tumors, and some forms of leukemia. Citation Format: Michael C. Cavalier. Covalent inhibitors of S100B (SBiXs) in malignant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3221. doi:10.1158/1538-7445.AM2014-3221
Case Definitions for Acute Coronary Heart Disease in Epidemiology and Clinical Research Studies
Authors: Russell V. Luepker, Fred S. Apple, Robert H. Christenson, Richard S. Crow, Stephen P. Fortmann, David Goff, Robert J. Goldberg, Mary M. Hand, Allan S. Jaffe, Desmond G. Julian, Daniel Levy, Teri Manolio, Shanthi Mendis, George Mensah, Andrzej Pajak, Ronald J. Prineas, K. Srinath Reddy, Veronique L. Roger, Wayne D. Rosamond, Eyal Shahar, A. Richey Sharrett, Paul Sorlie, Hugh Tunstall-Pedoe
Journal: Circulation (2003)

HomeCirculationVol. 108, No. 20Case Definitions for Acute Coronary Heart Disease in Epidemiology and Clinical Research Studies
Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival
Authors: Ibrahim Batal, Sacha A De Serres, Kassem Safa, Vanesa Bijol, Takuya Ueno, Maristela L Onozato, A John Iafrate, Jan M Herter, Andrew H Lichtman, Tanya N Mayadas, Indira Guleria, Helmut G Rennke, Nader Najafian, Anil Chandraker
Journal: Journal of the American Society of Nephrology (2015)

Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients. High dendritic cell density was associated with poor allograft survival independent of clinical variables. Moreover, high dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. We then explored the association between dendritic cells and histologic variables associated with poor prognosis. Multivariate analysis revealed an independent association between the densities of dendritic cells and T cells. In biopsy samples with high dendritic cell density, electron microscopy showed direct physical contact between infiltrating lymphocytes and cells that have the ultrastructural morphologic characteristics of dendritic cells. The origin of graft dendritic cells was sought in nine sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor dendritic cells predominated initially, the majority of dendritic cells in late allograft biopsy samples were of recipient origin. Our data highlight the prognostic value of dendritic cell density in allograft biopsy samples, suggest a new role for these cells in shaping graft inflammation, and provide a rationale for targeting dendritic cell recruitment to promote long-term allograft survival.
CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha.
Authors: C Caux, B Vanbervliet, C Massacrier, C Dezutter-Dambuyant, B de Saint-Vis, C Jacquet, K Yoneda, S Imamura, D Schmitt, J Banchereau
Journal: The Journal of Experimental Medicine (1996)

Human dendritic cells (DC) can now be generated in vitro in large numbers by culturing CD34+ hematopoietic progenitors in presence of GM-CSF+TNF alpha for 12 d. The present study demonstrates that cord blood CD34+ HPC indeed differentiate along two independent DC pathways. At early time points (day 5-7) during the culture, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 emerge independently. Both precursor subsets mature at day 12-14 into DC with typical morphology and phenotype (CD80, CD83, CD86, CD58, high HLA class II). CD1a+ precursors give rise to cells characterized by the expression of Birbeck granules, the Lag antigen and E-cadherin, three markers specifically expressed on Langerhans cells in the epidermis. In contrast, the CD14+ progenitors mature into CD1a+ DC lacking Birbeck granules, E-cadherin, and Lag antigen but expressing CD2, CD9, CD68, and the coagulation factor XIIIa described in dermal dendritic cells. The two mature DC were equally potent in stimulating allogeneic CD45RA+ naive T cells. Interestingly, the CD14+ precursors, but not the CD1a+ precursors, represent bipotent cells that can be induced to differentiate, in response to M-CSF, into macrophage-like cells, lacking accessory function for T cells. Altogether, these results demonstrate that different pathways of DC development exist: the Langerhans cells and the CD14(+)-derived DC related to dermal DC or circulating blood DC. The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts.
Metabolic reduction of chromium by alveolar macrophages and its relationships to cigarette smoke.
Authors: F L Petrilli, G A Rossi, A Camoirano, M Romano, D Serra, C Bennicelli, A De Flora, S De Flora
Journal: Journal of Clinical Investigation (1986)

Pulmonary alveolar macrophages (PAM), obtained by bronchoalveolar lavage from 47 individuals, reduced hexavalent chromium [Cr(VI)] and decreased its mutagenicity. Their specific activity--mostly mediated by cytosolic, enzyme-catalyzed mechanisms--was significantly higher than in corresponding preparations of mixed-cell populations from human peripheral lung parenchyma or bronchial tree, or from rat lung or liver. At equivalent number of PAM, Cr(VI) reduction, total protein, and some oxidoreductase activities were significantly increased in smokers. No appreciable variation could be detected between lung cancer and noncancer patients. In rats, the Cr(VI)-reducing activity of PAM preparations was induced by Aroclor 1254. Thus, alveolar macrophages provide crucial defense mechanisms not only by phagocytizing metals, but also by metabolically reducing Cr(VI). The epithelial-lining fluid (ELF) also displayed some Cr(VI) reduction. Together with already investigated metabolic processes occurring inside lung cells, these mechanisms are expected to determine thresholds in the pulmonary carcinogenicity of chromium.
Safety and Biological Activity of Repeated Doses of Recombinant Human Flt3 Ligand in Patients with Bone Scan-Negative Hormone-Refractory Prostate Cancer
Authors: Celestia S. Higano, Nicholas J. Vogelzang, Jeffrey A. Sosman, Anyang Feng, Dania Caron, Eric J Small
Journal: Clinical Cancer Research (2004)

The purpose of this study was to evaluate the safety, biological activity, and feasibility of repeated doses of the dendritic cell (DC)-stimulating agent Flt3 ligand (FL) in patients with bone scan-negative hormone-refractory prostate cancer.Thirty-one patients with hormone-refractory prostate cancer who had elevated prostate-specific antigen (PSA) levels and negative bone scans were enrolled. Six cycles (28 days each) were planned. In the first cycle, patients were randomized to FL or placebo. All patients received open-label FL during the next five courses. DC, anti-FL antibody, and PSA levels were measured every 15 days to assess biological activity.DCs increased markedly in FL-treated patients from precycle to day 15, and the increase was consistent in each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% precycle and from 10.1% to 13.9% on day 15, and after the first cycle, absolute counts on day 15 were approximately 29-fold higher than precycle levels. Natural killer cell counts (CD56(+)) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22). Twenty-two of 27 patients tested developed nonneutralizing anti-FL antibody. The most frequently experienced toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007).FL was well tolerated. FL consistently produced an increase in DC count without any evidence of decreasing response with continued exposure. The expansion of DCs and the slowing of PSA velocity after administration of FL suggest potential clinical applications in the immunotherapy of prostate cancer.
Efficacy and tolerance of rifampicin–linezolid compared with rifampicin–cotrimoxazole combinations in prolonged oral therapy for bone and joint infections
Authors: S. Nguyen, A. Pasquet, L. Legout, E. Beltrand, L. Dubreuil, H. Migaud, Y. Yazdanpanah, E. Senneville
Journal: Clinical Microbiology and Infection (2009)
MicroRNA-210 as a Novel Therapy for Treatment of Ischemic Heart Disease
Authors: Shijun Hu, Mei Huang, Zongjin Li, Fangjun Jia, Zhumur Ghosh, Maarten A. Lijkwan, Pasquale Fasanaro, Ning Sun, Xi Wang, Fabio Martelli, Robert C. Robbins, Joseph C. Wu
Journal: Circulation (2010)

MicroRNAs are involved in various critical functions, including the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. We hypothesize that microRNA-210 can rescue cardiac function after myocardial infarction by upregulation of angiogenesis and inhibition of cellular apoptosis in the heart.Using microRNA microarrays, we first showed that microRNA-210 was highly expressed in live mouse HL-1 cardiomyocytes compared with apoptotic cells after 48 hours of hypoxia exposure. We confirmed by polymerase chain reaction that microRNA-210 was robustly induced in these cells. Gain-of-function and loss-of-function approaches were used to investigate microRNA-210 therapeutic potential in vitro. After transduction, microRNA-210 can upregulate several angiogenic factors, inhibit caspase activity, and prevent cell apoptosis compared with control. Afterward, adult FVB mice underwent intramyocardial injections with minicircle vector carrying microRNA-210 precursor, minicircle carrying microRNA-scramble, or sham surgery. At 8 weeks, echocardiography showed a significant improvement of left ventricular fractional shortening in the minicircle vector carrying microRNA-210 precursor group compared with the minicircle carrying microRNA-scramble control. Histological analysis confirmed decreased cellular apoptosis and increased neovascularization. Finally, 2 potential targets of microRNA-210, Efna3 and Ptp1b, involved in angiogenesis and apoptosis were confirmed through additional experimental validation.MicroRNA-210 can improve angiogenesis, inhibit apoptosis, and improve cardiac function in a murine model of myocardial infarction. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.