tbuckley/cabot-search huggingface dataset:
Hematopoietic growth factors.
Authors: C A Sieff
Journal: Journal of Clinical Investigation (1987)

The process of blood cell formation, by which a small number of self-renewing stem cells give rise to lineage committed pro- genitor cells that subsequently proliferate and differentiate to produce the circulating mature blood cells, is sustained through- out life by a group of glycoprotein hormonal growth factors.These hormones are known collectively as the colony-stimulating factors (CSFs)' (1); the term derives from the in vitro observation that the CSFs stimulate progenitor cells of different hemato- poietic cell lineages to form discrete colonies of recognizable maturing cells.The different factors have been operationally de- fined by prefixes denoting the major type of colony produced, e.g., granulocyte maprophage CSF (GM-CSF).Not only is the presence of CSF5 necessary for the proliferation of progenitor cells but these factors affect the function of mature cells as well (2-8); furthermore, they may be the major regulators ofincreased cell production during states of increased demand.It is not yet clear whether they play a pathogenetic role in some forms of leukemia.During the past few years, the genes for five murine and human factors have been cloned, and recombinant forms ofthe proteins produced and purified.The recombinant CSFs have similar actions to their natural counterparts.The prospect of their availability in large quantities has provided the impetus for intensive investigation into their actions, to identify circumstances in which they may be therapeutically useful.The he- matopoietic system with its regulators also serves as a paradigm for other systems with self-renewing stem cell populations sustaining the production ofboth shortand long-lived mature cells. Types ofCSFRecent data on the biological activities ofseveral highly purified recombinant hormones have led to the appreciation that the existing nomenclature is inadequate.For example, although hu- man GM-CSF was initially described as a factor stimulating production ofgranulocyte and/or macrophage colonies, it is now
Novel Genetic Approach for In Vivo Vascular Imaging in Mice
Authors: Benjamin B. Bartelle, César A. Berríos-Otero, Joe J. Rodriguez, Anne E. Friedland, Orlando Aristizábal, Daniel H. Turnbull
Journal: Circulation Research (2012)

The formation and maintenance of a functional vasculature is essential for normal embryonic development, and genetic changes that affect the vasculature underlie pathogenesis in many human diseases. In vivo imaging in mouse models is required to understand the full complexity of mammalian vascular formation, which is a dynamic and 3-dimensional process. Optical microscopy of genetically expressed fluorescent reporter proteins offers high resolution but limited depth of penetration in vivo. Conversely, there are a plethora of molecular probes for alternative in vivo vascular imaging modalities, but few options for genetic control of contrast enhancement.To develop a reporter system for multimodal imaging of genetic processes involved in mammalian vascular biology.To approach this problem, we developed an optimal tagging system based on Biotag-BirA technology. In the resulting Biotag reporter system, coexpression of 2 interacting proteins results in biotin labeling of cell membranes, thus enabling multimodal imaging with "avidinated" probes. To assess this approach for in vivo imaging, we generated transgenic mice that expressed the Biotag-BirA transgene from a minimal Tie2 promoter. A variety of imaging methods were used to show the utility of this approach for quantitative analysis in embryonic and adult models of vascular development, using intravascular injection of avidinated probes for near infrared, ultrasound, and magnetic resonance imaging.The present results demonstrate the versatility of the Biotag system for studies of vascular biology in genetically engineered mice, providing a robust approach for multimodal in vivo imaging of genetic processes in the vasculature.
Accuracy of computed tomographic colonography in a nationwide multicentre trial, and its relation to radiologist expertise
Authors: D. Heresbach, M. Djabbari, F. Riou, C. Marcus, A. Le Sidaner, M. A. Pierredon-Foulogne, T. Ponchon, M. Boudiaf, J. A. Seyrig, H. Laumonier, D. Luet, M. Giraud-Cohen, A. L. Pelletier, A. Charachon, F. Ramaholimihaso, P. Bouillet, M. Veyrac, S. Ficarelli, K. Vahedi, J. Keruhel, H. Lamouliatte, C. Ridereau-Zins, Y. Bouhnik, M. Tissier, B. Diris, A. M. Zagdanski, J. M. Josselin, S. Hamonic, Y. Gandon
Journal: Gut (2011)

<h3>Objective</h3> Reports on the accuracy of computed tomographic colonography (CTC) mainly involve series from expert institutions. The aims of this study were to assess CTC accuracy in a nationwide population and to relate it to radiologist performance in their initial training. <h3>Design</h3> Nationwide multicentre trial. <h3>Setting</h3> Twenty-eight radiologists, working in 26 mostly academic clinical units, were involved in the study after having attended a formal specialised 2-day training session on CTC. They worked through a training set of 52 cases with automatic feedback after an attempt at each case. <h3>Patients</h3> The study enrolled 845 patients with average and high risk of colorectal cancer, 737 of whom had both complete CTC and videocolonoscopy data, which constituted the dataset. <h3>Interventions</h3> Patients underwent same-day CTC followed by videocolonoscopy with segmental unblinding of CTC results. <h3>Main outcome measures</h3> Sensitivity, specificity and positive and negative predictive values for detection of polyps ≥6 mm in per-patient and per-lesion analyses of CTC without computer-aided detection. <h3>Results</h3> Sensitivity, specificity and positive and negative predictive values for patients with polyps ≥6 mm were 69% (95% CI 61% to 77%), 91% (95% CI 89% to 94%), 67% (95% CI 59% to 74%) and 92% (95% CI 90% to 94%), respectively. Univariate analysis showed that the detection rate for polyps ≥6 mm was linked to neither radiologist case volume nor number of polyps, but was related to sensitivity achieved in the training set. Pooled sensitivity was 72% (95% CI 63% to 80%) versus 51% (95% CI 40% to 60%) for radiologists achieving above and below median sensitivity in the training set (61%), respectively. Multivariate analysis showed that sensitivity for polyps ≥6 mm in the training set was the only remaining significant predictive factor for subsequent performance. <h3>Conclusions</h3> Radiologist sensitivity CTC for detection of polyps ≥6 mm in training was the sole independent predictor for subsequent sensitivity in detection of such polyps.
Intravascular Ultrasound Evidence for Coarctation Causing Symptomatic Renal Artery Stenosis
Authors: Trude C. Leertouwer, Elma J. Gussenhoven, Lukas C. van Dijk, Jeroen A. van Essen, Jan Honkoop, Jaap Deinum, Peter M. T. Pattynama
Journal: Circulation (1999)

A recent study of human cadaveric renal arteries revealed that renal artery narrowing could be due not only to atherosclerotic plaque compensated for by adaptive remodeling, but also to hitherto undescribed focal narrowing of an otherwise normal renal arterial wall (ie, coarctation). The present study investigated whether vessel coarctation could be identified in patients with symptomatic renal artery stenosis (RAS).Consecutive symptomatic patients with angiographically proven atherosclerotic RAS who were referred for stent placement were studied by 30-MHz intravascular ultrasound before intervention (n=18) or after predilatation (n=18). Analysis included assessment of the media-bounded area and plaque area (PLA) at the most stenotic site and at a distal reference site (most distal cross-section in the main renal artery with normal appearance). Coarctation was considered present whenever the target/reference media-bounded area was </=85%. Before intervention, coarctation was observed in 9 of 18 patients and adaptive remodeling in 9 of 18 patients. Coarctation lesions had a significantly smaller PLA than adaptive remodeled lesions (P=0.001). Similarly, despite predilatation, coarctation was seen in 8 of 18 patients who had significantly smaller PLAs (P=0. 008) when compared with those patients who had adaptive remodeled lesions. No differences in severity of RAS or angiographic or clinical parameters were observed.Low-plaque coarctation may cause a considerable proportion of symptomatic RAS, which is angiographically and clinically indistinguishable from plaque-rich RAS.
βII‐Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin
Authors: Xiuling Zhi, Ling Lin, Shaoxian Yang, Krithika Bhuvaneshwar, Hongkun Wang, Yuriy Gusev, Mi‐Hye Lee, Bhaskar Kallakury, Narayan Shivapurkar, Katherine Cahn, Xuefei Tian, John L. Marshall, Stephen W. Byers, Aiwu R. He
Journal: Hepatology (2014)

βII‐Spectrin (SPTBN1) is an adapter protein for Smad3/Smad4 complex formation during transforming growth factor beta (TGF‐β) signal transduction. Forty percent of SPTBN1 +/− mice spontaneously develop hepatocellular carcinoma (HCC), and most cases of human HCC have significant reductions in SPTBN1 expression. In this study, we investigated the possible mechanisms by which loss of SPTBN1 may contribute to tumorigenesis. Livers of SPTBN1 +/− mice, compared to wild‐type mouse livers, display a significant increase in epithelial cell adhesion molecule‐positive (EpCAM + ) cells and overall EpCAM expression. Inhibition of SPTBN1 in human HCC cell lines increased the expression of stem cell markers EpCAM, Claudin7, and Oct4, as well as decreased E‐cadherin expression and increased expression of vimentin and c‐Myc, suggesting reversion of these cells to a less differentiated state. HCC cells with decreased SPTBN1 also demonstrate increased sphere formation, xenograft tumor development, and invasion. Here we investigate possible mechanisms by which SPTBN1 may influence the stem cell traits and aggressive behavior of HCC cell lines. We found that HCC cells with decreased SPTBN1 express much less of the Wnt inhibitor kallistatin and exhibit decreased β‐catenin phosphorylation and increased β‐catenin nuclear localization, indicating Wnt signaling activation. Restoration of kallistatin expression in these cells reversed the observed Wnt activation. Conclusion : SPTBN1 expression in human HCC tissues is positively correlated with E‐cadherin and kallistatin levels, and decreased SPTBN1 and kallistatin gene expression is associated with decreased relapse‐free survival. Our data suggest that loss of SPTBN1 activates Wnt signaling, which promotes acquisition of stem cell‐like features, and ultimately contributes to malignant tumor progression. (H epatology 2015;61:598‐612)
Does beta2 adrenoceptor (ADRβ2) density vary in circulating lymphyocytes compared with monocytes
Authors: Li Ping Chung, Svetlana Baltic, Grant Waterer, Philip Thompson
Journal: European Respiratory Journal (2011)

Circulating lymphocytes are increasingly used as a surrogate cell type to reflect changes in ADRβ2 density elsewhere in the body, particularly the respiratory system. However, ADRβ2 density is non-uniform among lymphocyte subsets and potentially varies between individuals.   Aim:  To assess the extent of variability in ADRβ2 density on human peripheral blood mononuclear cells (PBMC) including lymphocytes and monocytes.   Method:  PBMC were isolated from 10 healthy subjects by density gradient centrifugation with Ficoll-Paque. Cell surface & total ADRβ2 of lymphocytes (CD14+) and monocytes (CD3+) measured using FACS. Geometric mean fluorescence (GMF) was used as the indices for ADRβ2 density per cell.   Result:  Surface ADRβ2  - GMF increased by 3.54 and 4.62 folds over negative controls for lymphocytes and monocytes respectively (p=0.16). However, distribution of GMF between samples suggests greater variability in ADRβ2 density in lymphocytes vs monocytes (p=0.06). Proportion of ADRβ2-positive cells was higher in monocytes vs lymphocytes (71.9% vs 36.7, p=0.02).  Total ADRβ2  – GMF increased by 12.4 and 9.61 folds for lymphocytes and monocytes respectively (p>0.05). Proportion of ADRβ2-positive cells were similar between samples (lymphocytes 80%, monocytes 86%, p>0.05) but greater variability was observed for lymphocytes (range 27–99%) vs monocytes (range 66–100%).   Conclusions:  Despite similarities in surface and total ADRβ2 density, lymphocytes display greater inter-subject variability compared with monocytes. This has implication in experimental designs & interpretation of changes in ADRβ2 density in studies using human PBMC as an alternative to primary cells from organ of interest.
Inhaled vilanterol trifenatate/fluticasone furoate increases maximum diaphragm contraction in severe COPD
Authors: Jenny Jagers, Michael Ji, Malcolm Johnson, Eric Wilde, Paul Easton
Journal: European Respiratory Journal (2014)

Inhaled vilanterol trifenatate/fluticasone furoate (VFF), an ultra long acting beta2 agonist/ICS combination (Relvar) may change respiratory muscle activation and diaphragm contractility. Beta agonist effects on respiratory muscle activity have been shown in normal mammals and COPD patients (Resp Phys 2008 161:253-60,Chest 2010 137:558-65). Magnetic supra maximal phrenic nerve stimulation (MagStim) was utilized to assess diaphragm contraction via measurement of mouth pressure. 6 patients with severe COPD (mean FEV1 0.68), very minimally reversible (no change in FRC, IC or lung volumes) were studied before and 2 hrs after 2 puffs of VFF while breathing quietly, recording mouth pressure, and airflow through a pneumotach. MagStim was discharged at FRC (end expiratory zero airflow) and at selected points in inspiration and expiration, unanticipated by the subject. For all subjects, pressure from maximum diaphragm contraction by MagStim increased significantly after VFF (p<0.01). Similarly at matching points during the breathing cycle, lengths shorter than FRC, maximal contraction pressure increased after VFF (p<0.01). In severe COPD subjects, diaphragm contraction at matching lengths is increased after vilanterol trifenatate/fluticasone furoate (Relvar).

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Neosyntheses of Neolacto- and Novel Ganglio-Series Gangliosides in a Rat Fibroblastic Cell Line Brought about by Transfection with the v-fes Oncogene-containing Gardner-Arnstein Strain Feline Sarcoma Virus-DNA
Authors: Hitoshi Nakaishi, Yutaka Sanai, Masabumi Shibuya, Masao Iwamori, Yoshitaka Nagai
Journal: Cancer Research (1988)

Transfection of retrovirus DNA from Gardner-Arnstein strain feline sarcoma virus containing v- fes oncogene into a rat fibroblastic cell line 3Y1 caused not only cell transformation but also a remarkable change in ganglioside expression. The ganglioside phenotype of the 3Y1 cells was characterized by the exclusive expression of GM3, along with a trace amount of “A” pathway-related gangliosides (GM2-GM1a-GD1a), whereas in the transfected transformant, 3Y1-GA, sialosylparagloboside containing N -acetyl neuraminic acid (NeuAc) and novel ganglio-series gangliosides (presumably GM1b and GD1α) were expressed in addition to GM3. Thus, the Gardner-Arnstein strain feline sarcoma virus DNA transfection opens two new ganglioside metabolic pathways, one leading to the synthesis of neolacto-series and the other to that of ganglio-series gangliosides. These results were in striking contrast to the cases of transfection with so-called “intranuclearly expressed” transforming genes, adenovirus E1, SV40-T, and myc , with which the same 3Y1 cells newly expressed GD3 with a concomitant decrease in precursor ganglioside GM3. The difference in underlying mechanisms of ganglioside metabolism shown by these two different types of oncogenes might reflect differences in the modes of action of the oncogenes and their biological activities.
Mucosal-associated Invariant T-Cell Function Is Modulated by Programmed Death-1 Signaling in Patients with Active Tuberculosis
Authors: Jing Jiang, Xinjing Wang, Hongjuan An, Bingfen Yang, Zhihong Cao, Yanhua Liu, Jinwen Su, Fei Zhai, Ruo Wang, Guangyu Zhang, Xiaoxing Cheng
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Mucosal-associated invariant T (MAIT) cells have been proven to play an important role in host defense against mycobacterial infection in animal infection models; however, the functional role of MAIT cells in patients with active tuberculosis (TB) is still largely unknown.Objectives: To understand the clinical features and functions of MAIT cells in patients with active TB.Methods: MAIT cells were analyzed in patients with pulmonary TB, tuberculous pleurisy, and tuberculous peritonitis by flow cytometry. The functions of MAIT cells were compared between patients with active TB and healthy control subjects.Measurements and Main Results: The frequency of MAIT cells was significantly reduced both in peripheral blood from patients with active pulmonary TB (P < 0.0001) and in tuberculous pleural effusions compared with healthy control subjects but not in ascitic fluids from patients with tuberculous peritonitis. A comparison of bacillus Calmette-Guérin (BCG)–stimulated cytokine production showed that patients with active TB had significantly higher production of IFN-γ (P = 0.0034) and tumor necrosis factor (TNF)-α (P = 0.0399) compared with healthy control subjects. In contrast, when MAIT cells were stimulated with Escherichia coli, patients with active TB had significantly lower production of IFN-γ (P = 0.0007) and TNF-α (P = 0.0032). MAIT cells in patients with active TB exhibited elevated expression of programmed death-1 (PD-1) (P = 0.0015), and blockade of PD-1 signaling resulted in a significantly higher frequency of BCG-stimulated IFN-γ production in MAIT cells (P = 0.0178).Conclusions: MAIT-cell immune response to antigen stimulation in patients with active TB is regulated by PD-1, which could be a potential target for TB immunotherapy.
Reciprocal and Complementary Role of <i>MET</i> Amplification and <i>EGFR </i>T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer
Authors: Kenichi Suda, Isao Murakami, Tatsuya Katayama, Kenji Tomizawa, Hirotaka Osada, Yoshitaka Sekido, Yoshihiko Maehara, Yasushi Yatabe, Tetsuya Mitsudomi
Journal: Clinical Cancer Research (2010)

In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold).These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.
STUDIES ON THE INHIBITION OF PROTEOLYTIC ENZYMES BY SERUM
Authors: N. Raphael Shulman
Journal: The Journal of Experimental Medicine (1952)

Variation in the inhibition of trypsin, chymotrypsin, and plasmin by serum was studied in 65 normal individuals and in 117 patients with a variety of diseases. It was shown that elevated inhibition for trypsin and chymotrypsin is associated with disease processes that bring about cellular destruction. Changes in the inhibition of trypsin and chymotrypsin were closely correlated with changes in the erythrocyte sedimentation rate and fibrinogen concentration that occur in association with disease. Intravenous typhoid vaccine was found to produce parallel changes in the inhibition of trypsin and chymotrypsin and in the fibrinogen concentration in human beings. It was concluded that the diagnostic significance of increased trypsin or chymotrypsin inhibition is the same as that of increased fibrinogen concentration; it is a common, non-specific response to a variety of pathological conditions and has no value as a specific diagnostic test. Increased plasmin inhibition occurred too infrequently to permit detailed study.
The ameliorating addict: An illusion reviewed
Authors: Jack Bergman, Klaus A. Miczek
Journal: Behavioral and Brain Sciences (1996)

Abstract It is difficult to accommodate compulsive drug use that destroys regulation by consequences in a unitary framework of melioration or maximization, especially as both are strategies of behavioral regulation. The “contradiction” of addictive behavior despite aversive consequences is an illusory issue because consequences that do not decrease addictive behavior cannot be considered punishing.
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Authors: Mark R. Duranski, James J.M. Greer, Andre Dejam, Sathya Jaganmohan, Neil Hogg, William Langston, Rakesh P. Patel, Shaw-Fang Yet, Xunde Wang, Christopher G. Kevil, Mark T. Gladwin, David J. Lefer
Journal: Journal of Clinical Investigation (2005)

Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitros-amines, and iron-nitrosylated heme proteins within 1–30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.