tbuckley/cabot-search huggingface dataset:
INDUCTION OF GUINEA PIG B-CELL LYMPHOKINE SYNTHESIS BY MITOGENIC AND NONMITOGENIC SIGNALS TO Fc, Ig, AND C3 RECEPTORS
Authors: S. M. Wahl, G. M. Iverson, J. J. Oppenheim
Journal: The Journal of Experimental Medicine (1974)

This study shows that bone marrow-derived lymphocytes of guinea pigs if appropriately activated produce a monocyte chemotactic factor (MNL CTX). Activation of B lymphocytes to produce a chemotactic lymphokine occurs subsequent to interactions with a variety of membrane-associated receptors. Polymeric B-cell mitogens with multiple binding sites, polymerized flagellin and lipopolysaccharide, initiated mediator synthesis. Furthermore, interaction of antigen-antibody complexes or aggregated gamma globulin with the Fc receptor and binding of antigen-antibody-complement complexes at the C3 receptor can effectively facilitate mediator production in the absence of a significant proliferative response. Additionally, intact anti-immunoglobulin but not its Fab fragments activated the B cells. An anti-Fab effectively converted the inactive Fab-bound B cells into producers of MNL CTX, suggesting that the basic mechanism of activation depended upon cross-linking of receptors. Thus, interaction of B-cell surface receptors such as Fc, Ig, and C3 sites with mitogenic as well as nonmitogenic molecules capable of bridging the receptors appears to trigger B-cell mediator production.
Oestrogen metabolism in lymphangioleiomyomatosis: catechol-O-methyltransferase pathway is not involved
Authors: B. Paquette
Journal: Thorax (2000)

<h3>ABSTRACT</h3> By surpassing the 50% inheritance limit of Mendel’s law of independent assortment, CRISPR-based gene drives have the potential to fight vector-borne diseases or suppress crop pests. However, contemporary gene drives could spread unchecked, posing safety concerns that limit their use in both laboratory and field settings. Current technologies also lack chemical control strategies, which could be applied in the field for dose, spatial and temporal control of gene drives. We describe in <i>Drosophila</i> the first gene-drive system controlled by an engineered Cas9 and a synthetic, orally-available small molecule.
Serum uric acid and the risk of respiratory disease: a population-based cohort study
Authors: Laura J Horsfall, Irwin Nazareth, Irene Petersen
Journal: Thorax (2014)

Uric acid is the most abundant molecule with antioxidant properties found in human blood serum. We examined the relationship between serum uric acid and the incidence of respiratory disease including any effect modification by smoking status.A cohort with serum uric acid measured between 1 January 2000 and 31 December 2012 was extracted from The Health Improvement Network primary care research database. New diagnoses of COPD and lung cancer were ascertained based on diagnostic codes entered into the medical records.During 1 002 496 person years (PYs) of follow-up, there were 3901 COPD diagnoses and 1015 cases of lung cancer. After multivariable adjustment, strong interactions with smoking status were detected (p<0.001) for both outcomes with significant negative relationships between serum uric acid and respiratory disease for current smokers but no strong relationships for never-smokers or ex-smokers. The relationships were strongest for lung cancer in heavy smokers (≥20 cigarettes per day) with predicted incidence rates 97 per 10 000 PYs (95% CI 68 to 126) in the lowest serum uric acid quintile (100-250 µmol/L) compared with a predicted 28 per 10 000 PYs (95% CI 14 to 41) in the highest quintile (438-700 µmol/L).Low levels of serum uric acid are associated with higher rates of COPD and lung cancer in current smokers after accounting for conventional risk factors.
Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation
Authors: Petra C. Kienesberger, Thomas Pulinilkunnil, Jeevan Nagendran, Martin E. Young, Juliane G. Bogner-Strauss, Hubert Hackl, Rammy Khadour, Emma Heydari, Guenter Haemmerle, Rudolf Zechner, Erin E. Kershaw, Jason R. B. Dyck
Journal: Cardiovascular Research (2013)

While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known. To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO). Within 4–6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKO mice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression. This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling.
Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance
Authors: Li Liu, Yiying Zhang, Nancy Chen, Xiaojing Shi, Bonny Tsang, Yi-Hao Yu
Journal: Journal of Clinical Investigation (2007)

Increased fat deposition in skeletal muscle is associated with insulin resistance. However, exercise increases both intramyocellular fat stores and insulin sensitivity, a phenomenon referred to as "the athlete's paradox". In this study, we provide evidence that augmenting triglyceride synthesis in skeletal muscle is intrinsically connected with increased insulin sensitivity. Exercise increased diacylglycerol (DAG) acyltransferase (DGAT) activity in skeletal muscle. Channeling fatty acid substrates into TG resulted in decreased DAG and ceramide levels. Transgenic overexpression of DGAT1 in mouse skeletal muscle replicated these findings and protected mice against high-fat diet–induced insulin resistance. Moreover, in isolated muscle, DGAT1 deficiency exacerbated insulin resistance caused by fatty acids, whereas DGAT1 overexpression mitigated the detrimental effect of fatty acids. The heightened insulin sensitivity in the transgenic mice was associated with attenuated fat-induced activation of DAG-responsive PKCs and the stress mediator JNK1. Consistent with these changes, serine phosphorylation of insulin receptor substrate 1 was reduced, and Akt activation and glucose 4 membrane translocation were increased. In conclusion, upregulation of DGAT1 in skeletal muscle is sufficient to recreate the athlete's paradox and illustrates a mechanism of exercise-induced enhancement of muscle insulin sensitivity. Thus, increasing muscle DGAT activity may offer a new approach to prevent and treat insulin resistance and type 2 diabetes mellitus.
Disruption of Autophagy at the Maturation Step by the Carcinogen Lindane Is Associated with the Sustained Mitogen-Activated Protein Kinase/Extracellular Signal–Regulated Kinase Activity
Authors: Elisabeth Corcelle, Marielle Nebout, Soumeya Bekri, Nils Gauthier, Paul Hofman, Philippe Poujeol, Patrick Fénichel, Baharia Mograbi
Journal: Cancer Research (2006)

Abstract Macroautophagy (hereafter referred to as autophagy) has emerged as a key tumor suppressor pathway. During this process, the cytosolic constituents are sequestered into autophagosomes, which subsequently fuse with lysosomes to become autolysosomes where their contents are finally degraded. Although a reduced autophagy has been shown in human tumors or in response to oncogenes and carcinogens, the underlying mechanism(s) remain(s) unknown. Here, we show that widely used carcinogen Lindane promotes vacuolation of Sertoli cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3, Rab7, and LAMP1, markers of autophagosomes, late endosomes, and lysosomes, respectively. Such Lindane-induced vacuolation results from significant delay in autophagy degradation, in relation with a decline of the lysosomal activity of aryl sulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Rather, the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) pathway is required for Lindane to disrupt the autophagic pathway. Most importantly, we provide the first evidence that sustained activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. Taken together, these findings strongly support that the aberrant sustained activation of ERK by the carcinogen Lindane disrupts the maturation of autophagosomes into functional autolysosomes. Our findings therefore suggest the possibility that high constitutive ERK activity found in all cancers may provide a malignant advantage by impeding the tumor suppressive function of autophagy. (Cancer Res 2006; 66(13): 6861-70)
Telomeres, Telomerase, and Cancer
Authors: C H Buys
Journal: New England Journal of Medicine (2000)

What accounts for the ability of cancer cells to proliferate in a manner that is out of control, whereas normal cells die after 40 to 60 cycles of replication? One mechanism that leads to the death of a normal cell is erosion of the structure that caps the ends of chromosomes — the telomere (from the Greek telos, meaning end, and meros, a component) — each time a cell divides. The clinical relevance of telomeres is that a cancer cell, unlike a normal cell, can repair eroded telomeres. The existence of this repair mechanism suggests a novel target for cancer . . .
Selected Atlases of Cardiovascular Nuclear Medicine
Authors: D. Van Nostrand, J. G. Llaurado
Journal: Clinical Nuclear Medicine (1994)

Each volume in the Atlases of Clinical Nuclear Medicine covers one anatomic region or system. Extensively illustrated with superb quality images, each atlas reveals the spectrum of normal scintigraphic findings as well as examples of both common and unusual conditions. Detailed figure legends describe the findings within each image, and most discuss the image's important teaching point. The text, which is descriptive yet concise, covers such topics as procedure technique, dosimetry, physiology, and scan interpretation. The Atlases of Clinical Nuclear Medicine fulfill equally the needs of practicing radiologists, nuclear medicine physicians, and residents seeking to utilize this helpful diagnostic modality more effectively. Selected Atlases of Cardiovascular Nuclear Medicine is comprised of five individual atlases in the areas of Myocardial Perfusion Images, Artifacts in 201 Thallium Spect Cardiac Perfusion Imaging, Artifacts in 99m Technetium Sestamibi SPECT Cardiac Perfusion Imaging, Cardiac Positron Emission Tomography, and Indium-111 Antimyosin Imaging of Myocardial Necrosis.
Value of Cytogenetic Analysis in the Treatment of Dermatofibrosarcoma Protuberans
Authors: Delphine Kerob, Florence Pedeutour, Christophe Leboeuf, Olivier Verola, Eric de Kerviler, Jean Marie Servant, Farid Sarandi, Guilhem Bousquet, Isabelle Madelaine-Chambrin, Christelle Pruvost, Fabien Calvo, Anne Janin, Celeste Lebbe
Journal: Journal of Clinical Oncology (2008)
Continuation of long term treatment with hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis.
Authors: E F Morand, P I McCloud, G O Littlejohn
Journal: Annals of the Rheumatic Diseases (1992)

BACKGROUND: Hydroxychloroquine is used for the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Long term studies have shown a high rate of termination of hydroxychloroquine treatment in patients with RA. Although it has been shown that discontinuation of treatment with hydroxychloroquine is associated with exacerbation of SLE, long term maintenance rates of treatment with hydroxychloroquine in patients with SLE have not been investigated. METHODS: Hydroxychloroquine use in patients with RA and SLE in a group of patients in a single community rheumatology practice was studied. Information was drawn from a computer drug use database containing details of the beginning and end of treatment. Data were analysed using life table methods. RESULTS: Four hundred and three treatment episodes (366 patients with RA, 37 patients with SLE) were observed over eight years. In patients with RA, the cumulative probability of discontinuing treatment was 37% at 12 months and 54% at 24 months. In contrast, hydroxychloroquine treatment of patients with SLE continued over significantly longer periods of time (p &lt; 0.001); the discontinuation probabilities at 12 and 24 months were 8 and 24% respectively. Treatment terminations were predominantly for inefficacy; terminations for toxicity were limited to the first 19 months of treatment. No ocular toxicity was observed. CONCLUSIONS: Treatment of patients with RA in a community rheumatology practice with hydroxychloroquine has a low probability of long term continuation, mostly because of inadequate control of disease manifestations rather than toxicity. In patients with SLE, treatment with hydroxychloroquine has a significantly higher probability of long term continuation.
β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
Authors: Philippe A. Halban, Kenneth S. Polonsky, Donald W. Bowden, Meredith A. Hawkins, Charlotte Ling, Kieren J. Mather, Alvin C. Powers, Christopher J. Rhodes, Lori Sussel, Gordon C. Weir
Journal: Diabetes Care (2014)

This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of β-cell failure; (2) identify and characterize genetic loci for T2D; (3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of β-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to β-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
The Power of Negative Thinking: Which Cells Limit Tumor Immunity?
Authors: Siuwah Tang, Michael T. Lotze
Journal: Clinical Cancer Research (2012)

Abstract Why human tumors grow infiltrated by specific antitumor T cells has been a mystery attributed to negative factors released directly by the tumor or indirectly through immune intermediaries. The frequency and phenotype of myeloid-derived suppressor cells in the peripheral blood of melanoma patients and healthy donors are surprisingly similar. Clin Cancer Res; 18(19); 5157–9. ©2012 AACR.
Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype
Authors: Ziad I. Dibbs, Abhinav Diwan, Shintaro Nemoto, Gilberto DeFreitas, Maha Abdellatif, Blase A. Carabello, Francis G. Spinale, Giora Feuerstein, Natarajan Sivasubramanian, Douglas L. Mann
Journal: Circulation (2003)

Background— Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF-α converting enzyme (TACE) to generate a 17-kDa form of “secreted” TNF. Whereas the effects of secreted TNF in the heart have been characterized extensively, the effects of transmembrane TNF in the heart are unknown. Methods and Results— We generated lines of transgenic mice with cardiac-restricted overexpression of a noncleavable, transmembrane form of TNF. We next treated a previously generated transgenic line of mice with cardiac-restricted expression of cleavable TNF (referred to as MHCsTNF mice) with a TACE inhibitor (DPC-IDR1) to determine whether TACE inhibition would prevent the transition from concentric hypertrophy to left ventricular (LV) dilation that occurs in this line of transgenic mice. Two of the founder lines did not have a demonstrable phenotype (M-41 and M-45), whereas a third line developed a concentric hypertrophic cardiac phenotype (M-48). Characterization of the M-48 line at 6 weeks of age showed that this line developed concentric hypertrophy, with an increase in myocyte cross-sectional area and reexpression of the fetal gene program. Four weeks of TACE inhibition abrogated the LV dilation in the MHCsTNF mice and resulted in an increase in LV wall thickness and increased myocyte cross-sectional area, thus mimicking the effects observed in the mice with noncleavable, transmembrane TNF. Conclusions— These studies show that transmembrane TNF is biologically active and provokes a concentric hypertrophic cardiac phenotype, thus suggesting that posttranslational processing (ie, secretion) of TNF is responsible for the dilated cardiomyopathic phenotype in mice with targeted, cardiac-restricted overexpression of TNF.
Conducting Polymer Electrodes for Electroencephalography
Authors: Pierre Leleux, Jean‐Michel Badier, Jonathan Rivnay, Christian Bénar, Thierry Hervé, Patrick Chauvel, George G. Malliaras
Journal: Advanced Healthcare Materials (2013)

Conducting polymer electrodes are developed on a flexible substrate for electroencephalography applications. These electrodes yield higher quality recordings than dry electrodes made from metal. Their performance is equivalent to commercial gel-assisted electrodes, paving the way for non-invasive, long-term monitoring of the human brain.
Structure–function relationship in COPD revisited: an in vivo microscopy view
Authors: Borja G Cosío, Hanaa Shafiek, Federico Fiorentino, Cristina Gómez, Meritxell López, Angel Rios, Ana Kersul, Bernardo Togores, Joan Palmer, Jaume Sauleda, Alvar Agustí
Journal: Thorax (2014)

<h3>Background</h3> Fibred confocal fluorescence microscopy (FCFM) is a novel technology that allows the in vivo assessment and quantification during bronchoscopy of the bronchial wall elastic fibre pattern, alveolar and vessel diameters and thickness of the elastic fibre in the alveolar wall. <h3>Aims</h3> To relate these structural characteristics with lung function parameters in healthy subjects, smokers with normal spirometry and patients with chronic obstructive pulmonary disease (COPD). <h3>Methods</h3> We performed FCFM in 20 never smokers, 20 smokers with normal spirometry and 23 patients with COPD who required bronchoscopy for clinical reasons. The bronchial wall elastic fibre pattern was classified as lamellar, loose and mixed pattern, and later confirmed pathologically. Airspace dimensions and extra-alveolar vessel diameters were measured. Lung function measurements and pulmonary CT scans were obtained in all participants. <h3>Results</h3> Patients with COPD were characterised by a significantly higher prevalence of loose fibre bronchial deposition pattern and larger alveolar diameter which correlated inversely with several lung function parameters (forced expiratory volume in 1 s (FEV<sub>1</sub>) , FEV<sub>1</sub>/forced vital capacity ratio, maximum expiratory flow, carbon monoxide transfer factor and carbon monoxide transfer coefficient; p&lt;0.05). Increased alveolar macrophages were demonstrated in active smokers with or without COPD. <h3>Conclusions</h3> This is the first FCFM study to describe in vivo microscopic changes in the airways and alveoli of patients with COPD that are related to lung function impairment. These findings open the possibility of assessing the in vivo effects of therapeutic interventions for COPD in future studies.
Gene Expression Profiles of Podocyte-Associated Molecules as Diagnostic Markers in Acquired Proteinuric Diseases
Authors: Holger Schmid, Anna Henger, Clemens D. Cohen, Karin Frach, Hermann-Josef Gröne, Detlef Schlöndorff, Matthias Kretzler
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. For identifying potential diagnostic markers of proteinuric glomerulopathies, glomerular mRNA levels of molecules relevant for podocyte function (α-actinin-4, glomerular epithelial protein 1, Wilms tumor antigen 1, synaptopodin, dystroglycan, nephrin, podoplanin, and podocin) were determined by quantitative real-time RT-PCR from microdissected glomeruli. Biopsies from 83 patients with acquired proteinuric diseases were analyzed (minimal change disease [MCD; n = 13], benign nephrosclerosis [ n = 16], membranous glomerulopathy [ n = 31], focal and segmental glomerulosclerosis [FSGS; n = 9], and controls [ n = 14]). Gene expression levels normalized to two different housekeeping transcripts (glyceraldehyde-3-phosphate-dehydrogenase and 18 S rRNA) did not allow a separation between proteinuric disease categories. However, a significant positive correlation between α-actinin-4, glomerular epithelial protein 1, synaptopodin, dystroglycan, Wilms tumor antigen 1, and nephrin was found in all analyzed glomeruli, whereas podocin mRNA expression did not correlate. Because varying amounts of housekeeper cDNA per glomerulus can confound expression ratios relevant for a subpopulation of cells, an “in silico” microdissection was performed using a podocyte-specific cDNA as a reference gene. Expression ratio of podocin to synaptopodin, the two genes with the most disparate expression, allowed a robust separation of FSGS from MCD and nephrosclerosis. Segregation of FSGS from MCD via this ratio was confirmed in an independent population of formaldehyde-fixed archival biopsies (MCD, n = 5; FSGS, n = 4) after glomerular laser capture microdissection. In addition, the expression marker was able to predict steroid responsiveness in diagnostically challenging cases of MCD versus FSGS ( n = 6). As the above approach can be performed as an add-on diagnostic tool, these molecular diagnostic parameters could give novel information for the management of proteinuric diseases. E-mail: kretzler@medpoli.med.uni-muenchen.de