tbuckley/cabot-search huggingface dataset:
Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation.
Authors: F Grimminger, K Hattar, C Papavassilis, B Temmesfeld, E Csernok, W L Gross, W Seeger, U Sibelius
Journal: The Journal of Experimental Medicine (1996)

Among the anti-neutrophil cytoplasmic antibodies (ANCA), those targeting proteinase 3 (PR3) have a high specificity for Wegener's granulomatosis (WG). It is known that a preceding priming of neutrophils with cytokines is a prerequisite for membrane surface expression of PR3, which is then accessible to autoantibody binding. Employing a monoclonal antibody directed against human PR3 and ANCA-positive serum from WG patients with specificity for PR3, we now investigated the role of free arachidonic acid (AA) in autoantibody-related human neutrophil activation. Priming of neutrophils with tumor necrosis factor (TNF-alpha) for 15 min or exposure to anti-PR3 antibodies or incubation with free AA (10 microM) as sole events did not provoke superoxide generation, elastase secretion or generation of 5-lipoxygenase products of AA. Similarly, the combination of TNF-alpha-priming and AA incubation was ineffective. When TNF-alpha-primed neutrophils were stimulated by anti-PR3 antibodies, superoxide and elastase secretion was provoked in the absence of lipid mediator generation. However, when free AA was additionally provided, a strong activation of the 5-lipoxygenase pathway was demasked, with the appearance of excessive quantities of leukotriene (LT)B4, LTA4, and 5-hydroxyeicosatetraenoic acid. Moreover, superoxide and elastase secretion were markedly amplified, and studies with 5-lipoxygenase inhibitors and a LTB4-antagonist demonstrated this was due to an LTB4-related autocrine loop of cell activation. In contrast, the increased synthesis of platelet-activating factor in response to TNF-alpha-priming and anti-PR3 stimulation did not contribute to the amplification loop of neutrophil activation under the given conditions. We conclude that anti-PR3 antibodies are potent inductors of the 5-lipoxygenase pathway in primed human neutrophils, and extracellular free AA, as provided at an inflammatory focus, synergizes with the autoantibodies to evoke full-blown lipid mediator generation, granule secretion and respiratory burst. Such events may be enrolled in the pathogenesis of focal necrotizing vascular injury in Wegener's granulomatosis.
Monoclonal gammopathy and antibody activity against the acetylcholine receptor
Authors: Richard E. Ahlberg, Ann Kari Lefvert
Journal: American Journal of Hematology (1988)

Abstract A 50‐year‐old woman with muscular fatigue and monoclonal gammopathy of unknown significance was shown to have high levels of antibodies against the acetylcholine receptor of the skeletal muscle endplate. The specific antibody activity was exclusively associated with the monoclonal component. There were no objective signs of myasthenia gravis. This is the first reported case with antibody activity against the acetylcholine receptor found in a monoclonal immunoglobulin fraction.
IT-22 * TARGETING THE IMMUNE CHECKPOINT NETWORK WITH miR-138 EXERTS THERAPEUTIC EFFICACY IN MURINE MODELS OF GLIOMA
Authors: E. K. Nduom, J. Wei, L.-Y. Kong, S. Xu, K. Gabrusiewicz, X. Ling, N. Huang, W. Qiao, S. Zhou, C. Ivan, J. Q. Chen, Y. Ji, L. Radvanyi, G. N. Fuller, M. Gilbert, C. A. Conrad, W. Overwijk, G. A. Calin, A. B. Heimberger
Journal: Neuro-Oncology (2014)

Antibody therapeutic targeting of the immune checkpoints CTLA-4 and PD-1 has demonstrated marked tumor regression in clinical trials; however, this requires multimodality treatment and has known toxicity. MicroRNAs (miRNAs) can modulate gene transcripts, including those of tumor-mediated immune suppressive pathways. MiRNAs can be delivered to the systemic immune compartment, which can initiate anti-tumor immune response, overcoming the issue of miRNA delivery to the tumor. To identify potential miRNA therapeutics, we exploited human glioblastoma miRNA expression assays followed by a screening process of predicted binding sites in the 3' UTR of immune suppressive pathways and immune checkpoints. MiR-138 emerged as a leading candidate with binding sites in the 3' UTR of CTLA-4 and PD-1, which were functionally confirmed with luciferase expression assays. The miR-138 targeting of CTLA-4 and PD-1 was further validated by expression analysis of transfected human CD4+ T cells. Using human glioma tumor microarrays and in situ hybridization, heterogeneous expression of miR-138 was found amongst all glioma grades and pathological subtypes. The PD-1 ligand, PD-L1, was frequently expressed in glioblastomas based on immunohistochemistry and ex vivo flow cytometry from human glioblastoma. Analysis of TCGA database revealed that co-expression of PD-1 and PD-L1 impacts glioblastoma survival. The role of CTLA-4 in glioblastoma-mediated immune suppression is well documented, suggesting that targeting of CTLA-4 and PD-1 with miR-138 in glioblastoma patients may have anti-tumor activity. In vivo treatment with miR-138 in immune-competent mice with GL261 gliomas demonstrated marked tumor regression, a 43% increase in median survival (P = 0.011), and an associated decrease in intratumoral FoxP3+ Tregs, CTLA-4, and PD-1 expression. Conversely, in an immune-incompetent animal background, miR-138 failed to exert any therapeutic effect, indicating that miR-138 mediates in vivo activity via the immune system. Cumulatively, our data indicate that miR-138 may be an active and novel immunotherapeutic agent for human glioblastoma patients.
Accelerated evolution associated with genome reduction in a free-living prokaryote
Authors: Alexis Dufresne, Laurence Garczarek, Frédéric Partensky
Journal: Genome biology (2005)

Three complete genomes of Prochlorococcus species, the smallest and most abundant photosynthetic organism in the ocean, have recently been published. Comparative genome analyses reveal that genome shrinkage has occurred within this genus, associated with a sharp reduction in G+C content. As all examples of genome reduction characterized so far have been restricted to endosymbionts or pathogens, with a host-dependent lifestyle, the observed genome reduction in Prochlorococcus is the first documented example of such a process in a free-living organism.Our results clearly indicate that genome reduction has been accompanied by an increased rate of protein evolution in P. marinus SS120 that is even more pronounced in P. marinus MED4. This acceleration has affected every functional category of protein-coding genes. In contrast, the 16S rRNA gene seems to have evolved clock-like in this genus. We observed that MED4 and SS120 have lost several DNA-repair genes, the absence of which could be related to the mutational bias and the acceleration of amino-acid substitution.We have examined the evolutionary mechanisms involved in this process, which are different from those known from host-dependent organisms. Indeed, most substitutions that have occurred in Prochlorococcus have to be selectively neutral, as the large size of populations imposes low genetic drift and strong purifying selection. We assume that the major driving force behind genome reduction within the Prochlorococcus radiation has been a selective process favoring the adaptation of this organism to its environment. A scenario is proposed for genome evolution in this genus.
Elevated Levels of Interleukin-8 in Donor Lungs Is Associated with Early Graft Failure after Lung Transplantation
Authors: ANDREW J. FISHER, SEAMAS C. DONNELLY, NIKHIL HIRANI, CHRISTOPHER HASLETT, ROBERT M. STRIETER, JOHN H. DARK, PAUL A. CORRIS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Increased levels of the neutrophil chemokine interleukin (IL)-8 in the lungs of severe trauma patients can predict subsequent development of acute respiratory distress syndrome. Because the lungs of brain-dead organ donors can contain high levels of IL-8, we hypothesized that this may predispose to early graft failure in the recipient after lung transplantation. Twenty-six organ donors prospectively satisfying clinical criteria for lung donation underwent bronchoalveolar lavage and lung biopsy to determine the effect of neutrophil infiltration and IL-8 expression in the donor lung on graft function and survival in 26 respective recipients after lung transplantation. Nine recipients developed severe graft dysfunction, of whom six subsequently died (median survival: 24 d [range: 5 to 39 d]); all others survived beyond 6 mo. The IL-8 signal in the donor lung correlated with the percent neutrophils in bronchoalveolar lavage fluid (BALF) before implantation (42.4 ± 7.24 [mean ± SE]%, p = 0.03) and with the degree of impairment in graft oxygenation after implantation (p = 0.01). An increased level of IL-8 in the donor BALF was associated with the development of severe early graft dysfunction (p = 0.027) and with early recipient mortality (p = 0.0034). Use of donor lungs with high IL-8 levels is associated with a poor prognosis after lung transplantation. Attenuating the donor's inflammatory response before organ retrieval may improve early outcome after lung transplantation, and help maximize lung use from the existing donor pool.
Pulmonary vein isolation for the treatment of atrial fibrillation in patients with impaired systolic function
Authors: Michael S Chen, Nassir F Marrouche, Yaariv Khaykin, A.Marc Gillinov, Oussama Wazni, David O Martin, Antonio Rossillo, Atul Verma, Jennifer Cummings, Demet Erciyes, Eduardo Saad, Mandeep Bhargava, Dianna Bash, Robert Schweikert, David Burkhardt, Michelle Williams-Andrews, Alejandro Perez-Lugones, Ahmad Abdul-Karim, Walid Saliba, Andrea Natale
Journal: Journal of the American College of Cardiology (2004)
When is fever malaria?
Authors: DavidH. Peters, RonaldH. Gray, Jef Van Den Ende, Erwin Van Den Enden, Alfons Van Gompel, Marc Wery, A. Rougemont, E. Brenner, Dominique Gendrel, Maryvonne Kombila, Dominique Richard-Lenoble
Journal: The Lancet (1992)
Identification of Novel Methylation Markers in Cervical Cancer Using Restriction Landmark Genomic Scanning
Authors: Sophia S. Wang, Dominic J. Smiraglia, Yue-Zhong Wu, Srimoyee Ghosh, Janet S. Rader, Kathleen R. Cho, Thomas A. Bonfiglio, Ritu Nayar, Christoph Plass, Mark E. Sherman
Journal: Cancer Research (2008)

Abstract Aberrant methylation of CpG islands in gene promoters often represents an early clonal event in carcinogenesis. Accordingly, defining methylation profiles may be useful for developing marker panels for early detection or predicting the risk of cancer precursors. To identify specific genes frequently methylated in cervical cancer, we conducted methylation profiling of 20 primary human cervical cancers using NotI-based restriction landmark genomic scanning (RLGS). Of 2,172 RLGS fragments analyzed (average, 1,753 CpG islands per patient), 186 RLGS fragments were lost in at least one tumor and 40 were lost in three or more. Methylation was identified in 19 (95%) of 20 tumor samples compared with normal DNA. Bisulfite sequencing was conducted to confirm RLGS results. Of the confirmed markers frequently methylated, we developed Methylight assays for two corresponding genes, nucleolar protein 4 (NOL4), and lipoma HMGIC fusion partner–like protein 4 (LHFPL4), which were methylated in 85% and 55% of cancers, respectively. Using these assays, we further confirmed frequent CpG island methylation in the original cancers and in another independent series of 15 cervical cancers. We also showed methylation at a reduced frequency in a set of carefully reviewed cytology specimens demonstrating cells exfoliated from cancer precursor lesions. In summary, we identified, for the first time, NOL4 and LHFPL4 as novel methylation targets specific for cervical cancer. Inclusion of NOL4 and LHFPL4 in evaluating methylation panels for early detection, risk prediction, and etiologic research on cervical cancer is warranted. [Cancer Res 2008;68(7):2489–97]
D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study
Authors: E. Bernardi, P. Prandoni, A. W A Lensing, G. Agnelli, G. Guazzaloca, G. Scannapieco, F. Piovella, F. Verlato, C. Tomasi, M. Moia, L. Scarano, A. Girolami
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective</b> To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. <b>Design</b> D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. <b>Main outcome measure</b> Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. <b>Setting</b> University research and affiliated centres. <b>Subjects</b> 946 patients with clinically suspected deep vein thrombosis. <b>Results</b> Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. <b>Conclusions</b> Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.
Steroid sulfatase inhibitors
Authors: Peter Nussbaumer, Andreas Billich
Journal: Medicinal Research Reviews (2004)

Abstract Steroid sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3‐hydroxy steroids, which are inactive transport or precursor forms of the active 3‐hydroxy steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential new therapeutic agents for the treatment of estrogen‐ and androgen‐dependent disorders. Indications range from cancers of the breast, endometrium and prostate to androgenetic alopecia and acne. In this review, we give a comprehensive summary of the current knowledge and problems in the field of medicinal chemistry of STS inhibitors. The various types of inhibitors are presented and their structure‐activity relationships are discussed. In addition to potent arylsulfamate‐based, irreversible inhibitors, novel types of reversible inhibitors were recently discovered. The recent publication of the X‐ray structure of STS will further boost research activities on this attractive target. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 4, 529–576, 2004
Genotoxic Stress–Induced Expression of p53 and Apoptosis in Leukemic Clam Hemocytes with Cytoplasmically Sequestered p53
Authors: Stefanie Böttger, Emily Jerszyk, Ben Low, Charles Walker
Journal: Cancer Research (2008)

Abstract In nature, the soft shell clam, Mya arenaria, develops a fatal blood cancer in which a highly conserved homologue for wild-type human p53 protein is rendered nonfunctional by cytoplasmic sequestration. In untreated leukemic clam hemocytes, p53 is complexed throughout the cytoplasm with overexpressed variants for both clam homologues (full-length variant, 1,200-fold and truncated variant, 620-fold above normal clam hemocytes) of human mortalin, an Hsp70 family protein. In vitro treatment with etoposide only and in vivo treatment with either etoposide or mitoxantrone induces DNA damage, elevates expression (600-fold) and promotes nuclear translocation of p53, and results in apoptosis of leukemic clam hemocytes. Pretreatment with wheat germ agglutinin followed by etoposide treatment induces DNA damage and elevates p53 expression (893-fold) but does not overcome cytoplasmic sequestration of p53 or induce apoptosis. We show that leukemic clam hemocytes have an intact p53 pathway, and that maintenance of this tumor phenotype requires nuclear absence of p53, resulting from its localization in the cytoplasm of leukemic clam hemocytes. The effects of these topoisomerase II poisons may result as mortalin-based cytoplasmic tethering is overwhelmed by de novo expression of p53 protein after DNA damage induced by genotoxic stress. Soft shell clam leukemia provides excellent in vivo and in vitro models for developing genotoxic and nongenotoxic cancer therapies for reactivating p53 transcription in human and other animal cancers displaying mortalin-based cytoplasmic sequestration of the p53 tumor suppressor, such as colorectal cancers and primary and secondary glioblastomas, though not apparently leukemias or lymphomas. [Cancer Res 2008;68(3):777–82]
Functional involvement of proteins, interacting with sphingolipids, in sphingolipid transport to the canalicular membrane in the human hepatocytic cell line, HepG2?
Authors: Mirjam M. P. Zegers, Kristien J. M. Zaal, Dick Hoekstra
Journal: Hepatology (1998)

A photoreactive sphingolipid precursor was used to investigate the potential involvement of protein-lipid interactions that may convey specificity to sphingolipid transport in the human hepatoma cell line, HepG2. A 125 I-labeled, photoreactive ceramide, 125 I-N 3 -Cer, was incubated with the cells and became incorporated into two sphingolipid products. The major product was photoreactive sphingomyelin ( 125 I-N 3 -SM) (25% of total radioactivity), while only minor amounts of photoreactive glucosylceramide ( 125 I-N 3 -GlcCer) were formed (&lt;2%). After photoactivation, a restricted number of proteins was labeled. Given the absolute amounts of the newly synthesized, photoreactive lipids and their precursor present in the cells, labeling of the proteins can be assumed to be derived from interaction with either ceramide (Cer) or sphingomyelin (SM), or both. To discriminate between these possibilities, photoactivation and protein analysis was performed in cells treated with D-threo-1-phenyl-2-decanoyl amino-3-morpholino-1-propanol (PDMP), an inhibitor of sphingolipid biosynthesis. In treated cells, the radioactive SM pool was reduced by ≈80% Concomitantly, labeling of a 60-kd protein, seen in control cells, decreased. Furthermore, the 60-kd protein is membrane-associated and insoluble in detergent at low temperature. Moreover, when cells containing photoreactive sphingolipids after a preincubation with the photoreactive Cer were photoactivated and subsequently incubated with fluorescent sphingolipid analogs, transport of the latter to the bile canalicular membrane, as observed in control cells, was inhibited. Taken together, the data suggest that distinct proteins, among them a 60-kd protein, may play a specific and functional role in sphingolipid transport to the bile canalicular membrane.
Imaging visual recognition: PET and fMRI studies of the functional anatomy of human visual recognition
Authors: Martha J. Farah, Geoffrey K. Aguirre
Journal: Trends in Cognitive Sciences (1999)

Until recently, the neural bases of visual object recognition in humans could be studied only by the use of brain-damaged subjects with naturally occurring lesions. Functional neuroimaging has given us the capability of studying visual recognition in the normal human brain. In the past ten years a number of PET and fMRI studies have attempted to isolate the neural substrates of human visual recognition. We have reviewed these studies and compared their conclusions regarding the anatomical locations of visual recognition processing in the human brain. The outcome was disappointing, revealing a wide range of locations. Our attempts to reduce the scatter by subgrouping the studies according to different task and stimulus properties were not successful. We discuss possible reasons for the lack of agreement among studies, including differences in the kinds of information yielded by lesion and imaging studies, and issues in the design and analysis of functional neuroimaging experiments. We conclude with a review of a more recent approach to the neuroimaging of human visual recognition, in which the effects of recognizing different types of visual stimuli are compared directly. With these experimental designs neuroimaging yields more replicable results, which also accord better with the known effects of lesions.
Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study
Authors: I. A. F. Van Der Mei, A.-L. Ponsonby, T. Dwyer, L. Blizzard, R. Simmons, B. V. Taylor, H. Butzkueven, T. Kilpatrick
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To examine whether past high sun exposure is associated with a reduced risk of multiple sclerosis. <b>Design</b> Population based case-control study. <b>Setting</b> Tasmania, latitudes 41-3°S. <b>Participants</b> 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth. <b>Main outcome measure</b> Multiple sclerosis defined by both clinical and magnetic resonance imaging criteria. <b>Results</b> Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage. <b>Conclusion</b> Higher sun exposure during childhood and early adolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation may therefore influence the development of multiple sclerosis.