tbuckley/cabot-search huggingface dataset:
Aptamer:Toxin Conjugates that Specifically Target Prostate Tumor Cells
Authors: Ted C. Chu, John W. Marks, Laura A. Lavery, Sarah Faulkner, Michael G. Rosenblum, Andrew D. Ellington, Matthew Levy
Journal: Cancer Research (2006)

Abstract We have used RNA aptamer:gelonin conjugates to target and specifically destroy cells overexpressing the known cancer biomarker prostate-specific membrane antigen (PSMA). Aptamer:toxin conjugates have an IC50 of 27 nmol/L and display an increased potency of at least 600-fold relative to cells that do not express PSMA. The aptamer not only promotes uptake into target cells but also decreases the toxicity of gelonin in non-target cells. These results validate the notion that “escort aptamers” may be useful for the treatment of specific tumors expressing unique antigen targets.(Cancer Res 2006; 66(12): 5989-92)
HMGA1 Is a Determinant of Cellular Invasiveness and <i>In vivo</i> Metastatic Potential in Pancreatic Adenocarcinoma
Authors: Siong-Seng Liau, Amarsanaa Jazag, Edward E. Whang
Journal: Cancer Research (2006)

Abstract HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNA–generating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser473. Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser473. HMGA1 overexpression–induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpression–induced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma. (Cancer Res 2006; 66(24): 11613-22)
Left Ventricular Form and Function
Authors: Gerald D. Buckberg, Myron L. Weisfeldt, Manel Ballester, Raphael Beyar, Daniel Burkhoff, H. Cecil Coghlan, Mark Doyle, Neal D. Epstein, Morteza Gharib, Ray E. Ideker, Neil B. Ingels, Martin M. LeWinter, Andrew D. McCulloch, Gerald M. Pohost, Leslie J. Reinlib, David J. Sahn, George Sopko, Francis G. Spinale, Henry M. Spotnitz, Francisco Torrent-Guasp, Edward P. Shapiro
Journal: Circulation (2004)
Large-Scale Phylogenomic Analyses Indicate a Deep Origin of Primary Plastids within Cyanobacteria
Authors: Alexis Criscuolo, Simonetta Gribaldo
Journal: Molecular Biology and Evolution (2011)

The emergence of photosynthetic eukaryotes has played a crucial role in evolution and has strongly modified earth's ecology. Several phylogenetic analyses have established that primary plastids arose from a cyanobacterium through endosymbiosis. However, the question of which present-day cyanobacterial lineage is most closely related to primary plastids has been unclear. Here, we have performed an extensive phylogenomic investigation on the origin of primary plastids based on the analysis of up to 191 protein markers and over 30,000 aligned amino acid sites from 22 primary photosynthetic eukaryotes and 61 cyanobacteria representing a wide taxonomic sampling of this phylum. By using a number of solutions to circumvent a large range of systematic errors, we have reconstructed a robust global phylogeny of cyanobacteria and studied the placement of primary plastids within it. Our results strongly support an early emergence of primary plastids within cyanobacteria, prior to the diversification of most present-day cyanobacterial lineages for which genomic data are available.
Recombinant soluble form of the human high-affinity immunoglobulin E (IgE) receptor inhibits IgE production through its specific binding to IgE-bearing B cells.
Authors: Y Yanagihara, K Kajiwara, K Ikizawa, T Koshio, K Okumura, C Ra
Journal: Journal of Clinical Investigation (1994)

A recombinant soluble form of the alpha subunit of the human high-affinity receptor for IgE (rsFc epsilon RI alpha), one of the potent IgE-binding molecules, was tested for its ability to regulate IL-4-induced IgE synthesis by human lymphocytes. Addition of rsFc epsilon RI alpha to cultures induced a dose-dependent inhibition of the T cell-dependent and independent synthesis of IgE. The suppression of IgE synthesis was observed at the protein and the mRNA levels, and it was IgE class specific. By flow cytometry, specific binding of rsFc epsilon RI alpha was detected on surface IgE-bearing B cells as well as on U266 cells, and it was completely blocked by preincubation with IgE. rsFc epsilon RI alpha bound to the cell surface IgE could be effectively dissociated not only by a large excess of IgE, but also by an anti-rsFc epsilon RI alpha mAb that competes with IgE for the binding to rsFc epsilon RI alpha. This mAb abolished the rsFc epsilon RI alpha-mediated suppression of IgE synthesis. These data suggest that rsFc epsilon RI alpha may have a function in selectively suppressing IgE synthesis through its interaction with the membrane-bound form of IgE.
Continuous Intravenous Epoprostenol for Pulmonary Hypertension Due to the Scleroderma Spectrum of Disease
Authors: David B. Badesch, Victor F. Tapson, Michael D. McGoon, Bruce H. Brundage, Lewis J. Rubin, Fredrick M. Wigley, Stuart Rich, Robyn J. Barst, Pamela S. Barrett, Kenneth M. Kral, Maria M. Jöbsis, James E. Loyd, Srinivas Murali, Adaani Frost, Reda Girgis, Robert C. Bourge, David D. Ralph, C. Gregory Elliott, Nicholas S. Hill, David Langleben, Robert J. Schilz, Vallerie V. McLaughlin, Ivan M. Robbins, Bertron M. Groves, Shelley Shapiro, Thomas A. Medsger, Sean P. Gaine, Evelyn Horn, James C. Decker, Katharine Knobil
Journal: Annals of Internal Medicine (2000)

Background: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. Objective: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. Design: Randomized, open-label, controlled trial. Setting: 17 pulmonary hypertension referral centers. Patients: 111 patients with moderate to severe pulmonary hypertension. Intervention: Epoprostenol plus conventional therapy or conventional therapy alone. Measurements: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. Results: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were−5.0 and 0.9 mm Hg, respectively (difference, −6.0 mm Hg [CI, −9.0 to −3.0 mm Hg], and the mean changes in pulmonary vascular resistance were −4.6 and 0.9 mm Hg/L per minute, respectively (difference, −5.5 mm Hg/L per minute [CI, −7.3 to −3.7 mm Hg/L per minute]. Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). Conclusions: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.
Staff costs are to blame for NHS deficits, say MPs
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Good standards of health care have been jeopardised by financial pressure on NHS trusts to balance their books, says a report by MPs that was published this week. 

The parliamentary health select committee's final report from its inquiry into NHS deficits says that the need to reduce deficits, rather than a desire to improve services, is driving changes currently taking place in the NHS. 

The MPs said that trusts were damaging the quality of care of patients and staff morale by cutting training budgets to solve their cash flow problems. Failures in financial management had occurred at all levels …
The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study
Authors: Carmen Stolwijk, Ivette Essers, Astrid van Tubergen, Annelies Boonen, Marloes T Bazelier, Marie L De Bruin, Frank de Vries
Journal: Annals of the Rheumatic Diseases (2014)

Objective To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls. Methods All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987–2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591). Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use. Results At diagnosis of AS, the proportion of patients with an EAM was 11.4% for AAU, 4.4% for psoriasis and 3.7% for IBD. Incidence rates of EAMs were 8.9/1000 person-years for AAU, 3.4/1000 person-years for psoriasis and 2.4 /1000 person-years for IBD in AS. The 20-year cumulative incidence was 24.5%, 10.1% and 7.5%, respectively. Risks of EAMs were 1.5-fold to 16-fold increased versus controls, with an adj HR of 15.5 (95% CI 11.6 to 20.7) for AAU, adj HR of 1.5 (95% CI 1.1 to 1.9) for psoriasis and adj HR of 3.3 (95% CI 2.3 to 4.8) for IBD. For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS. Conclusions The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls. Hazard patterns are different for each of the EAMs.
Inhibitory activity of anti‐β<sub>2</sub>‐glycoprotein I antibody on factor va degradation by activated‐protein C and its cofactor protein S
Authors: Juzo Matsuda, Kengo Gohchi, Kazuo Kawasugi, Moritaka Gotoh, Noriko Saitoh, Miyo Tsukamoto
Journal: American Journal of Hematology (1995)

We investigated the influence of anti-beta 2-glycoprotein I (aGPI), which recently has come to be regarded as anti-cardiolipin antibody (aCL) itself, on factor Va (FVa) degradation by activated protein C/protein S system. We found that aGPI had an inhibitory effect on FVa degradation with beta 2-glycoprotein I-dependency, thus suggesting aGPI/aCL is a highly possible factor as the pathogenesis of thrombosis observed in aGPI/aCL-positive patients.
Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases
Authors: Stefan Siebert, Alexander Tsoukas, Jamie Robertson, Iain McInnes
Journal: Pharmacological Reviews (2015)

The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti-interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways.
Avidity for antigen shapes clonal dominance in CD8<b>+</b> T cell populations specific for persistent DNA viruses
Authors: David A. Price, Jason M. Brenchley, Laura E. Ruff, Michael R. Betts, Brenna J. Hill, Mario Roederer, Richard A. Koup, Steven A. Migueles, Emma Gostick, Linda Wooldridge, Andrew K. Sewell, Mark Connors, Daniel C. Douek
Journal: The Journal of Experimental Medicine (2005)

The forces that govern clonal selection during the genesis and maintenance of specific T cell responses are complex, but amenable to decryption by interrogation of constituent clonotypes within the antigen-experienced T cell pools. Here, we used point-mutated peptide–major histocompatibility complex class I (pMHCI) antigens, unbiased TCRB gene usage analysis, and polychromatic flow cytometry to probe directly ex vivo the clonal architecture of antigen-specific CD8+ T cell populations under conditions of persistent exposure to structurally stable virus-derived epitopes. During chronic infection with cytomegalovirus and Epstein-Barr virus, CD8+ T cell responses to immunodominant viral antigens were oligoclonal, highly skewed, and exhibited diverse clonotypic configurations; TCRB CDR3 sequence analysis indicated positive selection at the protein level. Dominant clonotypes demonstrated high intrinsic antigen avidity, defined strictly as a physical parameter, and were preferentially driven toward terminal differentiation in phenotypically heterogeneous populations. In contrast, subdominant clonotypes were characterized by lower intrinsic avidities and proportionately greater dependency on the pMHCI–CD8 interaction for antigen uptake and functional sensitivity. These findings provide evidence that interclonal competition for antigen operates in human T cell populations, while preferential CD8 coreceptor compensation mitigates this process to maintain clonotypic diversity. Vaccine strategies that reconstruct these biological processes could generate T cell populations that mediate optimal delivery of antiviral effector function.
Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis
Authors: J. Stuart Elborn, John Perrett, Kristina Forsman-Semb, Joanna Marks-Konczalik, Kulasiri Gunawardena, Neil Entwistle
Journal: European Respiratory Journal (2012)

The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.
NI-10 * A MASS SPECTROMETRY IMAGING PLATFORM TO STUDY DRUG-SUSCEPTIBILITY OF BRAIN TUMORS
Authors: D. Calligaris, D. Loginov, R. Machaidze, J. A. Alberta, C. D. Stiles, J. C. Love, N. Y. R. Agar
Journal: Neuro-Oncology (2014)

Brain tumor heterogeneity poses significant challenges to their study and moreover to their treatment. A tool that could characterize a tumor specimen based on its cellular composition and response to treatment could assist the treating neuro-oncologist in determining the optimal treatment. We have developed a chip to culture dissociated cells in an organized array to categorize cell populations and subject them to targeted therapy. The chip was designed for analysis by optical and mass spectrometry imaging. The microwell array coupled to matrix assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) is used for the identification of clinical markers of response to targeted therapy. The new microwell array was validated for single-cell imaging by mass spectrometry based on correlation to fluorescence microscopy. Adherent NIH3T3 mouse fibroblasts expressing the enhanced GFP reporter gene and/or U87 cells stained with DAPI were incubated on microwell plates to allow their isolation at the bottom of each well. After cell fixation, the chip was imaged by fluorescence microscopy to determine the total number of wells occupied by cells, and the number of cells per well. The chips were coated with the CHCA matrix and analyzed by MALDI MSI. The statistical analyses of the MALDI MSI data revealed molecular signatures characteristic of each cell type, and mostly assigned to phospholipids. We also monitored the U87 cell response to a targeted inhibitor treatment to identify single-cell barcoding of drug response by MALDI MSI. The platform is further applied to the analysis of dissociated cells from surgical glioma specimens to characterize their heterogeneity and evaluate targeted treatment response. The proposed research has the potential to open ways for more comprehensive diagnostic approaches and to accompany them with direct evaluation of drug effect evaluation for the tailoring of brain cancer treatment.
Investigating the link between the presence of enteroaggregative Escherichia coli and infectious intestinal disease in the United Kingdom, 1993 to 1996 and 2008 to 2009
Authors: M A Chattaway, R Harris, C Jenkins, C Tam, J E Coia, J Gray, M Iturriza-Gomara, J Wain
Journal: Eurosurveillance (2013)

There are an estimated 17 million human diarrhoea cases annually in the United Kingdom. In 2008 and 2009, enteroaggregative E. coli (EAEC) were identified in 1.9% of stools. However, it remains unclear whether there is a causal link between presence of EAEC and disease. This study used bacterial load, the presence of co-infections and demographic data to assess if EAEC was independently associated with intestinal infectious disease. Quantitative real-time PCR data (Ct values) generated directly from stool specimens for several pathogen targets were analysed to identify multiple pathogens, including EAEC, in the stools of cases and healthy controls. Sensitivity and specificity using Ct value (60% and 60%) was not useful for identifying cases or controls, but an independent association between disease and EAEC presence was demonstrated: multivariate logistic regression for EAEC presence (odds ratio: 2.41; 95% confidence interval: 1.78–3.26; p<0.001). The population-attributable fraction was 3.3%. The group of bacteria known as EAEC are associated with gastrointestinal disease in at least half of the cases with EAEC positive stools. We conclude that the current definition of EAEC, by plasmid gene detection, includes true pathogens as well as non-pathogenic variants.
Long-term potentiation: What's learning got to do with it?
Authors: Tracey J. Shors, Louis D. Matzel
Journal: Behavioral and Brain Sciences (1997)

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with “Hebbian” descriptions of memory formation. Other characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms, provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism.