tbuckley/cabot-search huggingface dataset:
Monocyte/Macrophage Suppression in CD11b Diphtheria Toxin Receptor Transgenic Mice Differentially Affects Atherogenesis and Established Plaques
Authors: Victoria Stoneman, Denise Braganza, Nichola Figg, John Mercer, Richard Lang, Martin Goddard, Martin Bennett
Journal: Circulation Research (2007)

Although monocytes/macrophages are considered important in atherogenesis, their role in established plaques is unclear. For example, macrophage content is associated with plaque instability, but their loss through cell death is observed at sites of plaque rupture. To examine the role of monocytes/macrophages in atherosclerosis, we developed CD11b–diphtheria toxin (DT) receptor (DTR) transgenic mice, whereby administration of DT selectively kills monocytes/macrophages. DT treatment reduced peripheral blood monocytes and tissue macrophages and inhibited macrophage function in CD11b-DTR mice and apolipoprotein E–null (apoE −/− ) mice transplanted with CD11b-DTR bone marrow. In atherogenesis experiments, DT markedly reduced plaque development and altered plaque composition, reducing collagen content and necrotic core formation. In mice with established plaques, acute DT treatment induced macrophage apoptosis and reduced macrophage content but did not induce plaque inflammation, thrombosis, or rupture. Furthermore, despite a 50% reduction in monocytes, chronic DT treatment of these mice did not alter plaque extent or composition, most likely because of ongoing recruitment/proliferation of monocytes with recovery of macrophage content. We conclude that monocytes/macrophages are critical to atherogenesis, but established plaques are more resistant to reductions in monocytes.
Anthracycline Cardiotoxicity: From Bench to Bedside
Authors: Luca Gianni, Eugene H. Herman, Steven E. Lipshultz, Giorgio Minotti, Narine Sarvazyan, Douglas B. Sawyer
Journal: Journal of Clinical Oncology (2008)

Anthracyclines remain among the most widely prescribed and effective anticancer agents. Unfortunately, life-threatening cardiotoxicity continues to compromise their usefulness. Despite more than four decades of investigation, the pathogenic mechanisms responsible for anthracycline cardiotoxicity have not been completely elucidated. In addition, new drugs and combination therapies often exacerbate the toxicity. The First International Workshop on Anthracycline Cardiotoxicity, held in fall 2006, in Como, Italy, focused on the state-of-the-art knowledge and discussed the research needed to address the cardiotoxicity of these drugs. Here, we incorporate these discussions into the framework of a broader review of preclinical and clinical issues.
Can Immunity to Breast Cancer Eliminate Residual Micrometastases?
Authors: Mary L. Disis, Sasha E. Stanton
Journal: Clinical Cancer Research (2013)

Abstract An effective immune response has the potential for breast cancer sterilization with marked reduction in the potential for disease relapse. Adaptive type I immune cells uniquely have the capability of (i) cytotoxic T-cell activation and proliferation until all antigen expressing cells are eradicated, (ii) traversing endothelial barriers to penetrate tumor deposits wherever they occur, and (iii) immunologic memory, which allows the persistence of destructive immunity over the years it may take for breast cancer micrometastases to become clinically evident. Numerous recent investigations suggest that some breast cancers stimulate the type of immunity that results in a decreased risk of relapse. Moreover, the endogenous type I tumor microenvironment or type I immunity induced by drugs or biologic agents may improve response to standard therapies, further lowering the probability of disease recurrence. Clin Cancer Res; 19(23); 6398–403. ©2013 AACR.
Time-Dependent Changes in Matrix Metalloproteinase Activity and Expression During the Progression of Congestive Heart Failure
Authors: Francis G. Spinale, Mytsi L. Coker, Chadwick V. Thomas, Jennifer D. Walker, Rupak Mukherjee, Latha Hebbar
Journal: Circulation Research (1998)

Abstract —The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs. After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a &gt;50% increase in LV dimension, a 56% fall in LV fractional shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by &gt;25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by &gt;100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by ≈2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CHF, early changes in LV myocardial MMP zymographic activity and protein levels occurred with the initiation and progression of LV dilation and dysfunction. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV myocardial MMPs.
Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects
Authors: T W Harrison
Journal: Thorax (2001)

<h3>BACKGROUND</h3> The potential for long term adverse effects from inhaled corticosteroids relates to their systemic absorption, usually assessed from proxy markers in short term studies. When fluticasone propionate and budesonide have been compared in this way the results have been inconsistent. To determine whether this is because of the subjects studied or the sensitivity of the systemic marker used, we have compared the effects of fluticasone propionate and budesonide in healthy and asthmatic subjects and investigated the effect of treatment on three systemic markers. <h3>METHODS</h3> Forty six healthy subjects were randomised to receive inhaled fluticasone propionate 1500 μg/day (via an Accuhaler), budesonide 1600 μg/day (via a Turbuhaler), or placebo; 31 subjects with moderately severe asthma were randomised to receive the same doses of fluticasone propionate or budesonide but not placebo. Systemic effects in healthy and asthmatic subjects were compared after 7 days. Treatment was continued for another 21 days in the subjects with asthma when systemic effects and asthma control were assessed. <h3>RESULTS</h3> At baseline healthy subjects had higher urinary levels of total cortisol metabolites (TCM) than subjects with asthma. After 7 days of treatment with fluticasone propionate urinary TCM levels in the healthy subjects were significantly lower than in the subjects with asthma (mean difference between groups 1663 μg/day, 95% CI 328 to 2938). This was not the case with budesonide, however, where urinary TCM levels in the healthy subjects remained above those in the asthmatic subjects (mean difference between groups 1210 μg/day, 95% CI –484 to 2904). Urinary TCM levels were considerably more sensitive to the effects of inhaled corticosteroids than morning serum cortisol or osteocalcin concentrations. Only budesonide reduced the serum level of osteocalcin. <h3>CONCLUSIONS</h3> When given by dry powder inhaler for 7 days, fluticasone propionate 1500 μg/day has a greater effect on the hypothalamic-pituitary-adrenal axis in healthy subjects than in subjects with asthma, but this is not the case for budesonide 1600 μg/day. These findings, together with the differences in sensitivity between systemic markers, explain many of the discrepancies in the literature.
Comparing and combining algorithms for computer-aided detection of pulmonary nodules in computed tomography scans: The ANODE09 study
Authors: Bram van Ginneken, Samuel G. Armato, Bartjan de Hoop, Saskia van Amelsvoort-van de Vorst, Thomas Duindam, Meindert Niemeijer, Keelin Murphy, Arnold Schilham, Alessandra Retico, Maria Evelina Fantacci, Niccolò Camarlinghi, Francesco Bagagli, Ilaria Gori, Takeshi Hara, Hiroshi Fujita, Gianfranco Gargano, Roberto Bellotti, Sabina Tangaro, Lourdes Bolaños, Francesco De Carlo, Piergiorgio Cerello, Sorin Cristian Cheran, Ernesto Lopez Torres, Mathias Prokop
Journal: Medical Image Analysis (2010)
Shigella induced reactive arthritis
Authors: J S H. Gaston
Journal: Annals of the Rheumatic Diseases (2005)

A long-haul travel syndrome?S higella infection is the least common of the gastroenteritis-inducing organisms which are associated with reactive arthritis (ReA) in developed countries, reflecting the scarcity of the organism in these environments.A recent thorough survey of Shigella infected subjects in Finland 1 describes an annual incidence of Shigella induced ReA of only 1.3 per million.This compares with the incidence figures of 46 per million for ReA due to Chlamydia infection, and 50 per million for other enteric pathogens, noted in a survey of the Oslo population. 2 However, the relevant denominator for Shigella induced ReA is not the population of Finland, but the population visiting distant travel destinations-for example Egypt, India, Thailand, Congo, and Turkey-all countries where the infection was acquired by the Finnish patients.Although these countries, particularly, Turkey, are increasingly common holiday destinations for sunstarved Northern Europeans, well under 5% of the population visit such countries in any 1 year, so the incidence of ReA is more like 30-40 per million in the exposed population.
Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system
Authors: Ikuo Hirano, Nelson Moy, Michael G Heckman, Colleen S Thomas, Nirmala Gonsalves, Sami R Achem
Journal: Gut (2012)

<h3>Abstract</h3> Brain-machine interfaces (BMIs) hold promise for the restoration of sensory and motor function and the treatment of neurological disorders, but clinical BMIs have not yet been widely adopted, in part because modest channel counts have limited their potential. In this white paper, we describe Neuralink's first steps toward a scalable high-bandwidth BMI system. We have built arrays of small and flexible electrode "threads", with as many as 3,072 electrodes per array distributed across 96 threads. We have also built a neurosurgical robot capable of inserting six threads (192 electrodes) per minute. Each thread can be individually inserted into the brain with micron precision for avoidance of surface vasculature and targeting specific brain regions. The electrode array is packaged into a small implantable device that contains custom chips for low-power on-board amplification and digitization: the package for 3,072 channels occupies less than (23 × 18.5 × 2) mm<sup>3</sup>. A single USB-C cable provides full-bandwidth data streaming from the device, recording from all channels simultaneously. This system has achieved a spiking yield of up to 85.5 % in chronically implanted electrodes. Neuralink's approach to BMI has unprecedented packaging density and scalability in a clinically relevant package.
Changes in energy content of lunchtime purchases from fast food restaurants after introduction of calorie labelling: cross sectional customer surveys
Authors: T. Dumanovsky, C. Y. Huang, C. A. Nonas, T. D. Matte, M. T. Bassett, L. D. Silver
Journal: BMJ (2011)

<b>Objective</b> To assess the impact of fast food restaurants adding calorie labelling to menu items on the energy content of individual purchases. <b>Design</b> Cross sectional surveys in spring 2007 and spring 2009 (one year before and nine months after full implementation of regulation requiring chain restaurants’ menus to contain details of the energy content of all menu items). <b>Setting </b>168 randomly selected locations of the top 11 fast food chains in New York City during lunchtime hours. <b>Participants</b> 7309 adult customers interviewed in 2007 and 8489 in 2009. <b>Main outcome measures</b> Energy content of individual purchases, based on customers’ register receipts and on calorie information provided for all items in menus. <b>Results</b> For the full sample, mean calories purchased did not change from before to after regulation (828 <i>v</i> 846 kcal, P=0.22), though a modest decrease was shown in a regression model adjusted for restaurant chain, poverty level for the store location, sex of customers, type of purchase, and inflation adjusted cost (847 <i>v</i> 827 kcal, P=0.01). Three major chains, which accounted for 42% of customers surveyed, showed significant reductions in mean energy per purchase (McDonald’s 829 <i>v</i> 785 kcal, P=0.02; Au Bon Pain 555 <i>v</i> 475 kcal, P&lt;0.001; KFC 927 <i>v</i> 868 kcal, P&lt;0.01), while mean energy content increased for one chain (Subway 749 <i>v</i> 882 kcal, P&lt;0.001). In the 2009 survey, 15% (1288/8489) of customers reported using the calorie information, and these customers purchased 106 fewer kilocalories than customers who did not see or use the calorie information (757 <i>v</i> 863 kcal, P&lt;0.001). <b>Conclusion</b> Although no overall decline in calories purchased was observed for the full sample, several major chains saw significant reductions. After regulation, one in six lunchtime customers used the calorie information provided, and these customers made lower calorie choices.
Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial
Authors: Simon Stewart, Jocasta Ball, John D Horowitz, Thomas H Marwick, Gnanadevan Mahadevan, Chiew Wong, Walter P Abhayaratna, Yih K Chan, Adrian Esterman, David R Thompson, Paul A Scuffham, Melinda J Carrington
Journal: The Lancet (2014)
Vemurafenib-induced toxic epidermal necrolysis: possible cross-reactivity with other sulfonamide compounds
Authors: T. Bellón, V. Lerma, O. González-Valle, C. González Herrada, F.J. de Abajo
Journal: British Journal of Dermatology (2015)

Vemurafenib is a newly licensed target-directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF(V600E) mutation; however, adverse cutaneous reactions are frequent. Few cases of life-threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross-reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib-induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross-reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.
T Cell Receptor (TCR) Mini-Gene mRNA Expression Regulated by Nonsense Codons: A Nuclear-associated Translation-like Mechanism
Authors: Shulin Li, Deana Leonard, Miles F. Wilkinson
Journal: The Journal of Experimental Medicine (1997)

Premature termination codons (PTCs) are known to decrease mRNA levels. Here, we report our investigation of the mechanism for this downregulation using the TCR-β gene, which acquires PTCs as a result of programmed rearrangements that occur during normal thymic development. We found that a mini-gene version of this gene, which contains only three TCR-β exons, exhibited efficient downregulation in response to PTCs. This demonstrates that the full coding sequence is not necessary for appropriate regulation. Mutation of the translation start AUG and a downstream in-frame AUG that displayed similarity to the Kozak consensus sequence reversed the downregulatory response to PTCs. Thus, an AUG start codon is required to define the reading frame of a PTC. Specific suppressor tRNAs also reversed the downregulatory response, strongly implicating the involvement of a translation-like process. Remarkably, the addition of suppressor tRNAs or the inactivation of the start AUGs caused a dramatic rise in the levels of PTC-bearing transcripts in the nuclear fraction prepared by two independent methods. Collectively, our results provide evidence for a codon-based surveillance mechanism associated with the nucleus that downregulates aberrant transcripts encoding potentially toxic polypeptides from nonproductively rearranged genes.
Inactive or moderately active human promoters are enriched for inter-individual epialleles
Authors: Carolina Gemma, Sreeram V Ramagopalan, Thomas A Down, Huriya Beyan, Mohammed I Hawa, Michelle L Holland, Paul J Hurd, Gavin Giovannoni, R David Leslie, George C Ebers, Vardhman K Rakyan
Journal: Genome biology (2013)

Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information.First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing.Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells
Authors: David K. Finlay, Ella Rosenzweig, Linda V. Sinclair, Carmen Feijoo-Carnero, Jens L. Hukelmann, Julia Rolf, Andrey A. Panteleyev, Klaus Okkenhaug, Doreen A. Cantrell
Journal: The Journal of Experimental Medicine (2012)

mTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8+ cytolytic T cell (CTL) fate. In some cell systems, mTORC1 couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control of glucose uptake and glycolysis. However, PI3K–Akt-independent mechanisms control glucose metabolism in CD8+ T cells, and the role of mTORC1 has not been explored. The present study now demonstrates that mTORC1 activity in CD8+ T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8+ T cells. We also show that PI3K- and Akt-independent pathways mediated by mTORC1 regulate the expression of HIF1 (hypoxia-inducible factor 1) transcription factor complex. This mTORC1–HIF1 pathway is required to sustain glucose metabolism and glycolysis in effector CTLs and strikingly functions to couple mTORC1 to a diverse transcriptional program that controls expression of glucose transporters, multiple rate-limiting glycolytic enzymes, cytolytic effector molecules, and essential chemokine and adhesion receptors that regulate T cell trafficking. These data reveal a fundamental mechanism linking nutrient and oxygen sensing to transcriptional control of CD8+ T cell differentiation.