tbuckley/cabot-search huggingface dataset:
Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558.
Authors: P G Heyworth, J T Curnutte, W M Nauseef, B D Volpp, D W Pearson, H Rosen, R A Clark
Journal: Journal of Clinical Investigation (1991)

Two of the cytosolic NADPH oxidase components, p47-phox and p67-phox, translocate to the plasma membrane in normal neutrophils stimulated with phorbol myristate acetate (PMA). We have now studied the translocation process in neutrophils of patients with chronic granulomatous disease (CGD), an inherited syndrome in which the oxidase system fails to produce superoxide due to lesions affecting any one of its four known components: the gp91-phox and p22-phox subunits of cytochrome b558 (the membrane-bound terminal electron transporter of the oxidase), p47-phox, and p67-phox. In contrast to normal cells, neither p47-phox nor p67-phox translocated to the membrane in PMA-stimulated CGD neutrophils which lack cytochrome b558. In one patient with a rare X-linked form of CGD caused by a Pro----His substitution in gp91-phox, but whose neutrophils have normal levels of this mutant cytochrome b558, translocation was normal. In two patients with p47-phox deficiency, p67-phox failed to translocate, whereas p47-phox was detected in the particulate fraction of PMA-stimulated neutrophils from two patients deficient in p67-phox. Our data suggest that cytochrome b558 or a closely linked factor provides an essential membrane docking site for the cytosolic oxidase components and that it is p47-phox that mediates the assembly of these components on the membrane.
Detection of Circulating Tumor Cells in Human Peripheral Blood Using Surface-Enhanced Raman Scattering Nanoparticles
Authors: Xu Wang, Ximei Qian, Jonathan J. Beitler, Zhuo Georgia Chen, Fadlo R. Khuri, Melinda M. Lewis, Hyung Ju C. Shin, Shuming Nie, Dong M. Shin
Journal: Cancer Research (2011)

The detection and characterization of circulating tumor cells (CTC) holds great promise for personalizing medicine and optimizing systemic therapy. However, low specificity, low sensitivity, and the time consuming nature of current approaches have impeded clinical adoption. Here we report a new method using surface-enhanced Raman spectroscopy (SERS) to directly measure targeted CTCs in the presence of white blood cells. SERS nanoparticles with epidermal growth factor peptide as a targeting ligand have successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck (SCCHN), with a range of 1 to 720 CTCs per milliliter of whole blood. Our technique may provide an important new clinical tool for management of patients with SCCHN and other cancers.
Variable Inhibition of Thrombospondin 1 against Liver and Lung Metastases through Differential Activation of Metalloproteinase ADAMTS1
Authors: Yoon-Jin Lee, Moritz Koch, Daniel Karl, Antoni X. Torres-Collado, Namali T. Fernando, Courtney Rothrock, Darshini Kuruppu, Sandra Ryeom, M. Luisa Iruela-Arispe, Sam S. Yoon
Journal: Cancer Research (2010)

Abstract Metastasis relies on angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors, including thrombospondin 1 (TSP1). The principal antiangiogenic activity of TSP1 resides in a domain containing three TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. In this study, we examined the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. TSP1 overexpression inhibited metastatic growth of colon or renal carcinoma cells in liver but not lung. Metastatic melanoma in liver grew more rapidly in Tsp1-null mice compared with controls, whereas in lung grew similarly in Tsp1-null mice or controls. Recombinant TSP1 was cleaved more efficiently in lysates from liver than lung. ADAMTS1 inhibition by neutralizing antibody, small interfering RNA, or genetic deletion abrogated cleavage activity. To confirm that lack of cleavage of TSP1 ablated its antiangiogenic function in the lung, we generated colon cancer cells stably secreting only the 3TSR domain and found that they inhibited formation of both liver and lung metastases. Collectively, our results indicate that the antiangiogenic activity of TSP1 is differentially regulated by ADAMTS1 in the liver and lung, emphasizing the concept that regulation of angiogenesis is varied in different tissue environments. Cancer Res; 70(3); 948–56
Fas Ligand Deficiency Impairs Tumor Immunity by Promoting an Accumulation of Monocytic Myeloid-Derived Suppressor Cells
Authors: Sanam Peyvandi, Stéphanie Buart, Boubekeur Samah, Marie Vétizou, Yanyan Zhang, Ludovic Durrieu, Mélanie Polrot, Salem Chouaib, Karim Benihoud, Fawzia Louache, Saoussen Karray
Journal: Cancer Research (2015)

The Fas receptor ligand FasL regulates immune cell levels by inducing apoptosis of Fas receptor-positive cells. Here, we studied the impact of host FasL on tumor development in mice. Genetically targeting FasL in naïve mice increased myeloid cell populations, but, in marked contrast, it reduced the levels of myeloid-derived suppressor cells (MDSC) in mice bearing Lewis lung carcinoma tumors. Analysis of the MDSC subset distribution revealed that FasL deficiency skewed cell populations toward the M-MDSC subset, which displays a highly immunosuppressive activity. Furthermore, tumor-bearing mice that were FasL-deficient displayed an enhanced proportion of tumor-associated macrophages and regulatory T cells. Overall, the immunosuppressive environment produced by FasL targeting correlated with reduced survival of tumor-bearing mice. These results disclose a new role for FasL in modulating immunosuppressive cells.
Machine Learning Methods for Protein Structure Prediction
Authors: None Jianlin Cheng, A.N. Tegge, P. Baldi
Journal: IEEE Reviews in Biomedical Engineering (2008)

Machine learning methods are widely used in bioinformatics and computational and systems biology. Here, we review the development of machine learning methods for protein structure prediction, one of the most fundamental problems in structural biology and bioinformatics. Protein structure prediction is such a complex problem that it is often decomposed and attacked at four different levels: 1-D prediction of structural features along the primary sequence of amino acids; 2-D prediction of spatial relationships between amino acids; 3-D prediction of the tertiary structure of a protein; and 4-D prediction of the quaternary structure of a multiprotein complex. A diverse set of both supervised and unsupervised machine learning methods has been applied over the years to tackle these problems and has significantly contributed to advancing the state-of-the-art of protein structure prediction. In this paper, we review the development and application of hidden Markov models, neural networks, support vector machines, Bayesian methods, and clustering methods in 1-D, 2-D, 3-D, and 4-D protein structure predictions.
Cyclical caspofungin for chronic pulmonary aspergillosis in sarcoidosis
Authors: Gregory J Keir, Benjamin Garfield, David M Hansell, Michael R Loebinger, Robert Wilson, Elisabetta A Renzoni, Athol U Wells, Toby M Maher
Journal: Thorax (2013)

<h3>Abstract</h3> In sarcoidosis, chronic pulmonary aspergillosis (CPA) may be associated with significant morbidity, and treatment failure rates are often high, even with newer triazole antifungal agents. We report a treatment regimen of cyclical caspofungin infusions in 10 patients with sarcoidosis and worsening CPA despite oral triazoles.
Mechanisms of Inhibition within the Telencephalon: “Where the Wild Things Are”
Authors: Gord Fishell, Bernardo Rudy
Journal: Annual Review of Neuroscience (2011)

In this review, we first provide a historical perspective of inhibitory signaling from the discovery of inhibition through to our present understanding of the diversity and mechanisms by which GABAergic interneuron populations function in different parts of the telencephalon. This is followed by a summary of the mechanisms of inhibition in the CNS. With this as a starting point, we provide an overview describing the variations in the subtypes and origins of inhibitory interneurons within the pallial and subpallial divisions of the telencephalon, with a focus on the hippocampus, somatosensory, paleo/piriform cortex, striatum, and various amygdala nuclei. Strikingly, we observe that marked variations exist in the origin and numerical balance between GABAergic interneurons and the principal cell populations in distinct regions of the telencephalon. Finally we speculate regarding the attractiveness and challenges of establishing a unifying nomenclature to describe inhibitory neuron diversity throughout the telencephalon.
Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis
Authors: Nicholas A. Manieri, Madison R. Mack, Molly D. Himmelrich, Daniel L. Worthley, Elaine M. Hanson, Lars Eckmann, Timothy C. Wang, Thaddeus S. Stappenbeck
Journal: Journal of Clinical Investigation (2015)

Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I₂ (PGI₂) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.
Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks
Authors: Xia Yang, Joshua L Deignan, Hongxiu Qi, Jun Zhu, Su Qian, Judy Zhong, Gevork Torosyan, Sana Majid, Brie Falkard, Robert R Kleinhanz, Jenny Karlsson, Lawrence W Castellani, Sheena Mumick, Kai Wang, Tao Xie, Michael Coon, Chunsheng Zhang, Daria Estrada-Smith, Charles R Farber, Susanna S Wang, Atila van Nas, Anatole Ghazalpour, Bin Zhang, Douglas J MacNeil, John R Lamb, Katrina M Dipple, Marc L Reitman, Margarete Mehrabian, Pek Y Lum, Eric E Schadt, Aldons J Lusis, Thomas A Drake
Journal: Nature Genetics (2009)
The Energy Content of Restaurant Foods Without Stated Calorie Information
Authors: Lorien E. Urban, Alice H. Lichtenstein, Christine E. Gary, Jamie L. Fierstein, Ashley Equi, Carolyn Kussmaul, Gerard E. Dallal, Susan B. Roberts
Journal: JAMA Internal Medicine (2013)

National recommendations for the prevention and treatment of obesity emphasize reducing energy intake through self-monitoring food consumption. However, little information is available on the energy content of foods offered by nonchain restaurants, which account for approximately 50% of restaurant locations in the United States.To measure the energy content of foods from independent and small-chain restaurants that do not provide stated information on energy content.We used bomb calorimetry to determine the dietary energy content of the 42 most frequently purchased meals from the 9 most common restaurant categories. Independent and small-chain restaurants were randomly selected, and 157 individual meals were analyzed.Area within 15 miles of downtown Boston.A random sample of independent and small-chain restaurants.Dietary energy.All meal categories provided excessive dietary energy. The mean energy content of individual meals was 1327 (95% CI, 1248-1406) kcal, equivalent to 66% of typical daily energy requirements. We found a significant effect of food category on meal energy (P ≤ .05), and 7.6% of meals provided more than 100% of typical daily energy requirements. Within-meal variability was large (average SD, 271 kcal), and we found no significant effect of restaurant establishment or size. In addition, meal energy content averaged 49% greater than those of popular meals from the largest national chain restaurants (P < .001) and in subset analyses contained 19% more energy than national food database information for directly equivalent items (P < .001).National chain restaurants have been criticized for offering meals with excess dietary energy. This study finds that independent and small-chain restaurants, which provide no nutrition information, also provide excessive dietary energy in amounts apparently greater than popular meals from chain restaurants or information in national food databases. A national requirement for accurate calorie labeling in all restaurants may discourage menus offering unhealthy portions and would allow consumers to make informed choices about ordering meals that promote weight gain and obesity.
Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study
Authors: D J Hole, G C M Watt, G Davey-Smith, C L Hart, C R Gillis, V M Hawthorne
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To assess the relation between forced expiratory volume in one second (FEV1) and subsequent mortality. <b>Design</b>: Prospective general population study. <b>Setting</b>: Renfrew and Paisley, Scotland. <b>Subjects</b>: 7058 men and 8353 women aged 45-64 years at baseline screening in 1972-6. <b>Main outcome measure</b>: Mortality from all causes, ischaemic heart disease, cancer, lung and other cancers, stroke, respiratory disease, and other causes of death after 15 years of follow up. <b>Results</b>: 2545 men and 1894 women died during the follow up period. Significant trends of increasing risk with diminishing FEV1 are apparent for both sexes for all the causes of death examined after adjustment for age, cigarette smoking, diastolic blood pressure, cholesterol concentration, body mass index, and social class. The relative hazard ratios for all cause mortality for subjects in the lowest fifth of the FEV1 distribution were 1.92 (95% confidence interval 1.68 to 2.20) for men and 1.89 (1.63 to 2.20) for women. Corresponding relative hazard ratios were 1.56 (1.26 to 1.92) and 1.88 (1.44 to 2.47) for ischaemic heart disease, 2.53 (1.69 to 3.79) and 4.37 (1.84 to 10.42) for lung cancer, and 1.66 (1.07 to 2.59) and 1.65 (1.09 to 2.49) for stroke. Reduced FEV1 was also associated with an increased risk for each cause of death examined except cancer for lifelong nonsmokers. <b>Conclusions</b>: Impaired lung function is a major clinical indicator of mortality risk in men and women for a wide range of diseases. The use of FEV1 as part of any health assessment of middle aged patients should be considered. Smokers with reduced FEV1 should form a priority group for targeted advice to stop smoking. <h3>Key messages</h3> These increased risks, with the exception of the cancers, are apparent for lifelong non-smokers FEV1 is second in importance to cigarette smoking as a predictor of subsequent all cause mortality and is as important as cholesterol in predicting mortality from ischaemic heart disease FEV1 should be included in health assessment of middle aged men and women Smokers with a reduced FEV1 should be targeted with advice to stop smoking
Molecularly Targeted Approaches to the Chemoprevention of Lung Cancer
Authors: Fadlo R. Khuri, Victor Cohen
Journal: Clinical Cancer Research (2004)

Abstract Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of β-carotene, α-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor β (RAR-β), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
Experimental Production of Pulmonary Hypertension and Pulmonary Atherosclerosis in the Rabbit
Authors: KAZUNOBU KOMURO, DAVID Y. ROSENZWEIG
Journal: Circulation Research (1967)

The experimental production of pulmonary atherosclerosis was studied in 39 rabbits. Variables examined included age, pulmonary hypertension after pneumonectomy, and high-fat diet. Right ventricular pressures were measured and then stress-strain elasticity measurements and histologic examination were made of the pulmonary arteries. High-fat diet alone produced neither right ventricular hypertension nor pulmonary atherosclerosis. Right ventricular hypertension occurred after pneumonectomy alone, but there were no anatomic changes unless the rabbits had eaten a high-fat diet. Pneumonectomy plus a high-fat diet was followed by persistent hypertension with right ventricular systolic pressures more than twice control values and by progressive pulmonary atherosclerosis consisting of discrete atheromata in the larger vessels and intimal fibrosis in the smaller arteries. No pathologic or physiologic differences were observed between the changes in the older (24 months) rabbits and the younger (6 months) ones, except in the measurements of elasticity. The old rabbit's pulmonary artery strip is slightly less extensible than that of the young rabbit, but pneumonectomy and high-fat diet did not reduce extensibility further. These preparations may serve adequately for the experimental study of pulmonary atherosclerosis.
Salmeterol xinafoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. UK Study Group
Authors: G Boyd
Journal: European Respiratory Journal (1995)

In severe chronic asthma, long-term oral steroids may be necessary to control symptoms. In patients in whom such treatment was under consideration, the efficacy and safety of salmeterol xinafoate 100 micrograms b.i.d. was investigated in a randomized, double-blind, placebo-controlled parallel-group, multicentre study. One hundred and nineteen chronic symptomatic asthmatics were randomized to receive either salmeterol, 100 micrograms b.i.d. (n = 55; baseline % predicted morning peak expiratory flow (PEF) 59%; forced expiratory volume in one second (FEV1) 66%) or placebo (n = 64; baseline % predicted morning PEF 63%; FEV1 66%) both via the Diskhaler. Morning and evening PEF and asthma symptoms were recorded in daily record booklets by the patient over a 12 week period. A significant improvement in morning PEF was achieved after 1 month in the salmeterol treated group; this persisted throughout the treatment period (estimated treatment difference 22 L.min-1). There was a significant increase in the proportion of symptom-free nights experienced by the salmeterol treated group (33 (SD 32) %) compared with placebo (13 (26) %), and a significant decrease in daily use of relief medication (mean decrease 5.1 (4.7) doses per day with salmeterol, 2.5 (4.0) doses with placebo). Both treatments were well-tolerated, with no evidence of any difference in the side-effects associated with beta 2-agonists. In conclusion, the addition of salmeterol (100 micrograms daily) to the existing treatment of chronic asthmatics under consideration for maintenance oral corticosteroid therapy is well-tolerated, improves lung function and provides additional symptom control.
Genetic and Nongenetic Determinants of Cell Growth Variation Assessed by High-Throughput Microscopy
Authors: Naomi Ziv, Mark L. Siegal, David Gresham
Journal: Molecular Biology and Evolution (2013)

In microbial populations, growth initiation and proliferation rates are major components of fitness and therefore likely targets of selection. We used a high-throughput microscopy assay, which enables simultaneous analysis of tens of thousands of microcolonies, to determine the sources and extent of growth rate variation in the budding yeast (Saccharomyces cerevisiae) in different glucose environments. We find that cell growth rates are regulated by the extracellular concentration of glucose as proposed by Monod (1949), but that significant heterogeneity in growth rates is observed among genetically identical individuals within an environment. Yeast strains isolated from different geographic locations and habitats differ in their growth rate responses to different glucose concentrations. Inheritance patterns suggest that the genetic determinants of growth rates in different glucose concentrations are distinct. In addition, we identified genotypes that differ in the extent of variation in growth rate within an environment despite nearly identical mean growth rates, providing evidence that alleles controlling phenotypic variability segregate in yeast populations. We find that the time to reinitiation of growth (lag) is negatively correlated with growth rate, yet this relationship is strain-dependent. Between environments, the respirative activity of individual cells negatively correlates with glucose abundance and growth rate, but within an environment respirative activity and growth rate show a positive correlation, which we propose reflects differences in protein expression capacity. Our study quantifies the sources of genetic and nongenetic variation in cell growth rates in different glucose environments with unprecedented precision, facilitating their molecular genetic dissection.
Requirement for the NF-κB Family Member RelA in the Development of Secondary Lymphoid Organs
Authors: Elizabeth Alcamo, Nir Hacohen, Leah C. Schulte, Paul D. Rennert, Richard O. Hynes, David Baltimore
Journal: The Journal of Experimental Medicine (2002)

The transcription factor nuclear factor (NF)-κB has been suggested to be a key mediator of the development of lymph nodes and Peyer's patches. However, targeted deletion of NF-κB/ Rel family members has not yet corroborated such a function. Here we report that when mice lacking the RelA subunit of NF-κB are brought to term by breeding onto a tumor necrosis factor receptor (TNFR)1-deficient background, the mice that are born lack lymph nodes, Peyer's patches, and an organized splenic microarchitecture, and have a profound defect in T cell–dependent antigen responses. Analyses of TNFR1/RelA-deficient embryonic tissues and of radiation chimeras suggest that the dependence on RelA is manifest not in hematopoietic cells but rather in radioresistant stromal cells needed for the development of secondary lymphoid organs.