tbuckley/cabot-search huggingface dataset:
Plasma levels of a viral protein as a diagnostic signal for the presence of mammary tumor: the effect of tumor removal.
Authors: E Ritzi, D S Martin, R L Stolfi, S Spiegelman
Journal: The Journal of Experimental Medicine (1977)

We have previously shown (1, 2) that mice with mammary tumors can always be identified by their very high plasma levels of gp52, a 52,000 mol wt glycoprotein of the mouse mammary tumor virus (MMTV). The present investigation demostrates that the tumor is the principal source of the plasma gp52 since surgical excision is invariably followed in the first 9 days by a sharp decreasing (10-100-fold) of the gp52 levels. Control animals in which the tumors were left in place by a "sham" surgical procedure maintained their high level of gp52, which continued to increase as the disease progressed. The behavior of the gp52 after surgical removal suggests that gp52 plasma concentrations are diagnostically and prognostically informative, as indicated by the following finding: (a) All tumor recurrences were correctly diagnosed by increases in gp52 levels, and some were detected 4-7 days before they were found by palpation. (b) Tumor regrowths were accompanied by continued increases in plasma gp52 concentrations at rates that usually matched the speed of tumor development. (c) The only animals that remained tumor free at the termination of the experiment were those that maintained their gp52 levels at or below 15 ng/ml. (d) The probability of a tumor-free animal relapsing within 2 wk is much higher if its gp52 level is above the mean. (e) More remarkably, the plasma levels of gp52 at the time of surgery are superior to the size of the tumors removed as prognostic indicators of eventual surgical "cures". The availability of a specific and sensitive systemic measure of disease status should augment the usefulness of the murine mammary tumor model by catalyzing a more rapid acquisition of information on the therapeutic effectiveness of the new and varied drug combinations being tested for adjuvant chemotherapy.
Cellular Interactions in Thymocyte Development
Authors: Graham Anderson, Nel C. Moore, John J. T. Owen, Eric J. Jenkinson
Journal: Annual Review of Immunology (1996)

Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4 − 8 − stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4 + 8 + stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity. Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge. Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.
Quantitative Comparison of Genetic Effects of Ethylating Agents on the Basis of DNA Adduct Formation. Use of O 6 -Ethylguanine as Molecular Dosimeter for Extrapolation from Cells in Culture to the Mouse
Authors: Albert A. van Zeeland, Georges R. Mohn, Angelika Neuhauser-Klaus, Udo H. Ehling
Journal: Environmental Health Perspectives (1985)

DNA-adduct formation and induction of gene mutations were determined simultaneously after treatment with the four ethylating agents, ethyl methanesulfonate (EMS), ethylnitrosourea (ENU), diethyl sulfate (DES), and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Both, in E. coli K-12 (NAL-resistance) and in V79 Chinese hamster cells in culture (HPRT-deficiency), the frequencies of mutation induction by all chemicals were the same when plotted against the amount of O6-ethylguanine formed in DNA, suggesting that this DNA adduct can be used as a common dosimeter for the comparisons of the frequencies of gene mutations induced by ethylating agents in various mutagenicity assay systems. Using ENU, such a comparison was performed between mutation induction in V79 cells in vitro and in the specific-locus assay in the mouse. The data indicate that at equal levels of O6-ethylguanine in the DNA of V79 cells and in testicular DNA from male mice treated with ENU, the frequencies of induced mutants in both assay systems were quite similar. These results support the concept that the determination of premutagenic DNA adducts in vivo can be used to monitor exposure to chemical mutagens and that genetic risk estimations may ultimately be performed on the basis of such measurements and of comparative mutagenesis in vitro and in vivo.
Epidermal Growth Factor Receptor Expression Identifies Functionally and Molecularly Distinct Tumor-Initiating Cells in Human Glioblastoma Multiforme and Is Required for Gliomagenesis
Authors: Stefania Mazzoleni, Letterio S. Politi, Mauro Pala, Manuela Cominelli, Alberto Franzin, Lucia Sergi Sergi, Andrea Falini, Michele De Palma, Alessandro Bulfone, Pietro L. Poliani, Rossella Galli
Journal: Cancer Research (2010)

Abstract Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFRpos and EGFRneg TIC subpopulations within the same tumor might affect clinical response to treatment. Cancer Res; 70(19); 7500–13. ©2010 AACR.
Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography.
Authors: D J Evans, R Murray, A H Kissebah
Journal: Journal of Clinical Investigation (1984)

Skeletal muscle sensitivity and responsiveness to insulin and their relationship to overall glucose disposal and insulin binding were determined in 89 premenopausal women of varying body fat topography (waist/hips girth ratio [WHR] 0.64-1.02) and obesity level (percentage of ideal body weight 92-230). As a marker of insulin action, the percentage of total glycogen synthase present in the I form (glucose-6-phosphate independent) was measured in quadriceps muscle biopsies. The increase in percentage of synthase I 1 h after oral glucose loading was not significantly different between nonobese and obese weight-matched subgroups of increasing WHR, but this response was maintained at the expense of increasing plasma insulin levels as the WHR rose. The increase in percentage of synthase I in response to submaximal steady state plasma insulin (SSPI) of approximately 100 microU/ml achieved by the infusion of somatostatin, insulin, and glucose, however, was significantly lower in obese than in nonobese subjects, and was inversely correlated with WHR. The increase in percentage of synthase I correlated inversely with the steady state plasma glucose (SSPG) concentration, which is an index of the efficiency of overall glucose disposal, and directly with insulin binding to circulating monocytes. Insulin binding also correlated inversely with WHR and with fasting plasma insulin levels. When obese subjects were separated into three weight-matched subgroups on the basis of increasing WHR, significant trends to decreased percentage of synthase I response, increased SSPG, and decreased insulin binding were found. In women with predominantly upper body obesity (WHR greater than 0.85), the increase in percentage of synthase in response to submaximal SSPI was diminished, but there was no impairment of percentage of synthase I responsiveness to supramaximal SSPI of approximately 1,000 microU/ml. At supramaximal SSPI levels, SSPG in four obese women was normal, whereas in five women, SSPG concentrations were markedly increased. Our results suggest that in premenopausal women, impaired skeletal muscle insulin sensitivity that results in decreased glucose storage capacity may contribute to the diminished efficiency of glucose disposal and insulin resistance that are associated with upper body obesity. The impairment in skeletal muscle sensitivity may be overcome in vivo at the expense of increasing plasma insulin levels, with maximal responsiveness remaining unimpaired. This defect may result from a reduction in insulin receptor number which could, in turn, be secondary to persistently elevated fasting plasma insulin levels. In some upper body segment obese women, however, an additional defect affecting other insulin-sensitive pathways may also be present.
Rheumatological complications associated with the use of indinavir and other protease inhibitors
Authors: E Florence
Journal: Annals of the Rheumatic Diseases (2002)

Several cases are reported of rheumatological pathology (temporomandibular dysfunction, frozen shoulder, Dupuytren9s disease, and tendinitis) most probably related to the intake of indinavir in HIV positive patients. A survey using an anonymous questionnaire of 878 people with HIV infection treated with antiretroviral drugs suggests that other protease inhibitors may also cause arthralgia.
The RET Kinase Inhibitor NVP-AST487 Blocks Growth and Calcitonin Gene Expression through Distinct Mechanisms in Medullary Thyroid Cancer Cells
Authors: Nagako Akeno-Stuart, Michelle Croyle, Jeffrey A. Knauf, Roberta Malaguarnera, Donata Vitagliano, Massimo Santoro, Christine Stephan, Konstantina Grosios, Markus Wartmann, Robert Cozens, Giorgio Caravatti, Doriano Fabbro, Heidi A. Lane, James A. Fagin
Journal: Cancer Research (2007)

Abstract The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N′-diphenyl urea with an IC50 of 0.88 μmol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented. [Cancer Res 2007;67(14):6956–64]
Risk of injury in norwegian male professional football
Authors: J Bjørneboe, R Bahr, T E Andersen
Journal: British Journal of Sports Medicine (2011)

Background Only one previous injury surveillance study (Ekstrand et al ., 2010) has been carried out for several seasons. Ekstrand et al . (2010) found that the injury incidence and pattern were stable during seven Champions League seasons. Objective To monitor trends in injury incidence and pattern in Norwegian male professional football over six seasons. Design Prospective cohort study where injuries and exposure were registered by team medical staff using the league injury surveillance system for six seasons (2002–2007). An injury was recorded when a player was unable to fully take part in football training or match play. Setting Tippeligaen, the top 14 male Norwegian professional teams. Main outcome measurement Injury incidence (injuries/1000 player-hours). Results A total of 2365 injuries were recorded; 1664 (70.4%) acute injuries and 701 (29.6%) overuse injuries. The overall incidence of acute injuries was 16.1 per 1000 match hours (95% CI 15.1 to 17.1) and 1.9 (95% CI 1.7 to 2.0) per 1000 h of football training. The incidence of overuse injuries was 1.4 (95% CI 1.3 to 1.5).The incidence of overuse injuries and acute training injuries was consistent during the six-year study period. However, the risk of acute match injury increased (p=0.004). We could not detect any shifts in injury type, location, severity or re-injuries. No significant difference in the risk of acute match injuries (rate ratio (RR): 0.92, 95% CI 0.78 to 1.08), acute training injuries (RR: 1.16, 95% CI 0.99 to 1.36) or overuse injuries (RR: 1.07, 95% CI 0.91 to 1.25) was observed between preseason (January-March) and competitive season (April-October). Conclusion The risk of acute match injuries in Norwegian male professional football increased during the six-season study period. However, we detected no change in the risk of training or overuse injuries or any difference between the preseason and competitive season.
Effect of airline travel on performance: a review of the literature
Authors: Whitney E Leatherwood, Jason L Dragoo
Journal: British Journal of Sports Medicine (2012)

The need for athletes to travel long distances has spurred investigation into the effect of air travel across multiple time zones on athletic performance. Rapid eastward or westward travel may negatively affect the body in many ways; therefore, strategies should be employed to minimise these effects which may hamper athletic performance. In this review, the fundamentals of circadian rhythm disruption are examined along with additional effects of airline travel including jet lag, sleep deprivation, travel at altitude and nutritional considerations that negatively affect performance. Evidence-based recommendations are provided at the end of the manuscript to minimise the effects of airline travel on performance.
Promoter Hypermethylation: A New Therapeutic Target Emerges in Urothelial Cancer
Authors: Richard J. Cote, Peter W. Laird, Ram H. Datar
Journal: Journal of Clinical Oncology (2005)

Significant changes in the global levels and regional patterns of DNA methylation are among the earliest and most frequent events known to occur in human cancers. 1 Alterations in DNA methylation have a direct impact on both the mutational and epigenetic components of neoplastic transformation.ImportanteffectsofDNAmethylationonthe genome include mutational burden of 5-methylcytosine, epigenetic effects of promoter methylation on gene transcription and potential gene activation, and induction of chromosomal instability by DNA hypomethylation. 2,3 Hypermethylationofcytosine-guaninedinucleotide(CpG)islands is associated with transcriptional repression, whereas hypomethylation may lead to increased potential for gene activity or chromosomal instability. CpG islands located in tumor suppressor gene promoters are normally unmethylated. Abnormal methylation of these regions may lead to progressive reduction in gene expression, thus transcriptionally silencing suppressor genes by a variety of mechanisms, including remodeling of local chromatin structure or inhibition of transcription factor binding, ultimately altering normal cellular growth properties. Application of novel molecular biologic techniques has increased our appreciation of the widespread changes in methylation patterns that occur during urinary bladder carcinogenesis. Epigenetic events, such as methylation, occur throughout all stages of tumorigenesis, including the early phases, and are increasingly recognized as major mechanisms involved in silencing tumor suppressor genes. A large number of genes have been reported to be hypermethylated in bladder cancer. The frequency of such events suggests that widespread alterations in the patterns of DNA methylation are common in bladder carcinogenesis. Some examples include the p16 gene (at CDKN2A INK4a locus on chromosome 9p21), E-cadherin gene (CDH1, encoding a transmembrane glycoprotein that modulates calcium-dependent intercellular adhesion), and RASSF1A gene (ras association domain family gene 1, isoform A). 4-6 Diminished CDH1 expression may lead to increase in betacateninactivityandproliferationinurothelialcarcinomas. 7 Aside from deletion and mutation, the p16 gene has been shown to be inactivated by promoter methylation. 8-11 Mutationordeletionofonep16alleleandhypermethylationof the remaining allele may be sufficient for loss of functional activity. Progressive inhibition of p16 expression by DNA methylation may result in loss of adequate growth regulatory function. Methylation of p16 has been observed in 27% to 60% of primary urothelial carcinomas. 12,13 Both
Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor–Induced Musculoskeletal Pain: SWOG S0927
Authors: Dawn L. Hershman, Joseph M. Unger, Katherine D. Crew, Danielle Awad, Shaker R. Dakhil, Julie Gralow, Heather Greenlee, Danika L. Lew, Lori M. Minasian, Cathee Till, James L. Wade, Frank L. Meyskens, Carol M. Moinpour
Journal: Journal of Clinical Oncology (2015)

Purpose Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides. Patients and Methods Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory–Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy–Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. Results Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein. Conclusion We found a substantial (&gt; 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups.
A Defect of Neuronal Nitric Oxide Synthase Increases Xanthine Oxidase-Derived Superoxide Anion and Attenuates the Control of Myocardial Oxygen Consumption by Nitric Oxide Derived From Endothelial Nitric Oxide Synthase
Authors: Shintaro Kinugawa, Harer Huang, Ziping Wang, Pawel M. Kaminski, Michael S. Wolin, Thomas H. Hintze
Journal: Circulation Research (2005)

Endothelial nitric oxide synthase (eNOS) plays an important role in the control of myocardial oxygen consumption (MVO2) by nitric oxide (NO). A NOS isoform is present in cardiac mitochondria and it is derived from neuronal NOS (nNOS). However, the role of nNOS in the control of MVO2 remains unknown. MVO2 in left ventricular tissues from nNOS-/- mice was measured in vitro. Stimulation of NO production by bradykinin or carbachol induced a significant reduction in MVO2 in wild-type (WT) mice. In contrast to WT, bradykinin- or carbachol-induced reduction in MVO2 was attenuated in nNOS-/-. S-methyl-L-thiocitrulline, a potent isoform selective inhibitor of nNOS, had no effect on bradykinin-induced reduction in MVO2 in WT. Bradykinin-induced reduction in MVO2 in eNOS-/- mice, in which nNOS still exists, was also attenuated. The attenuated bradykinin-induced reduction in MVO2 in nNOS-/- was restored by preincubation with Tiron, ascorbic acid, Tempol, oxypurinol, or SB203850, an inhibitor of p38 kinase, but not apocynin. There was an increase in lucigenin-detectable superoxide anion (O2-) in cardiac tissues from nNOS-/- compared with WT. Tempol, oxypurinol, or SB203850 decreased O2- in all groups to levels that were not different from each other. There was an increase in phosphorylated p38 kinase normalized by total p38 kinase protein level in nNOS-/- compared with WT mice. These results indicate that a defect of nNOS increases O2- through the activation of xanthine oxidase, which is mediated by the activation of p38 kinase, and attenuates the control of MVO2 by NO derived from eNOS.