tbuckley/cabot-search huggingface dataset:
A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts
Authors: Eric J Suh, Matthew Y Remillard, Aster Legesse-Miller, Elizabeth L Johnson, Johanna MS Lemons, Talia R Chapman, Joshua J Forman, Mina Kojima, Eric S Silberman, Hilary A Coller
Journal: Genome biology (2012)

Abstract Background Although quiescence (reversible cell cycle arrest) is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts. Results Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29 , which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further. Conclusions microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts.
Technology &amp; tools development
Authors: E. Pefani, N. Panoskaltsis, A. Mantalaris, M. C. Georgiadis, E. N. Pistikopoulos, A. Aguilar-Mahecha, J. Lafleur, C. Seguin, M. Rosenbloom, E. Przybytkowski, M. Pelmus, Z. Diaz, G. Batist, M. Basik, J. Tavernier, L. Brunet, J. Bazot, M. Chemelle, C. Dalban, S. Guiu, C. di Martino, J. Lehtio, M. Branca, H. Johansson, M. Orre, V. Granholm, J. Forshed, M. Perez-Bercoff, L. Kall, K. V. Nielsen, L. Andresen, S. Muller, S. Matthiesen, A. Schonau, R. Oktriani, A. Wahyono, S. Haryono, A. Utomo, T. Aryandono, Z. Diaz, T. Gagnon-Kugler, C. Rousseau, A. Aguilar-Mahecha, T. Alcindor, R. Aloyz, S. Assouline, M. Basik, D. Bachvarov, L. Belanger, E. Camlioglu, M. Cartillone, B. Chabot, R. Christodoulopoulos, C. Courtemanche, A. Constantin, N. Benlimame, I. Dao, R. Dalfen, L. Gosselin, F. Habbab, M. Hains, T. Haliotis, T. H. Nielsen, M. Joncas, P. Kavan, R. Klink, A. Langlaben, M. Lebel, B. Lesperance, K. Mann, J. Masson, P. Metrakos, S. McNamara, W. H. Miller, M. Orain, L. Panasci, E. Paquet, M. Phillie, S. Qureshi, D. Rodrigue, A. Salman, A. Spatz, B. Tetu, A. Tosikyan, M. Tsatoumas, T. Vuong, G. Batist, R. Ruijtenbeek, R. Houtman, R. de Wijn, P. Boender, R. Hilhorst, Y. Cohen, A. Onn, A. Lax, A. Yosepovich, S. Litz, S. Kalish, R. Felemovicius, G. Hout-Silony, M. Gutman, M. Shabtai, D. Rosin, A. Valeanu, E. Winkler, M. Sklair-Levy, B. Kaufman, I. Barshack, V. Canu, A. Sacconi, F. Biagioni, F. Mori, A. di Benedetto, L. Lorenzon, S. di Agostino, A. Cambria, S. Germoni, G. Grasso, R. Blandino, V. Panebianco, V. Ziparo, O. Federici, P. Muti, S. Strano, F. Carboni, M. Mottolese, M. G. Diodoro, E. Pescarmona, A. Garofalo, G. Blandino, T. Ho, L. Feng, S. Lintula, K. A. Orpana, J. Stenman, S. El Messaoudi, F. Mouliere, M. del Rio, A. S. Guedj, C. Gongora, F. M. Molina, P. J. Lamy, E. Lopez-Crapez, F. Rolet, M. Mathonnet, M. Ychou, D. Pezet, A. R. Thierry, M. Manuarii, O. Tredan, T. Bachelot, G. Clapisson, A. Courtier, G. Parmentier, T. Rabeony, A. Grives, S. Perez, J. F. Mouret, D. Perol, S. Chabaud, I. Ray-Coquard, I. Labidi-Galy, P. Heudel, J. Y. Pierga, C. Caux, J. Y. Blay, N. Pasqual, C. Menetrier-Caux
Journal: Annals of Oncology (2012)
Inhibitors of prostaglandin synthesis augment beta-adrenergic responsiveness in canine coronary arteries.
Authors: G Rubanyi, P M Vanhoutte
Journal: Circulation Research (1985)

The effects of inhibition of endogenous prostaglandin synthesis on the release of norepinephrine from sympathetic nerves and on postjunctional adrenergic responsiveness were studied in isolated canine left circumflex coronary arteries. In rings, suspended for isometric tension recording and contracted with prostaglandin F2 alpha, transmural electrical stimulation caused frequency-dependent relaxations, which were blocked by propranolol and augmented by indomethacin. In superfused strips, previously incubated with [3H]norepinephrine, electrical stimulation (2 Hz) increased the overflow of tritiated neurotransmitter; indomethacin did not influence basal or evoked [3H]norepinephrine overflow. Exogenous norepinephrine caused relaxations in rings contracted with prostaglandin F2 alpha, but increases in tension in potassium-depolarized tissues which could be abolished by phentolamine; isoproterenol induced relaxations in both cases. Indomethacin significantly augmented the relaxation in response to exogenous norepinephrine (during contractions with prostaglandin F2 alpha) and reversed norepinephrine-induced contractions (during potassium-depolarization) into relaxation. Other cyclooxygenase inhibitors had comparable effects. In the presence of propranolol, indomethacin did not diminish contractions evoked by norepinephrine in depolarized rings. Relaxations induced by sodium nitroprusside or acetylcholine during contractions caused by prostaglandin F2 alpha or potassium chloride were not affected by indomethacin. The augmentation of beta-adrenergic responsiveness by indomethacin was abolished by exogenous prostacyclin. The prostacyclin synthetase inhibitor tranylcypromine and exogenous prostaglandin E2 depressed beta-adrenergic responsiveness. Indomethacin did not affect the facilitatory action of phosphodiesterase inhibition on beta-adrenergic relaxation. The data suggest that endogenous prostaglandins (most probably prostacyclin and prostaglandin E2) exert a "braking" effect on beta-adrenergic responsiveness in coronary arterial smooth muscle.
Quantifying the Excess Risk of Type 2 Diabetes by Body Habitus Measurements Among Australian Aborigines Living in Remote Areas
Authors: Srinivas Kondalsamy-Chennakesavan, Wendy E. Hoy, Zhiqiang Wang, Jonathan Shaw
Journal: Diabetes Care (2008)

To quantify the risk for type 2 diabetes by body habitus measurements among remote-living Australian Aborigines relative to that measured in the general Australian population (as characterized by the Australian Diabetes, Obesity and Lifestyle [AusDiab] study).Anthropometric measurements and diabetes status were assessed by standard procedures among Aborigines (n = 1,456) and Australians aged >or=25 years (n = 11,247). Age-adjusted odds ratios (ORs) for diabetes among Aborigines relative to AusDiab participants were calculated by commonly used categories of body size measurements.The OR (95% CI) values for diabetes among normal, overweight, and obese (by waist) Aboriginal women relative to AusDiab women were 2.6 (0.6-11.5), 13.1 (6.7-25.7), and 6.1 (4.6-8.0), respectively, and for Aboriginal men relative to AusDiab men, they were 7.6 (4.6-12.5), 7.6 (4.3-13.4), and 5.2 (3.4-8.0), respectively. Rates of diabetes were also excessive in Aborigines for each standard category of BMI.Higher rates of diabetes, even at normal and lower body habitus measurements, among Aborigines suggest that strategies for prevention should expand beyond exclusive focus on diet and weight management.
Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease
Authors: Bo Zhu, Alistair L.J. Symonds, Joanne E. Martin, Dimitris Kioussis, David C. Wraith, Suling Li, Ping Wang
Journal: The Journal of Experimental Medicine (2008)

Maintaining tolerance of T cells to self-antigens is essential to avoid autoimmune disease. How self-reactive T cells are kept functionally inactive is, however, unknown. In this study, we show that early growth response gene 2 (Egr-2), a zinc-finger transcription factor, is expressed in CD44(high) T cells and controls their proliferation and activation. In the absence of Egr-2, CD44(high), but not CD44(low) T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4(+)CD44(high) T cells leads to the development of a late onset lupuslike autoimmune disease characterized by the accumulation of interferon (IFN)-gamma and interleukin (IL)-17-producing CD4(+) T cells, loss of tolerance to nuclear antigens, massive infiltration of T cells into multiple organs and glomerulonephritis. We found that the expression of cyclin-dependent kinase inhibitor p21cip1 was impaired in Egr-2-deficient T cells, whereas the expression of IFN-gamma and IL-17 in response to T cell receptor ligation was significantly increased, suggesting that Egr-2 activates the expression of genes involved in the negative regulation of T cell proliferation and inflammation. These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease.
Transcription factor activation and mitogenic synergism in airway smooth muscle cells
Authors: T.L. Ediger, N.A. Schulte, T.J. Murphy, M.L. Toews
Journal: European Respiratory Journal (2003)

Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophosphatidic acid (LPA) and epidermal growth factor (EGF) leads to strikingly synergistic stimulation of mitogenesis. The purpose of this study was to explore potential sites for signal integration mediating synergism, focusing on extracellular signal-regulated kinase (ERK) and transcription factors involved in proliferation and inflammation as likely candidates. Activation of ERK was analysed by immunoblotting. Transcription factor activation was assessed using HASM cells transduced with luciferase reporter gene constructs. LPA and EGF both activated ERK but had no synergistic effect when combined. LPA and EGF both activated activator protein (AP)‐1, cyclic adenosine monophosphate response element-binding protein, nuclear factor of activated T‐cells and the serum response element; however, only AP‐1 activation exhibited synergism. Activation of the inhibitory guanine nucleotide-binding protein and of ERK signalling pathways were required for most transcription factor responses to LPA. In contrast, nuclear factor (NF)‐κB was activated by LPA but not EGF and NF‐κB activation was completely blocked only when Rho was inhibited. Rapid activation of Rho was observed in response to LPA but not to EGF. Importantly, inhibition of Rho selectively blocked synergism in both AP‐1 activation and mitogenesis. In summary, extracellular signal-regulated kinase activation is required for many transcription factor responses to lysophosphatidic acid and epidermal growth factor, however it is not synergistic. Activation of activator protein‐1 is synergistic, and Rho activation by lysophosphatidic acid is required for synergism in both activator protein‐1 activation and mitogenesis.
Motives for competition among athlete's of selected sports and games at inter-varsity level
Authors: Ashutosh Acharya, Jayashree Acharya
Journal: British Journal of Sports Medicine (2010)

To find out the motives of male intervarsity level players in India (N=160) for participating in sports competition in the event of basketball (N=40), track and field (N=40), football (40) and gymnastics (40) in the age group of 18–25 years with a mean and SD of 19.47 ± 1.42. Motives for competition questionnaire (Blood, Suinn, 1982) was used to measure the variables. This questionnaire has 19 categories. To examine the hypothesis, descriptive and comparative statistics of analysis of variance was calculated. A significant difference was found in physical fitness and health scores as the obtained ‘f’ value of 5.12 was greater than required value of 4.00 at 3.156 df, mean difference was found between basketball players and football players. Significant difference was also found in friendship and personal association scores, as the obtained ‘f’ value of 7.65 was greater than the required value of 4.00 at 3.156 df, mean difference was found basketball players and football players as well as between football players and gymnasts. The mean differences were tested at 0.05 level of significance. No significant difference was found in other 17 categories of motives (social approval, competition, self mastery, life style, fear of failure, success and achievement, tangible pay offs, recognition, intimidation/control, heterosexuality, competing conditions/crowd, independence/individuality, family, emotional release, status, self-direction/awareness and understanding reasons) for competition among the selected group players.
Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man.
Authors: S M Lum, J T Nicoloff, C A Spencer, E M Kaptein
Journal: Journal of Clinical Investigation (1984)

The present study was undertaken to define the source of endogenous triiodothyronine (T3) production responsible for maintaining serum T3 levels in euthyroid subjects with depressed serum thyroxine (T4) values. After withdrawal from 4 wk of exogenous T3 administration, a 22% decline in serum T3 values (from 129 +/- 6 to 99 +/- 4 ng/dl) was observed in six euthyroid subjects, despite a twofold reduction in serum T4 concentrations (from 7.5 +/- 0.5 to 3.2 +/- 0.5 micrograms/dl). This was accompanied by a nearly twofold increase in serum T3/T4 ratio values (17 +/- 1 to 29 +/- 6) but no significant alteration in reverse T3/T4 ratio values. This phenomenon did not appear to be thyroid stimulating hormone (TSH) dependent, since base-line serum TSH values were subnormal. Nor was it dependent on changes in thyroid gland function, since a blunted T3 response to exogenous bovine TSH occurred and pharmacologic doses of iodide did not influence the phenomenon. The finding in three athyreotic subjects that serum T3/T4 ratio values increased from 14 +/- 1 on T4 therapy (mean serum T4, 9.6 +/- 0.8 micrograms/dl and T3, 132 +/- 8 ng/dl) to 40 +/- 2 after withdrawal from 2 wk of T3 administration (serum T4 1.2 +/- 0.1 micrograms/dl and T3 46 +/- 3 ng/dl) provided direct evidence that an alteration in peripheral thyroid hormone metabolism was probably responsible for these findings previously observed in euthyroid subjects. The results of this study support the possible existence in euthyroid man of a peripheral tissue autoregulatory mechanism for maintaining serum T3 values in states of T4 deficiency. Whether this process involves an alteration in the efficiency of T4 to T3 conversion or the rate of T3 clearance is presently unknown.
Late, Heparin-Induced Bleeding after Retrograde Arterial Catheterization
Authors: J. DAVID BRISTOW, ARTHUR J. SEAMAN, FRANK E. KLOSTER, RODNEY H. HERR, HERBERT E. GRISWOLD
Journal: Circulation (1968)

Three patients with ball-valve prostheses were given heparin after percutaneous retrograde aortic catheterization from the femoral artery. The drug was given prophylactically in one case and because of the development of signs of systemic embolism soon after catheterization in the other two. After 3 or more days of heparin therapy, serious bleeding developed at the site of percutaneous catheter entry. The timing and incidence of this complication are in marked contrast to experience with this procedure in individuals who did not receive heparin. Preliminary experience is presented from right and left heart catheterizations in patients whose prothrombin-proconvertin times were allowed to remain in or near the therapeutic range. No hemorrhagic complications were observed.
On the Interplay of Microvasculature, Parenchyma, and Memory in Type 2 Diabetes
Authors: Frank C. van Bussel, Walter H. Backes, Paul A. Hofman, Robert J. van Oostenbrugge, Alfons G. Kessels, Martin P. van Boxtel, Miranda T. Schram, Coen D. Stehouwer, Joachim E. Wildberger, Jacobus F. Jansen
Journal: Diabetes Care (2015)

OBJECTIVE Type 2 diabetes is associated with accelerated cognitive decline, especially regarding memory for which the hippocampus plays an essential role. The pathophysiological mechanisms still remain to be elucidated. The purpose of this study is to examine whether hippocampal microvascular and microstructural changes are related to type 2 diabetes (based on status or based on fasting blood glucose [FBG] levels) and verbal memory performance. RESEARCH DESIGN AND METHODS Thirty-nine participants with type 2 diabetes (64.5 ± 6.1 years old) and 34 participants without type 2 diabetes (58.3 ± 9.2 years old) underwent detailed cognitive assessments and 3-Tesla MRI using intravoxel incoherent motion (IVIM) MRI. Multivariate regression analyses controlling for age, sex, education level, BMI, systolic blood pressure, hematocrit level, and relative hippocampal volume were performed to examine associations between hippocampal IVIM measures, type 2 diabetes (status and FBG), and memory performance. RESULTS For the microvasculature, blood perfusion volume (f) was larger in participants with type 2 diabetes, f and blood flow (fD*) increased with higher FBG levels, and microvascular pseudodiffusion (D*) and fD*, which are indicative of altered microvasculature, were higher in participants with both relatively high FBG levels and low memory performance. In addition, fD* increased with lower memory performance. For the parenchymal microstructure, the diffusion (D), indicative of injured microstructure, was higher with reduced memory performance. CONCLUSIONS In addition to the parenchymal microstructure, especially the microvascular properties of the hippocampus are altered in participants with both type 2 diabetes and memory problems and possibly hint at an underlying vascular mechanism.
2-Methoxyestradiol, an Endogenous Mammalian Metabolite, Radiosensitizes Colon Carcinoma Cells through c-Jun NH2-Terminal Kinase Activation
Authors: HuiChao Zou, Masaaki Adachi, Kohzoh Imai, Masato Hareyama, Katsuji Yoshioka, Shiguang Zhao, Yasuhisa Shinomura
Journal: Clinical Cancer Research (2006)

Abstract Purpose: 2-Methoxyestradiol (2ME), an estrogen metabolite, induces apoptosis in various cell types. We investigated whether 2ME pretreatment can radiosensitize colon adenocarcinoma cells. Experimental Design: Radiosensitizing effects of 2ME were evaluated by cell death, clonogenic assay, nuclear fragmentation, and tumor progression of xenografts. Ionizing radiation–induced DNA damage was evaluated by histone H2AX phosphorylation and its foci. The c-Jun NH2-terminal kinase (JNK) activation was evaluated by anti-phosphorylated JNK antibody and inhibited by the JNK-specific inhibitor SP600125 or dominant-negative SEK1 expression. Results: Clonogenic assays revealed that 2ME, but not estradiol, radiosensitized three colon carcinoma cells, DLD-1, HCT-8, and HCT-15, and strongly suppressed tumor progression of DLD-1 xenografts. Gene transfer–mediated Bcl-xL overexpression largely abolished both augmented apoptosis and reduced survival fractions. Pretreatment with 2ME enhanced H2AX phosphorylation, its foci, and phosphorylation of ATM kinase and delayed re-entry of cell cycle progression after ionizing radiation. Augmentation of both radiosensitivity and H2AX phosphorylation was substantially reduced by SP600125 or overexpression of a dominant-negative mutant SEK1. Conclusion: 2ME radiosensitized colon carcinoma cells through enhanced DNA damage via JNK activation, thereby representing a novel radiosensitizing therapy against colon cancer.
Redefining the Target: Chemotherapeutics as Antiangiogenics
Authors: Kathy D. Miller, Christopher J. Sweeney, George W. Sledge
Journal: Journal of Clinical Oncology (2001)

ABSTRACT: Angiogenesis, or new blood vessel formation, is now known to play an important role in both growth and metastasis of many cancers. The central importance of angiogenesis and the understanding of how new blood vessels are formed, has led to novel therapies designed to interrupt this process. Though specific antiangiogenic compounds have only recently entered the clinic, they herald a new era, one in which biology is the basis for therapy. The intense interest in angiogenesis has also lead to a re-examination of the activity of many established cytotoxic agents. Claims of antiangiogenic activity abound, unfortunately, with no common criteria and often little evidence of clinical relevance. What are we to think? Have oncologists unknowingly been administering antiangiogenic therapy all these years? If chemotherapeutics are really antiangiogenics in disguise, why have they failed to cure most solid tumors? Might the hard-learned lessons of chemotherapy resistance pertain to the novel antiangiogenics as well? Though we can offer no certain answers to these important questions, we do offer a framework on which to order the rapidly burgeoning literature. We suggest criteria by which a cytotoxic agent might reasonably be considered to have meaningful antiangiogenic activity. Finally, we describe potential mechanisms of resistance to antiangiogenic chemotherapies—some of which may apply to the pure antiangiogenics currently in development.
BiP/GRP78 Is an Intracellular Target for MDA-7/IL-24 Induction of Cancer-Specific Apoptosis
Authors: Pankaj Gupta, Mark R. Walter, Zao-zhong Su, Irina V. Lebedeva, Luni Emdad, Aaron Randolph, Kristoffer Valerie, Devanand Sarkar, Paul B. Fisher
Journal: Cancer Research (2006)

Abstract Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206, is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GRP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine. (Cancer Res 2006; 66(16): 8182-91)