tbuckley/cabot-search huggingface dataset:
Identification and Characterization of a New Growth Hormone–Releasing Peptide Receptor in the Heart
Authors: V. Bodart, J. F. Bouchard, N. McNicoll, E. Escher, P. Carrière, E. Ghigo, T. Sejlitz, M. G. Sirois, D. Lamontagne, H. Ong
Journal: Circulation Research (1999)

Abstract —Hexarelin, a synthetic hexapeptide of the growth hormone–releasing peptide (GHRP) family with strong growth hormone (GH)–releasing activity, features protecting activity against postischemic ventricular dysfunction in hearts from GH-deficient and senescent rats. To document whether hexarelin action is mediated through specific cardiac receptors, perfusion of Langendorff rat hearts with hexarelin and binding studies were carried out. In the Langendorff rat heart system, hexarelin induced a dose-dependent increase in coronary perfusion pressure. Nifedipine, chelerythrine, and bisindolylmaleimide partially inhibited the vasoconstriction induced by hexarelin, suggesting that this effect was mediated at least in part by L-type Ca 2+ channels and protein kinase C. In contrast, diclofenac and 1-(7-carboxyheptyl)imidazole were without effect, suggesting that prostaglandins and thromboxanes were not involved in the coronary vasoconstriction induced by hexarelin. To characterize the hexarelin binding sites in the rat heart, [ 125 I]Tyr-Bpa-Ala-hexarelin was used as photoactivatable radioligand in saturation and competitive binding studies. We specifically labeled a hexarelin receptor with an M r of 84 000 in rat cardiac membranes. Saturation binding curves revealed a single class of binding sites with a K d of 14.5 nmol/L and a density of 91 fmol/mg of protein. Competition binding studies gave an IC 50 of 2.9 μmol/L for hexarelin; MK-0677 and EP51389, both potent GH secretagogues, did not displace the binding of the photoactivatable derivative from rat cardiac membranes. Interestingly, both compounds were devoid of any vasoconstrictive activity. These results suggest the existence of a new class of hexarelin receptor in the heart, whose role in the regulation of the coronary vascular tone is yet to be determined.
miR-300 inhibits epithelial to mesenchymal transition and metastasis by targeting Twist in human epithelial cancer
Authors: Jingshuang Yu, Furong Xie, Xin Bao, Wantao Chen, Qin Xu
Journal: Molecular Cancer (2014)

Epithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT. The expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo. Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC). MiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3′UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo. Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens. Down-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy.
Aromatase Inhibitors: Rationale and Use in Breast Cancer
Authors: Cynthia Osborne, Debu Tripathy
Journal: Annual Review of Medicine (2005)

Considerable data implicate estrogens in breast cancer carcinogenesis and progression. In the postmenopausal woman, estrogens are produced in breast tissues and many other sites throughout the body when androgen precursors are converted into estrogens via the enzyme aromatase. Inhibition of this enzyme with aromatase inhibitors (AIs) has demonstrated reductions in systemic as well as intratumoral estrogens. These drugs have now been utilized in large phase 3 randomized trials and have led to greater improved clinical benefit than the “gold standard,” tamoxifen. Questions remain about the long-term side effects and safety profile of AIs. They are associated with increasing incidence of osteoporosis and bone fractures. Nevertheless, AIs add to our armamentarium for therapy and possible prevention of breast cancer.
Self‐renewal of hepatoblasts under chemically defined conditions by iterative growth factor and chemical screening
Authors: Linjie Lv, Qingwang Han, Yinghao Chu, Muzi Zhang, Lin Sun, Wanguo Wei, Caixia Jin, Wenlin Li
Journal: Hepatology (2014)

Tissue‐specific stem/progenitor cells are essential to mediate organogenesis and tissue homeostasis. In addition, these cells have attracted significant interest for their therapeutic potential. However, it remains challenging to expand most types of these cells in vitro . In this study we devised a screening strategy aimed at identifying growth factors and small molecules that can sustain self‐renewal of mouse hepatoblasts. This approach began with a defined basal condition, on top of which collections of growth factors and bioactive small molecules were screened for maintaining self‐renewal of primary hepatoblasts. The initially identified proteins and small molecules were then combined in the basal media for subsequent screening to identify additional molecules that can synergistically promote hepatoblast self‐renewal. This strategy was performed iteratively to eventually define a small molecule and growth factor cocktail, including epidermal growth factor, glycogen synthase kinase 3 inhibitor, transforming growth factor β receptor inhibitor, lysophosphatidic acid, and sphingosine 1‐phosphate, which was sufficient to sustain long‐term self‐renewal of the murine hepatoblasts under chemically defined conditions. These expanded hepatoblasts retain the ability to respond to liver developmental cues and produce functional hepatocytes and form bile duct‐like structures. Conclusion : Our work established a chemically defined condition that allows long‐term expansion of hepatoblasts, improved our understanding of hepatoblast self‐renewal, and highlights the power of phenotypic screening to enable self‐renewal of somatic stem/progenitor cells. (H epatology 2015;61:337–347)
TR-08 * TARGETED COMBINATORIAL APPROACH FOR TREATMENT OF PEDIATRIC LOW GRADE GLIOMAS IN THE CONTEXT OF BRAFV600E AND KIAA1549:BRAF MUTATIONS
Authors: A. K. Olow, S. Mueller, X. Yang, R. Hashizume, J. Meyerowitz, W. Weiss, A. C. Resnick, A. J. Waanders, M. S. Berger, N. Gupta, C. D. James, D. A. Haas-Kogan
Journal: Neuro-Oncology (2015)

Pediatric low-grade gliomas (PLGG) constitute the most common group of central nervous system tumors in children.Viewed as a chronic disease, ideal therapy for PLGG should carry limited side effects that can be best achieved through selective, personalized therapy.Despite the known heterogeneity of PLGGs and characterized driver mutations most children are still treated with Overall survival
Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice
Authors: Sanjay Jain, Amanda Knoten, Masato Hoshi, Hongtao Wang, Bhupinder Vohra, Robert O. Heuckeroth, Jeffrey Milbrandt
Journal: Journal of Clinical Investigation (2010)

The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcgamma, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcgamma binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.
Précis of<i>The Emperor's New Mind: Concerning computers, minds, and the laws of physics</i>
Authors: Roger Penrose
Journal: Behavioral and Brain Sciences (1990)

Abstract The emperor's new mind (hereafter Emperor ) is an attempt to put forward a scientific alternative to the viewpoint of “strong AI,” according to which mental activity is merely the acting out of some algorithmic procedure. John Searle and other thinkers have likewise argued that mere calculation does not, of itself, evoke conscious mental attributes, such as understanding or intentionality, but they are still prepared to accept the action the brain, like that of any other physical object, could in principle be simulated by a computer. In Emperor I go further than this and suggest that the outward manifestations ofconscious mental activity cannot even be properly simulated by calculation. To support this view, I use various arguments to show that the results of mathematical insight, in particular, do not seem to be obtained algorithmically. The main thrust ofthis work, however, is to present an overview ofthe present state of physical understanding and to show that an important gap exists at the point where, quantum and classical physics meet, as well as to speculate on how the conscious brain might be taking advantage ofwhatever new physics is needed to fill this gap to achieve its nonalgorithmic effects.
Contemporary perspectives in rehabilitation. Volume I Thermal agents in rehabilitation
Authors: Margaret John
Journal: British Journal of Sports Medicine (1987)

discouraged.It is possible that at least some of the not inconsiderable number of patients with a past history of injury to an area may have avoided further problems with care and attention to fitness of that part of the body.All these findings reinforce the continuing need for improved eduction of people undertaking sport to try to reduce the number of injuries that may result, to limit their severity and reduce recurrences.This is especially so for racquet sports which have such a wide appeal to a large age range in the general population.
The effects of transport inhibitors on sodium outflux and influx in red blood cells: evidence for exchange diffusion
Authors: Michael J. Dunn
Journal: Journal of Clinical Investigation (1970)

Active sodium transport (outflux or efflux) in red blood cells generally has been measured by assessing the amount of outflux inhibited by digitalis glycosides (outflux-fraction I). The presence of a ouabain-uninhibited sodium outflux (outflux-fraction II) attributable either to a second active transport mechanism or to exchange diffusion has been the subject of recent investigations. In the present study a variety of transport inhibitors, including ouabain, ethacrynic acid, furosemide, oligomycin, and amiloride, were studied for their effects on these components of sodium transport in RBC. In the presence of ouabain both ethacrynic acid and furosemide exerted similar effects on sodium outflux, inhibiting approximately 0.5 mmoles/L of cells per hr. This component of sodium outflux has been called outflux-fraction II. Ethacrynic acid showed no inhibitory potency when ouabain and furosemide were present, thereby suggesting that the same outflux component (fraction II) was affected by ethacrynic acid and by furosemide. In addition, furosemide reduced sodium influx to the same extent that it reduced sodium outflux. Outflux-fraction II, as defined by furosemide, did not contribute a net sodium outflux. These results of sodium outflux and influx experiments confirm the existence of a transport pathway which does not contribute to net flux and which fits the definition of exchange diffusion. The inhibitory effect of furosemide on outflux-fraction II remained despite the use of a sulfhydryl protective reagent, whereas the effect of ethacrynic acid was obliterated. No combination of inhibitors was found which affected the residual or uninhibited sodium outflux (0.4-0.5 mmoles/liter of cells per hr). Oligomycin possessed an inhibitory potency less than that of ouabain, and it exerted no effect on sodium outflux if it was superimposed upon ouabain inhibition. Amiloride proved to be a very weak inhibitor of sodium outflux in human erythrocytes.
Comparative Survival of Lethally Irradiated Inbred Male Mice Inoculated With Marrow From Virgin or Multiparous Female Donors
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1975)

The response of marrow from virgin female donors to the antigens controlled by the Y chromosome of syngeneic male recipients varied with different strains of mice and was independent of their H-2 genotype. Marrow from syngeneic multiparous donors might produce a greater response to male antigens than that observed with marrow from virgin females. The sensitization of the mother to her male progeny indicated that these antigens were expressed before parturition. The reduced responsiveness of mothers to some alloantigens and the accompanying increased responsiveness to male antigens suggested a difference in the time during embryonic development when these antigens were expressed.
Increased IgG Fc and C3 Rosette‐Forming Capacity of Granulocytes from Patients with Psoriasis
Authors: Miklós Csató, Zita Kabók, Attila Dobozy
Journal: Allergy (1984)

In the present work the proportions of IgG Fc and C3 rosette‐forming granulocytes were studied in patients with severe psoriasis. The percentages of erythrocyte‐antibody and C3 rosette‐forming granulocytes from psoriasis patients were significantly higher than those of healthy individuals. Sera from patients with psoriasis did not influence the rosette formation by granulocytes from healthy persons. The increased IgC Ft and C3 receptor activities of granulocytes in psoriasis may account for the hyperactivity of these cells enhancing the susceptibility of the polymorphonuclears for at least some naturally occurring stimuli.
Interferon–inducible T Cell Alpha Chemoattractant (I-TAC): A Novel Non-ELR CXC Chemokine with Potent Activity on Activated T Cells through Selective High Affinity Binding to CXCR3
Authors: Katherine E. Cole, Christine A. Strick, Timothy J. Paradis, Kevin T. Ogborne, Marcel Loetscher, Ronald P. Gladue, Wen Lin, James G. Boyd, Bernhard Moser, Douglas E. Wood, Barbara G. Sahagan, Kuldeep Neote
Journal: The Journal of Experimental Medicine (1998)

Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2-activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-gamma-inducible 10-kD protein (IP-10) and IFN-gamma- induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-gamma and IL-1 together results in an approximately 400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1-stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.
Effects of laparoscopic cholecystectomy on global respiratory muscle strength.
Authors: N Rovina, D Bouros, N Tzanakis, M Velegrakis, S Kandilakis, F Vlasserou, N M Siafakas
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Laparoscopic cholecystectomy has a better postoperative outcome than the traditional open technique, which has been shown to significantly affect respiratory muscle function. The aim of this study was to investigate the effects of laparoscopic surgery on respiratory function, and particularly that of the respiratory muscles. Respiratory muscle strength was assessed in 26 patients who underwent laparoscopic cholecystectomy and in 25 who underwent open cholecystectomy by measuring mouth pressure during maximum static inspiratory (PImax) and expiratory (PEmax) efforts. PImax, PEmax, and blood gases were measured 24 h preoperatively (-24 h) as well as 24 h (+24 h) and 48 h (+48 h) postoperatively. FEV1 and FVC were measured at -24 h and +48 hr, and the ratio of FEV1 to FVC (FEV1/FVC) was calculated. PImax decreased at +24 h and +48 h in both groups, but this decrease was significantly greater in the patients who had open surgery, (p < 0.01, and p < 0.005, respectively). Similarly, PEmax was significantly smaller in the open- than in the laparoscopic-surgery group (p < 0.0001) at +48 h. Spirometric indices showed a more severe restrictive defect at +48 h after open surgery than after laparoscopy (p = 0.01). The arterial oxygen tension (PaO2) was significantly greater in the laparoscopic- than in the open-surgery group at +24 h (p < 0.007). Laparoscopic cholecystectomy caused smaller decreases in respiratory muscle strength than did open surgery. This accords with the hypothesis of phrenic nerve inhibition during open surgery. The results are of clinical importance, since they may explain the different outcomes with the two techniques.
Diarrhoea and malabsorption in acquired immune deficiency syndrome: a study of four cases with special emphasis on opportunistic protozoan infestations.
Authors: R Modigliani, C Bories, Y Le Charpentier, M Salmeron, B Messing, A Galian, J C Rambaud, A Lavergne, B Cochand-Priollet, I Desportes
Journal: Gut (1985)

Chronic diarrhoea is frequent in acquired immune deficiency syndrome (AIDS) but has been poorly investigated so far. We report four patients with AIDS in whom diarrhoea and malabsorption were outstanding features, and who underwent extensive digestive investigations. Diarrhoea was a presenting symptom in all subjects and was of secretory type in three of them. D-xylose and vitamin B12 were malabsorbed in all cases; steatorrhea was found in the two patients who could ingest significant amounts of fat. Faecal alpha 1-antitrypsin clearance was increased in all subjects. Search for digestive pathogens showed unusual protozoans in all patients: in case 1, optical and electron microscopy revealed the presence in the cytoplasm of villous enterocytes of Microsporidia protozoans still unreported in AIDS. Stool and jejunal fluid examination showed Isospora belli in case 2 and Cryptosporidium in cases 3 and 4. On histological and ultrastructural study the former was localised in the cytoplasm of a few enterocytes and the latter was scattered throughout the villus and crypt brush border. Otherwise small intestinal histology only showed minor non-specific changes and the enterocytes were ultrastructurally normal. In patient 3 the slow marker intestinal perfusion technique showed a profuse fluid secretion in the duodenum and proximal jejunum. All patients needed prolonged total parenteral nutrition. Cryptosporidium and Microsporidia could not be eradicated despite multiple drug trials. Isospora belli was transiently cured by pyrimethamine-sulphadiazine. Only patient 2 is presently at home, and patients 1, 3, and 4 died after two, six, and nine months of total parenteral nutrition, respectively.
Potassium Channels and Proliferation of Vascular Smooth Muscle Cells
Authors: William F. Jackson
Journal: Circulation Research (2005)

otassium channels play a major role in the immediate and long term regulation of vascular smooth muscle function. 1The activity of these ion channels determines and regulates cell membrane potential, which, in turn, regulates the open state probability of voltage-gated Ca 2ϩ channels, Ca 2ϩ influx, and intracellular Ca 2ϩ .The concentration of intracellular Ca 2ϩ not only regulates the immediate contractile responses of smooth muscle cells (ie, vascular tone), 1 but also the long term responses of these cells through control of gene expression. 2By their effect on membrane potential, K ϩ channels also establish the electrochemical gradient that determines the movement of other ions across the plasma membrane.In addition, potassium channels participate significantly in cell volume regulation. 3ver the past two decades it has become apparent that K ϩ channels also play an important role in cell proliferation. 4 -8 In vascular smooth muscle cells, investigators have identified increased expression of intermediate conductance, Ca 2ϩ -activated K ϩ (IK Ca ) channels (KCa3.1,locus: KCNN4) associated with proliferation, 4 and recent studies have shown that selective inhibition of these channels prevents vascular smooth muscle proliferation associated with injury-induced restenosis. 9The study by Miguel-Velado et al in this issue of Circulation Research 10 confirms an important role for K ϩ channels in vascular smooth muscle cell proliferation.The authors extend this area by showing that Kv3.4 channel (locus: KCNC4) expression is increased in proliferating smooth muscle cells from human uterine artery and that blockade of these channels inhibits proliferation.These K V channels also have been implicated in proliferation of an oral squamous cell carcinoma, 11,12 and their expression is increased in growth cones of retinal ganglion cells. 13Although Kv3.4 channels, and other members of the voltage-gated K ϩ channel superfamily of K ϩ channels such as Kv1.3, 5,8 Kv10.1, and Kv11.1, 5 have been implicated in proliferation of other cell types, the study by Miguel-Velado and associates 10 is the first to suggest that the Kv3 family participates in proliferation of smooth muscle cells.This finding is significant for several reasons.First, it suggests that there may be regional or cell-specific differences in the K ϩ channels that