tbuckley/cabot-search huggingface dataset:
ACTIONS OF SYMPATHOMIMETIC AMINES AND THEIR ANTAGONISTS ON SKELETAL MUSCLE
Authors: W.C. BOWMAN, M.W. NOTT
Journal: Pharmacological Reviews (1969)

Epinephrine exerts a direct action on mammalian muscle fibers which is mediated via β-receptors. Activation of these receptors results in prolongation of the active state of white, fast-contracting muscles and curtailment of the active state of red, slow-contracting muscles. In chronically denervated mammalian muscles of both types, and in chronically denervated avian muscles, activation of the β-receptors increases the fibrillary discharge and the tone exerted by the muscles. It is suggested that these effects on muscle contractility may arise through activation of the adenyl cyclase/cyclic 3' ,5'-AMP system, which in turn leads to changes in the rates of uptake of Ca2+ by the sarcoplasmic reticulum. Activation of the β-receptors also increases the muscle demarcation potential, presumably as a result of hyperpolarization of the muscle fiber membranes. Under sensitive conditions, this effect can be shown to lead to a depressant effect on neuromuscular transmission.

Epinephrine also exerts an initial faciitatory action on neuromuscular transmission in all types of muscle, and this is mediated via α-receptors, probably located in the motor nerve endings, activation of which appears to cause an inincrease in the amount of acetylcholine released by the nerve impulse. Hyperpolarization of motor nerve endings increases release of transmitter by nerve impulses, and epinephrine may act by hyperpolarizing some part of the terminal membrane. It may be that, although mediated by different types of receptor, epinephrine exerts an effect on the coupling of excitation and transmitter release in nerve which is analogous to its action on excitation-contraction coupling in muscle, both effects involving changes in the levels of free calcium ions. Cyclic 3' ,5'-AMP may also be a mediator in the facilitatory effect on neuromuscular transmission, and this fact implies the unusual situation that, in nerve, increased levels of the nucleotide may be evoked through α-receptors.

The defatiguing action of epinephrine and sympathetic stimulation in mammalian fast-contracting muscles mainly involves the prejunctional α-receptors, but the postjunctional β-receptors also contribute. In fatigued frog muscle, only prejunctional α-receptors are involved. Apart from an indirect action arising from circulatory changes, epinephrine is without a defatiguing effect in red, slow-contracting mammalian muscles.

A consideration of the effective doses of catecholamines suggests that only the action of epinephrine on the sensitive slow-contracting red muscle fibers has any physiological significance. This action is probably responsible for the enhancement of physiological tremor and of Parkinsonian tremor produced by catecholamines in man, and for the tremor often associated with phaeochromocytoma.
Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7
Authors: Veit Hornung, Margit Guenthner-Biller, Carole Bourquin, Andrea Ablasser, Martin Schlee, Satoshi Uematsu, Anne Noronha, Muthiah Manoharan, Shizuo Akira, Antonin de Fougerolles, Stefan Endres, Gunther Hartmann
Journal: Nature Medicine (2005)
Molecular Pathways: Can Activin-like Kinase Pathway Inhibition Enhance the Limited Efficacy of VEGF Inhibitors?
Authors: Rupal S. Bhatt, Michael B. Atkins
Journal: Clinical Cancer Research (2014)

The vascular endothelial growth factor (VEGF) pathway is critical for tumor angiogenesis. However, VEGF pathway inhibition has been limited by intrinsic and acquired resistance. Simultaneously targeting multiple steps involved in tumor angiogenesis is a potential means of overcoming this resistance. Activin like kinase 1 (ALK1) and endoglin (ENG) have effects on angiogenesis that are distinct from those of VEGF. Whereas VEGF is important for vessel initiation, ALK1 and endoglin are involved in vessel network formation. Thus, ALK1 and endoglin pathway inhibitors are attractive partners for VEGF-based combination antiangiogenic therapy. Genetic evidence supports a role for this receptor family and its ligands, bone morphogenetic proteins (BMP) 9 and 10, in vascular development. Patients with genetic alterations in ALK1 or endoglin develop hereditary hemorrhagic telangiectasia, a disorder characterized by abnormal vessel development. There are several inhibitors of the ALK1 pathway advancing in clinical development for treatment of various tumor types, including renal cell and ovarian carcinomas. Targeting of alternate angiogenic pathways, particularly in combination with VEGF pathway blockade, holds the promise of optimally inhibiting angiogenically driven tumor progression. Clin Cancer Res; 20(11); 2838-45. ©2014 AACR.
Dominant protein interactions that influence the pathogenesis of conformational diseases
Authors: Jordan Wright, Xiaofan Wang, Leena Haataja, Aaron P. Kellogg, Jaemin Lee, Ming Liu, Peter Arvan
Journal: Journal of Clinical Investigation (2013)

Misfolding of exportable proteins can trigger endocrinopathies. For example, misfolding of insulin can result in autosomal dominant mutant INS gene-induced diabetes of youth, and misfolding of thyroglobulin can result in autosomal recessive congenital hypothyroidism with deficient thyroglobulin. Both proinsulin and thyroglobulin normally form homodimers; the mutant versions of both proteins misfold in the ER, triggering ER stress, and, in both cases, heterozygosity creates potential for cross-dimerization between mutant and WT gene products. Here, we investigated these two ER-retained mutant secretory proteins and the selectivity of their interactions with their respective WT counterparts. In both cases and in animal models of these diseases, we found that conditions favoring an increased stoichiometry of mutant gene product dominantly inhibited export of the WT partner, while increased relative level of the WT gene product helped to rescue secretion of the mutant partner. Surprisingly, the bidirectional consequences of secretory blockade and rescue occur simultaneously in the same cells. Thus, in the context of heterozygosity, expression level and stability of WT subunits may be a critical factor influencing the effect of protein misfolding on clinical phenotype. These results offer new insight into dominant as well as recessive inheritance of conformational diseases and offer opportunities for the development of new therapies.
Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε
Authors: Clyde W. Hodge, Jacob Raber, Thomas McMahon, Helen Walter, Ana Maria Sanchez-Perez, M. Foster Olive, Kristin Mehmert, A. Leslie Morrow, Robert O. Messing
Journal: Journal of Clinical Investigation (2002)

Mice lacking protein kinase Cε (PKCε) are supersensitive to positive allosteric modulators of gamma aminobutyrate type A (GABAA) receptors. Since many of these compounds are anxiolytic, we examined whether anxiety-like behavior is altered in these mice. PKCε-null mice showed reduced anxiety-like behavior and reduced levels of the stress hormones corticosterone and adrenocorticotrophic hormone (ACTH). This was associated with increased sensitivity to neurosteroid modulators of GABAA receptors. Treatment of PKCε-null mice with the GABAA receptor antagonist bicuculline restored corticosterone levels and anxiety-like behavior to wild-type levels. These results suggest that increased GABAA receptor sensitivity to neurosteroids contributes to reduced anxiety-like behavior and stress hormone responses in PKCε-null mice. The findings also suggest PKCε as a possible therapeutic target for development of anxiolytics.
Collagen and Elastin Content in Canine Arteries Selected from Functionally Different Vascular Beds
Authors: GRACE M. FISCHER, JOSEP G. LLAURADO
Journal: Circulation Research (1966)

The amount of collagen and elastin in normal canine arteries was determined biochemically in nine different sites. The total collagen and elastin ranges from 58 to 75% of the weight of the dry defatted artery. Reasons are adduced to propose that the expression of results as the ratio of collagen to elastin (C/E) is a useful index of the relative distensibility for the maintenance tension of arterial wall. Two arteries, carotid and renal, which are pathways to blood pressure sensors, have a statistically significantly higher C/E than the femoral and mesenteric arteries, which are pathways to regulated beds. The highest C/E was found in the coronary artery. Results are interpreted in relation to the function of the vascular beds to which the representative arterial specimens belong.
Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response
Authors: Ronald F van Vollenhoven, Michelle A Petri, Ricard Cervera, David A Roth, Beulah N Ji, Christi S Kleoudis, Z John Zhong, William Freimuth
Journal: Annals of the Rheumatic Diseases (2012)

To identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets.The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect.Pooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA-SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA-SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life.These findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. CLINICALTRIALS.GOV: identifiers NCT00424476 and NCT00410384.
Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging
Authors: K. Darwiche, P. Zarogoulidis, K. Baehner, S. Welter, R. Tetzner, J. Wohlschlaeger, D. Theegarten, T. Nakajima, L. Freitag
Journal: Annals of Oncology (2013)
Notch and Vascular Smooth Muscle Cell Phenotype
Authors: David Morrow, Shaunta Guha, Catherine Sweeney, Yvonne Birney, Tony Walshe, Colm O’Brien, Dermot Walls, Eileen M. Redmond, Paul A. Cahill
Journal: Circulation Research (2008)

The Notch signaling pathway is critical for cell fate determination during embryonic development, including many aspects of vascular development. An emerging paradigm suggests that the Notch gene regulatory network is often recapitulated in the context of phenotypic modulation of vascular smooth muscle cells (VSMC), vascular remodeling, and repair in adult vascular disease following injury. Notch ligand receptor interactions lead to cleavage of receptor, translocation of the intracellular receptor (Notch IC), activation of transcriptional CBF-1/RBP-Jκ–dependent and –independent pathways, and transduction of downstream Notch target gene expression. Hereditary mutations of Notch components are associated with congenital defects of the cardiovascular system in humans such as Alagille syndrome and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recent loss- or gain-of-function studies have provided insight into novel Notch-mediated CBF-1/RBP-Jκ–dependent and –independent signaling and cross-regulation to other molecules that may play a critical role in VSMC phenotypic switching. Notch receptors are critical for controlling VSMC differentiation and dictating the phenotypic response following vascular injury through interaction with a triad of transcription factors that act synergistically to regulate VSMC differentiation. This review focuses on the role of Notch receptor ligand interactions in dictating VSMC behavior and phenotype and presents recent findings on the molecular interactions between the Notch components and VSMC-specific genes to further understand the function of Notch signaling in vascular tissue and disease.
ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver
Authors: Pierre-Damien Denechaud, Pascale Bossard, Jean-Marc A. Lobaccaro, Lesley Millatt, Bart Staels, Jean Girard, Catherine Postic
Journal: Journal of Clinical Investigation (2008)

The transcription factor carbohydrate-responsive element–binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver–pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us to study the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXRα/β knockout compared with wild-type mice, suggesting that the activation of these genes by glucose occurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXRα/β with specific cofactors. Finally, siRNA silencing of ChREBP in LXRα/β knockout hepatocytes abrogated glucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP in glucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver.
Intensive Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer
Authors: A. D. Elias, L. Ayash, E. Frei, A. T. Skarin, M. Hunt, C. Wheeler, G. Schwartz, R. Mazanet, I. Tepler, J. P. Eder, M. McCauley, T. Herman, L. Schnipper, K. H. Antman
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Intensive Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer Get access Anthony D. Elias, Anthony D. Elias Department of MedicineBoston, Mass Anthony Elias, M.D., Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Search for other works by this author on: Oxford Academic PubMed Google Scholar Lois Ayash, Lois Ayash Department of MedicineBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Emil Frei, III, Emil Frei, III Department of MedicineBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Arthur T. Skarin, Arthur T. Skarin Department of MedicineBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Myla Hunt, Myla Hunt Division of BiostatisticsBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Cathy Wheeler, Cathy Wheeler Beth Isreal Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Gary Schwartz, Gary Schwartz Beth Isreal Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Rosemary Mazanet, Rosemary Mazanet Department of MedicineBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Isidore Tepler, Isidore Tepler Beth Isreal Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Paul Eder, J. Paul Eder Beth Isreal Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Mary McCauley, Mary McCauley Department of MedicineBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Terence Herman, Terence Herman Division of Radiation Therapy, Dana-Farber Cancer InstituteBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Lowell Schnipper, Lowell Schnipper Beth Isreal Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Karen H. Antman Karen H. Antman Department of MedicineBoston, Mass * “Notes” section following “References”. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 7, 7 April 1993, Pages 559–566, https://doi.org/10.1093/jnci/85.7.559 Published: 07 April 1993 Article history Received: 10 June 1992 Revision received: 23 December 1992 Accepted: 29 December 1992 Published: 07 April 1993
Diagnosis of Intra-amniotic Infection by Proteomic Profiling and Identification of Novel Biomarkers
Authors: Michael G. Gravett
Journal: JAMA (2004)

Intra-amniotic infection (IAI) is commonly associated with preterm birth and adverse neonatal sequelae. Early diagnosis of IAI, however, has been hindered by insensitive or nonspecific tests.To identify unique protein signatures in rhesus monkeys with experimental IAI, a proteomics-based analysis of amniotic fluid was used to develop diagnostic biomarkers for subclinical IAI in amniotic fluid and blood of women with preterm labor.Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry, gel electrophoresis, and tandem mass spectrometry were used to characterize amniotic fluid peptides in 19 chronically instrumented pregnant rhesus monkeys before and after experimental IAI. Candidate biomarkers were determined by liquid chromatography-tandem mass spectrometry. Polyclonal antibodies were generated from synthetic peptides for validation of biomarkers of IAI. Amniotic fluid peptide profiles identified in experimental IAI were subsequently tested in a cohort of 33 women admitted to Seattle, Wash, hospitals between June 25, 1991, and June 30, 1997, with preterm delivery at 35 weeks or earlier associated with subclinical IAI (n = 11), preterm delivery at 35 weeks or earlier without IAI (n = 11), and preterm contractions with subsequent term delivery at later than 35 weeks (n = 11).Identification of peptide biomarkers for occult IAI.Protein expression profiles in amniotic fluid showed unique signatures of overexpression of polypeptides in the 3- to 5-kDa and 10- to 12-kDa molecular weight ranges in all animals after infection and in no animal prior to infection. In women, the 10- to 12-kDa signature was identified in all 11 patients with subclinical IAI, in 2 of 11 with preterm delivery without IAI, and in 0 of 11 with preterm labor and term delivery without infection (P<.001). Peptide fragment analysis of the diagnostic peak in amniotic fluid identified calgranulin B and a unique fragment of insulinlike growth factor binding protein 1, which were also expressed in maternal serum. Mapping of other amniotic fluid proteins differentially expressed in IAI identified several immunoregulators not previously described in amniotic fluid.This proteomics-based characterization of the differential expression of amniotic fluid proteins in IAI identified a distinct proteomic profile in an experimental primate chorioamnionitis model that detected subclinical IAI in a human cohort with preterm labor. These diagnostic protein expression signatures, complemented by immunodetection of specific biomarkers in amniotic fluid and in maternal serum, might have application in the early detection of IAI.
Apoptosis in insulin-secreting cells. Evidence for the role of intracellular Ca2+ stores and arachidonic acid metabolism.
Authors: Y P Zhou, D Teng, F Dralyuk, D Ostrega, M W Roe, L Philipson, K S Polonsky
Journal: Journal of Clinical Investigation (1998)

This study investigated the role of intracellular free Ca2+ concentration ([Ca2+]i) in apoptosis in MIN6 cells, an insulin secreting cell line, and in mouse islets. Thapsigargin, an inhibitor of sarcoendoplasmic reticulum Ca2+-ATPases (SERCA), caused a time- and concentration-dependent decrease in the viability of MIN6 cells and an increase in DNA fragmentation and nuclear chromatin staining changes characteristic of apoptosis. Two structurally distinct SERCA inhibitors, cyclopiazonic acid and 2,5-di-[t-butyl]-1,4-hydroquinone also caused apoptosis, but agents that increased [Ca2+]i by other mechanisms did not induce apoptosis in MIN6 cells. Carbachol- or ionomycin-releasible intracellular Ca2+ stores were completely depleted in cells treated by SERCA inhibitors, but not by other agents that increase [Ca2+]i. The ability of thapsigargin to induce cell death was not affected by blocking Ca2+ influx or by clamping [Ca2+]i with a cytosolic Ca2+ buffer suggesting that the process did not depend on changes in [Ca2+]i per se. However, application of the lipoxygenase inhibitors 5,8,11-eicosatrienoic acid and nordihydroguaiaretic acid partially prevented MIN6 cell apoptosis, while exposure of cells to the product of lipoxygenase, 12-hydroxy-[5,8,10,14]-eicosatetraenoic acid, caused apoptosis. In contrast, inhibition of cyclooxygenase with indomethacin did not abolish thapsigargin-induced apoptosis in MIN6 cells. Our findings indicate that thapsigargin causes apoptosis in MIN6 cells by depleting intracellular Ca2+ stores and leading to release of intermediate metabolites of arachidonic acid metabolism.