tbuckley/cabot-search huggingface dataset:
Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves
Authors: Luigi A. Venetucci, Andrew W. Trafford, David A. Eisner
Journal: Circulation Research (2006)

Diastolic waves of Ca 2+ release have been shown to activate delayed afterdepolarizations as well as some cardiac arrhythmias. The aim of this study was to investigate whether increasing ryanodine receptor open probability alone or in the presence of β-adrenergic stimulation produces diastolic Ca release from the sarcoplasmic reticulum (SR). When voltage-clamped rat ventricular myocytes were exposed to caffeine (0.5 to 1.0 mmol), diastolic Ca 2+ release was seen to accompany the first few stimuli but was never observed in the steady state. We attribute the initial phase of diastolic Ca 2+ release to a decrease in the threshold SR Ca 2+ content required to activate Ca 2+ waves and its subsequent disappearance to a decrease of SR content below this threshold. Application of isoproterenol (1 μmol/L) increased the amplitude of the systolic Ca 2+ transient and also the SR Ca 2+ content but did not usually produce diastolic Ca 2+ release. Subsequent addition of caffeine, however, resulted in diastolic Ca 2+ release. We estimated the time course of recovery of SR Ca 2+ content following recovery from emptying with a high (10 mmol/L) concentration of caffeine. Diastolic Ca 2+ release recommenced only when SR content had increased back to its final level. We conclude that increasing ryanodine receptor open probability alone does not produce arrhythmogenic diastolic Ca 2+ release because of the accompanying decrease of SR Ca 2+ content. β-Adrenergic stimulation increases SR content and thereby allows the increased ryanodine receptor open probability to produce diastolic Ca 2+ release. The implications of these results for arrhythmias associated with abnormal ryanodine receptors are discussed.
Targeting the Jak/STAT pathway for immunosuppression
Authors: J J O'Shea
Journal: Annals of the Rheumatic Diseases (2004)

While many effective immunosuppressive drugs exist and are in wide use, most target ubiquitously expressed molecules. Examples include steroids, ciclosporin A, tacrolimus, mycophenolate mofetil, and sirolimus. Consequently, these drugs have adverse effects unrelated to their immunosuppressive actions, and much effort has been directed towards identifying molecular targets with expression restricted to immune and inflammatory cells. In principle, such drugs could provide immunosuppression yet lack the toxicity associated with current therapies.

It is now well established that cytokines have critical roles in regulating immunity and inflammation; indeed targeting cytokines themselves has been an effective new strategy for immunosuppression.1 However, targeting intracellular cytokine signalling also now appears to be a viable new approach. Janus kinases (Jaks) and signal transducers and activators of transcription (STATs) have been demonstrated to be critical elements in signalling by certain families of cytokines. Importantly, the generation of a selective inhibitor of Jak3 appears to be feasible and effective. This report discusses the approach of targeting Jaks and STATs, with emphasis on Jak3 and a newly identified Jak3 antagonist.

Cytokines comprise more than 50 secreted factors that regulate processes ranging from body growth, lactation, and adiposity to haematopoiesis but are especially important for regulating inflammatory and immune responses.2 That is, cytokines control both innate and adaptive immunity and are critical for lymphoid development and homoeostasis, as well as the ultimate differentiation of helper and memory T cells.

Interleukin (IL)-2, 4, 7, 9, 15, and 21 comprise one family of cytokines that uses a common receptor subunit termed the common γ chain, or γc (table 1).3–5 These cytokines are particularly important with respect to lymphoid development and function. For instance, IL-7 is critical for lymphocyte development and function and mice lacking IL-7R expression have arrested thymocyte development at the double negative (CD4–CD8–) stage.6–11 …
Randomised controlled trial of the Lidcombe programme of early stuttering intervention
Authors: Mark Jones, Mark Onslow, Ann Packman, Shelley Williams, Tika Ormond, Ilsa Schwarz, Val Gebski
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To evaluate the efficacy of the Lidcombe programme of early stuttering intervention by comparison to a control group. <b>Design</b> A pragmatic, open plan, parallel group, randomised controlled trial with blinded outcome assessment. <b>Setting</b> Two public speech clinics in New Zealand. <b>Participants</b> Stuttering preschool children who presented to the speech clinics for treatment. Inclusion criteria were age 3-6 years and frequency of stuttering of at least 2% syllables stuttered. Exclusion criteria were onset of stuttering during the six months before recruitment and treatment for stuttering during the previous 12 months. 54 participants were randomised: 29 to the Lidcombe programme arm and 25 to the control arm. 12 of the participants were girls. <b>Intervention</b> Lidcombe programme of early stuttering intervention. <b>Main outcome measures</b> Frequency of stuttering was measured as the proportion of syllables stuttered, from audiotaped recordings of participants9 conversational speech outside the clinic. Parents in both arms of the trial collected speech samples in three different speaking situations before randomisation and at three, six, and nine months after randomisation. <b>Results</b> Analysis showed a highly significant difference (P = 0.003) at nine months after randomisation. The mean proportion of syllables stuttered at nine months after randomisation was 1.5% (SD 1.4) for the treatment arm and 3.9% (SD 3.5) for the control arm, giving an effect size of 2.3% of syllables stuttered (95% confidence interval 0.8 to 3.9). This effect size was more than double the minimum clinically worthwhile difference specified in the trial protocol. <b>Conclusions</b> The results provide evidence from a randomised controlled trial to support early intervention for stuttering. The Lidcombe programme is an efficacious treatment for stuttering in children of preschool age.
Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Outcomes During Warfarin Therapy
Authors: Mitchell K Higashi, David L Veenstra, L Midori Kondo, Ann K Wittkowsky, Sengkeo L Srinouanprachanh, Fred M Farin, Allan E Rettie
Journal: JAMA (2002)

ContextWarfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established.ObjectiveTo determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy.Design and SettingRetrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash.ParticipantsTwo hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included.Main Outcome MeasuresAnticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events.ResultsAmong 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, χ25 = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P = .004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86).ConclusionsThe results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.
Locally Disordered Methylation Forms the Basis of Intratumor Methylome Variation in Chronic Lymphocytic Leukemia
Authors: Dan A. Landau, Kendell Clement, Michael J. Ziller, Patrick Boyle, Jean Fan, Hongcang Gu, Kristen Stevenson, Carrie Sougnez, Lili Wang, Shuqiang Li, Dylan Kotliar, Wandi Zhang, Mahmoud Ghandi, Levi Garraway, Stacey M. Fernandes, Kenneth J. Livak, Stacey Gabriel, Andreas Gnirke, Eric S. Lander, Jennifer R. Brown, Donna Neuberg, Peter V. Kharchenko, Nir Hacohen, Gad Getz, Alexander Meissner, Catherine J. Wu
Journal: Cancer Cell (2014)
Involvement of the Hedgehog signalling pathway in idiopathic pulmonary fibrosis
Authors: Natacha Cigna, Elika Farrokhi Moshai, Marchal-Sommé Joëlle, Lidwine Stervinou-Wémeau, Dehoux Monique, Paul Soler, Bruno Crestani, Arnaud Mailleux
Journal: European Respiratory Journal (2011)

Identification of new therapeutic targets in idiopathic pulmonary fibrosis (IPF) is required. We hypothesized that, in the adult lung, SHH pathway plays a critical role during the alveolar repair process and lung fibrogenesis.

Methods: We determined the expression pattern of several members of the SHH pathway in lung biopsies and primary cultured fibroblasts from controls and IPF patients. We also examined the expression profile of SHH pathway after TGF-β stimulation in fibroblasts. We characterized the action of recombinant SHH and cyclopamine, an inhibitor of SHH pathway, on the effect of TGF-β on fibroblast differentiation markers.

Results: In lung biopsies, the ligand SHH, the receptor Patched (PTC), the transmembrane protein Smoothened (SMO) and the transcription factors GLI 1-2-3 were detected in both control and IPF tissues. Compared to controls, PTC was decreased in IPF, both in epithelial cells and fibroblasts. SMO was maintained and GLI2 was localized in the nuclei in IPF. In vitro, there was no difference between control and IPF fibroblasts in the expression of HH signalling components. After TGF-β stimulation, PTC, SMO and GLI3 mRNA were strongly inhibited while GLI2 was increased. Cyclopamine inhibited TGF-β induced expression of myofibroblast differentiation markers in control fibroblasts. IPF fibroblasts were less sensitive to cyclopamine treatment. Though, addition of recombinant SHH had no effect.

Conclusions: Our results show that the signaling pathway downstream of SMO is activated in IPF. SMO activity is also necessary to TGF-β induced myofibroblastic differentiation. These data support a pro-fibrotic action of the SHH pathway in IPF.
Molecular aspects of adrenergic modulation of cardiac L-type Ca channels
Authors: M VANDERHEYDEN, T WIJNHOVEN, T OPTHOF
Journal: Cardiovascular Research (2004)

L-type Ca2+ channels are predominantly regulated by β-adrenergic stimulation, enhancing L-type Ca2+ current by increasing the mean channel open time and/or the opening probability of functional Ca2+ channels. Stimulation of β-adrenergic receptors (ARs) results in an increased cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and consequently activation of protein kinase (PK) A and phosphorylation of L-type Ca2+ channels by this enzyme. β1-Adrenergic receptors couple exclusively to the G protein Gs, producing a widespread increase in cAMP levels in the cell, whereas β2-adrenergic receptors couple to both Gs and Gi, producing a more localized activation of L-type Ca2+ channels. Other signaling intermediates (protein kinase C, protein kinase G or protein tyrosine kinase (PTK)) either have negative effects on L-type Ca2+ current, or they interact with the stimulatory effect of the protein kinase A pathway.
Survival and Cause of Death in Aging Germfree Athymic Nude and Normal Inbred C3Hf/He Mice2
Authors: J. M. Holland, T. J. Mitchell, L. C. Gipson, M. S. L. C.
Journal: JNCI Journal of the National Cancer Institute (1978)

Mortality rate and relative risk for specific diseases were compared between male and female athymlc and normal C3Hf/He mice under germfree conditions. Athymlc mice showed significantly reduced overall survival rates, most of which could be attributed to an increased risk for lymphoreticular neoplasms. Although athymic mice were at an increased risk for lymphoreticular diseases, they were at significantly reduced risk for some, but not all, groups of solid tumors. A decreased probability of death with or from solid tumors was a possible explanation for the observation that a significantly greater proportion of athymlc mice died from “natural causes.” The fact that maximum longevities attained by athymlc mice were no different than longevltles of normal controls suggests that thymic aplasia does not influence life-span per se but does influence the relative incidence of specific pathologic states. A specific consideration was whether chronic degenerative diseases indicative of autoimmune processes (i.e., degeneration of vasculature, renal glomerulus, or thyroid gland) were more prevalent in aging athymic mice. Because histologic evidence for these progressive disease processes was not obtained, it appears unlikely that clinically significant autoimmune phenomena are significant factors controlling morbidity or mortality in germfree athymic mice on a C3Hf/He background.
Diffuse Vascular Spasm Associated With 4-Bromo-2,5-Dimethoxyamphetamine Ingestion
Authors: J. Scott Bowen
Journal: JAMA (1983)

A 39-year-old previously healthy man experienced diffuse, progressive, peripheral arterial spasm 36 hours after the ingestion of concentrated high-grade 4-bromo-2,5-dimethoxyamphetamine. Vasospasm responded readily to intra-arterial and intravenous vasodilators. Excessively high doses of this hallucinogen may cause diffuse arterial spasm. (<i>JAMA</i>1983;249:1477-1479)
Influence of incremental aerobic exercise on homocysteine level in young males
Authors: Effat Bambaeichi, Mahdi Aliakbar Najari, Behroz Barjasteh
Journal: British Journal of Sports Medicine (2010)

Recent studies showed that elevated concentration of plasma homocysteine can be one of the risk factors for cardiovascular disease. The aim of this investigation was to study the effect of 8 weeks incremental aerobic exercise on homocysteine. Twenty-eight sedentary young males (mean ± SD; age: 19±1.2 years and percentage of body fat: 25±1.5) participated in this study, divided into control and experimental groups. The experimental group participated in a regular 8 weeks incremental aerobic exercise while the control group was prevented from any sport activity and just participated in pre- and post-testing. All participants were healthy and free of any medication and they did not have any sport activities during the last 6 months before entering study. However, at least one of their relatives suffered from cardiovascular risk factors. Maximal consumption oxygen (VO 2 max) was assessed by Bruce incremental treadmill. The blood samples were taken at 07:00 to 8:00 in the morning after an overnight fast for plasma homocysteine. The results showed significant difference in maximum oxygen consumption between experimental and control group in post-test (F=31, p&lt;0.05). No significant effect was found for 8 weeks incremental aerobic exercise on homocysteine concentration (p&gt;0.05). There was no significant difference in homocysteine level in post-test between experimental (X=17.9±8.2 mm/mol/l) and control group (X=15.7±4.8 mm/mol/l) (p&gt;0.05). In conclusion, 8 weeks incremental aerobic exercise cannot reduce plasma homocysteine as risk factors for cardiovascular disease in sedentary young males.
Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines
Authors: Christiane Houde, Yulin Li, Lynda Song, Kevin Barton, Qing Zhang, John Godwin, Sucha Nand, Amir Toor, Serhan Alkan, N. Veronique Smadja, Hervé Avet-Loiseau, Carmen S. Lima, Lucio Miele, Lionel J. Coignet
Journal: Blood (2004)
Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line.
Authors: H Nakamura, K Yoshimura, N G McElvaney, R G Crystal
Journal: Journal of Clinical Investigation (1992)

The respiratory manifestations of cystic fibrosis (CF) are characterized by neutrophil-dominated airway inflammation. Since a variety of inflammatory stimuli are capable of inducing bronchial epithelial cells to express the gene for IL-8, a cytokine that attracts and activates neutrophils, mediators in respiratory epithelial lining fluid (ELF) of CF individuals might induce IL-8 production by epithelial cells, thus recruiting neutrophils to the airways. BET-1A human bronchial epithelial cells at rest or incubated with normal ELF showed little IL-8 gene expression, but after incubation with CF ELF, a marked increase in IL-8 transcript levels was observed. CF ELF contained high levels of neutrophil elastase (NE) and various serine protease inhibitors prevented CF ELF from inducing IL-8 gene expression in BET-1A cells, suggesting that NE was the dominant inducer for IL-8 production in CF ELF. The addition of purified NE caused BET-1A cells to increase IL-8 gene transcription with accumulation of mRNA transcripts and to release IL-8-like neutrophil chemotactic activity. These observations suggest a self-perpetuating inflammatory process on the CF bronchial surface where NE released by neutrophils induced the bronchial epithelium to secrete IL-8, which in turn recruits additional neutrophils to the bronchial surface.
Immunologic Aspects of 1,2-Dimethylhydrazine-Induced Colon Tumors in Rats2
Authors: Annie B-K. Garmaise, Adrianne E. Rogers, Calvin A. Saravis, Norman Zamcheck, Paul M. Newberne
Journal: JNCI Journal of the National Cancer Institute (1975)

Investigation of immunologic aspects of colon tumors induced in rats by 1,2-dimethylhydrazine demonstrated that: 1) An antigen in an extract of colon tumors was not detected in the normal colon. It was related to antigens in rat fetuses and did not cross-react immunologically with carcinoembryonic antigen. 2) Mucinous adenocarcinomas of the colon were significantly associated spatially with lymphoid follicles.
The Genetics of the Amyloidoses
Authors: Joel N. Buxbaum, Clement E. Tagoe
Journal: Annual Review of Medicine (2000)

▪ Abstract The amyloidoses are diseases in which abnormalities in the secondary structure of precursor proteins result in decreased solubility under physiologic conditions, with subsequent organ compromise. A total of 18 proteins have been definitively identified as amyloid precursors associated with human disease. Mutations in the genes that encode some of these proteins produce autosomal dominant disease in mid to late adult life. Until recently, the late onset has obscured the familial nature of some of the disorders. This is especially true in the apparently sporadic diseaseproducing deposits found even later in life. In many instances, these deposits are derived from precursors encoded by wild-type genes (perhaps influenced by alleles that are polymorphic in the normal population); in other cases, they represent autosomal dominant disease with age-dependent penetrance. The genetic aspects of amyloid diseases produced by the deposition of four different proteins have been investigated in detail and provide insights into the particular diseases and amyloidogenesis in general.
A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks.
Authors: John S Reece-Hoyes, Bart Deplancke, Jane Shingles, Christian A Grove, Ian A Hope, Albertha JM Walhout
Journal: Genome biology (2005)

Abstract Background Transcription regulatory networks are composed of interactions between transcription factors and their target genes. Whereas unicellular networks have been studied extensively, metazoan transcription regulatory networks remain largely unexplored. Caenorhabditis elegans provides a powerful model to study such metazoan networks because its genome is completely sequenced and many functional genomic tools are available. While C. elegans gene predictions have undergone continuous refinement, this is not true for the annotation of functional transcription factors. The comprehensive identification of transcription factors is essential for the systematic mapping of transcription regulatory networks because it enables the creation of physical transcription factor resources that can be used in assays to map interactions between transcription factors and their target genes. Results By computational searches and extensive manual curation, we have identified a compendium of 934 transcription factor genes (referred to as wTF2.0). We find that manual curation drastically reduces the number of both false positive and false negative transcription factor predictions. We discuss how transcription factor splice variants and dimer formation may affect the total number of functional transcription factors. In contrast to mouse transcription factor genes, we find that C. elegans transcription factor genes do not undergo significantly more splicing than other genes. This difference may contribute to differences in organism complexity. We identify candidate redundant worm transcription factor genes and orthologous worm and human transcription factor pairs. Finally, we discuss how wTF2.0 can be used together with physical transcription factor clone resources to facilitate the systematic mapping of C. elegans transcription regulatory networks. Conclusion wTF2.0 provides a starting point to decipher the transcription regulatory networks that control metazoan development and function.