tbuckley/cabot-search huggingface dataset:
Localization of muscarinic receptor mRNAs in rat heart and intrinsic cardiac ganglia by in situ hybridization.
Authors: D B Hoover, R H Baisden, S X Xi-Moy
Journal: Circulation Research (1994)

Although the heart is considered a relatively pure source of m2 muscarinic receptors, the possible expression of other muscarinic receptor genes at discrete sites within the myocardium or by intrinsic cardiac ganglia had not been evaluated. Accordingly, the present study used in situ hybridization histochemistry with 35S-labeled oligonucleotide probes to address this issue. Initial experiments demonstrated that the localization of m2 mRNA was similar to that reported for muscarinic receptors labeled with the nonselective muscarinic antagonist quinuclidinyl benzilate; however, there were two important exceptions. The conducting system contained less message than expected, whereas the intrinsic cardiac ganglia contained more. The mismatch between muscarinic receptor and m2 mRNA densities in the conducting system could not be explained by the local expression of other muscarinic receptor genes, since m1, m3, and m4 mRNAs were not detected at this or any other site within the myocardium. However, the presence of a high density of prejunctional muscarinic receptors in the conducting system would be consistent with such a mismatch. Surprisingly, the intrinsic cardiac ganglia contained more than four times as much m2 mRNA as found in the atria. This level of message may be necessary for the production of prejunctional receptors on cholinergic nerve fibers within the heart and receptors localized to the ganglion cell bodies. The ganglia also contained smaller amounts of m1 and m4 mRNAs. These observations suggest that prejunctional muscarinic receptors could have a prominent role in regulating cholinergic neurotransmission in the conducting system and that multiple muscarinic receptors are present in the intrinsic cardiac ganglia.
Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010
Authors: Alize J. Ferrari, Fiona J. Charlson, Rosana E. Norman, Scott B. Patten, Greg Freedman, Christopher J.L. Murray, Theo Vos, Harvey A. Whiteford
Journal: PLoS Medicine (2013)

Background Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease. Methods and Findings Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and dysthymia for 1.4% (0.9%–2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and dysthymia for 0.5% (0.3%–0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs. Conclusions GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden. Please see later in the article for the Editors' Summary
Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib
Authors: Rossana Maffei, Stefania Fiorcari, Silvia Martinelli, Leonardo Potenza, Mario Luppi, Roberto Marasca
Journal: Journal of Hematology & Oncology (2015)

Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements.
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial
Authors: Stephen B Hanauer, Brian G Feagan, Gary R Lichtenstein, Lloyd F Mayer, S Schreiber, Jean Frederic Colombel, Daniel Rachmilewitz, Douglas C Wolf, Allan Olson, Weihang Bao, Paul Rutgeerts
Journal: The Lancet (2002)
Incidence of the adult respiratory distress syndrome in the state of Utah.
Authors: G E Thomsen, A H Morris
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To determine the incidence of the adult respiratory distress syndrome (ARDS) in Utah, we prospectively screened intensive-care-unit (ICU) patients for ARDS in six of the 40 general acute-care hospitals in Utah. Over a 1-yr period, we diagnosed severe ARDS (oxygenation criterion: PaO2/PAO2 < or = 0.2) in 110 patients. Of these patients, 27 were not residents of Utah. We estimated that there were 58 undetected Utah residents with ARDS in the remaining 34 Utah acute-care hospitals. We also estimated that one Utah resident per year received ARDS care outside Utah. Incorporating these two estimates, we calculated an estimated upper limit for ARDS incidence in Utah of 8.3 ARDS patients per 100,000 total Utah population per year. Using only directly identified Utah residents with ARDS, we calculated the absolute lower limit for ARDS incidence in Utah to be 4.8 ARDS patients per 100,000 Utah population per year. The incidence of ARDS in Utah is about an order of magnitude less than the 1972 National Heart and Lung Institute Task Force estimate of ARDS incidence in the United States, but agrees with more recently published ARDS incidence figures.
HIV-Positive–to–HIV-Positive Kidney Transplantation — Results at 3 to 5 Years
Authors: Elmi Muller, Zunaid Barday, Marc Mendelson, Delawir Kahn
Journal: New England Journal of Medicine (2015)

The outcome of kidney transplantation in human immunodeficiency virus (HIV)–positive patients who receive organs from HIV-negative donors has been reported to be similar to the outcome in HIV-negative recipients. We report the outcomes at 3 to 5 years in HIV-positive patients who received kidneys from HIV-positive deceased donors.
ROS Fusion Tyrosine Kinase Activates a SH2 Domain–Containing Phosphatase-2/Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Signaling Axis to Form Glioblastoma in Mice
Authors: Al Charest, Erik W. Wilker, Margaret E. McLaughlin, Keara Lane, Ram Gowda, Shanie Coven, Kevin McMahon, Steven Kovach, Yun Feng, Michael B. Yaffe, Tyler Jacks, David Housman
Journal: Cancer Research (2006)

Abstract Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain–containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches. (Cancer Res 2006; 66(15): 7473-81)
Egr-1 negatively regulates calsequestrin expression and calcium dynamics in ventricular cells
Authors: Amanda Kasneci, Naomi M. Kemeny-Suss, Svetlana V. Komarova, Lorraine E. Chalifour
Journal: Cardiovascular Research (2008)

The transcription factor early growth response-1 (Egr-1) is increased in models of cardiac pathology; however, it is unclear how Egr-1 impacts the heart. We sought to identify how Egr-1 regulates expression of proteins involved in cardiomyocyte calcium homeostasis. Protein expression was measured by immunoblotting in control cardiac differentiated H9c2 cells or in H9c2 cells overexpressing wild-type Egr-1 (Egr-1) or an Egr-1 (I293F) mutant. Microspectrofluorimetry of fura-2-loaded cells was used to study calcium dynamics. Chromatin immunoprecipitation with anti-Egr-1 antibody was used to identify Egr-1-associated DNA. Calsequestrin (CSQ) expression was reduced in Egr-1- and profoundly reduced in I293F-expressing cells. Calreticulin, triadin, sarcoendoplasmic reticulum ATPase 2a, phospholamban, and phosphoserine 16-phospholamban expression was unaffected. Calcium release from CSQ-dependent ryanodine-sensitive stores was reduced in Egr-1 and absent in I293F-expressing cells. In contrast, calcium release from calreticulin-dependent inositol 1,4,5-trisphosphate stores was unaffected. In vivo and in vitro chromatin immunoprecipitation demonstrated Egr-1 binding to the CSQ2 promoter. The Egr-1-binding region contains overlapping Egr-1, SP1, and nuclear factor of activated T-cells (NFAT) sites and a CpG island. Reciprocal immunoprecipitation coupled to immunoblots indicated Egr-1:NFAT3 binding was present in all cells lines. Treatment with cyclosporin A, inhibition of DNA methylation using 5-azadeoxycytidine, or inhibition of protein acetylation using sodium butyrate reduced CSQ expression. Our data suggest that Egr-1:DNA binding at the promoter, DNA methylation, and protein acetylation are important in CSQ repression. Moreover, we demonstrate that a reduction in CSQ protein is associated with abnormal calcium dynamics. We conclude that Egr-1 acts as a transcriptional repressor at the CSQ promoter, resulting in downregulation of CSQ, the major calcium storage protein that links excitation–contraction coupling in the cardiac sarcoendoplasmic reticulum.
Explaining Calcium-Dependent Gating of Anoctamin-1 Chloride Channels Requires a Revised Topology
Authors: Kuai Yu, Charity Duran, Zhiqiang Qu, Yuan-Yuan Cui, H. Criss Hartzell
Journal: Circulation Research (2012)

Rationale: Ca 2+ -activated Cl channels play pivotal roles in the cardiovascular system. They regulate vascular smooth muscle tone and participate in cardiac action potential repolarization in some species. Ca 2+ -activated Cl channels were recently discovered to be encoded by members of the anoctamin (Ano, also called Tmem16) superfamily, but the mechanisms of Ano1 gating by Ca 2+ remain enigmatic. Objective: The objective was to identify regions of Ano1 involved in channel gating by Ca 2+ . Methods and Results: The Ca 2+ sensitivity of Ano1 was estimated from rates of current activation, and deactivation in excised patches rapidly switched between zero and high Ca 2+ on the cytoplasmic side. Mutation of glutamates E702 and E705 dramatically altered Ca 2+ sensitivity. E702 and E705 are predicted to be in an extracellular loop, but antigenic epitopes introduced into this loop are not accessible to extracellular antibodies, suggesting this loop is intracellular. Cytoplasmically applied membrane-impermeant sulfhydryl reagents alter the Ca 2+ sensitivity of Ano1 E702C and E705C as expected if E702 and E705 are intracellular. Substituted cysteine accessibility mutagenesis of the putative re-entrant loop suggests that E702 and E705 are located adjacent to the Cl conduction pathway. Conclusions: We propose an alternative model of Ano1 topology based on mutagenesis, epitope accessibility, and cysteine-scanning accessibility. These data contradict the popular re-entrant loop model by showing that the putative fourth extracellular loop (ECL 4) is intracellular and may contain a Ca 2+ binding site. These studies provide new perspectives on regulation of Ano1 by Ca 2+ .
Histogenesis of Coronary Arteriosclerosis
Authors: HENRY D. MOON, JAMES F. RINEHART
Journal: Circulation (1952)

The coronary arteries of 250 individuals dying suddenly from traumatic or natural causes were studied. Many different histopathologic processes were found to participate in the development of coronary arteriosclerosis. The earliest changes which occurred, even in infants, were increased fibroblastic activity, deposits of mucopolysaccharide and degeneration of elastic tissue. These changes were not related to lipid deposition. Moderately advanced lesions were characterized by regeneration of elastic tissue, formation of collagen and lipid deposition. The far-advanced lesions showed hyalinization, abundant lipid deposition, calcification, intramural hemorrhage and thrombosis. The possible mechanisms involved in the development of coronary arteriosclerosis are discussed.
Epstein–Barr Virus — Oncogen or Mitogen?
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1980)

The discovery in 1964 of a new type of herpesvirus in the neoplastic cells of a patient with Burkitt's lymphoma triggered an avalanche of research whose implications we are just beginning to appreciate. The virus, now known as the Epstein–Barr (EB) virus, was soon found not only in other cases of Burkitt's African lymphoma, but also in nasopharyngeal carcinoma in the Orient. Of equal importance was the demonstration that the EB virus causes infectious mononucleosis. As a result, research on this agent spread rapidly through Europe, Africa, Asia, and North America. Roizman's1 comment, "Not since the heyday of poliomyelitis research . . .
Phase I Study of G3139, a <i>bcl-2</i> Antisense Oligonucleotide, Combined With Carboplatin and Etoposide in Patients With Small-Cell Lung Cancer
Authors: Charles M. Rudin, Mark Kozloff, Philip C. Hoffman, Martin J. Edelman, Robyn Karnauskas, Ronald Tomek, Livia Szeto, Everett E. Vokes
Journal: Journal of Clinical Oncology (2004)

Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC.Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated.Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed.The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.
Low lung volume alters contractile properties of airway smooth muscle in sheep
Authors: M.A. McClean, M.J. Matheson, K. McKay, P.R.A. Johnson, A-C. Rynell, A.J. Ammit, J.L. Black, N. Berend
Journal: European Respiratory Journal (2003)

Breathing at volumes lower than functional residual capacity (FRC) can induce changes in nonasthmatic airways consistent with the behaviour of asthmatic airways. This study investigated the chronic effect of breathing at volumes lower than FRC on the contractility of airway smooth muscle and myosin light chain kinase (MLCK) content and activity. Sheep of three age groups (neonate, adolescent and adult) had their FRC reduced by ∼25% for 4 weeks using a leather corset. Contractile responses to carbachol were then recorded in isolated tracheal strips and bronchial rings. MLCK content and activity were assessed by immunoblotting. The rate of stress generation increased in the bronchial smooth muscle of both adult and adolescent but not neonatal corseted sheep: adolescent corseted versus control, 65.0±4.1 versus 103.4±7.0 s (to reach 50% maximum stress), respectively; and adult corseted versus control, 57.0±6.4 versus 93.4±8.2 s, respectively. This was not due to increases in either bronchial or tracheal smooth muscle amount or MLCK content and activity. The present results indicate that chronic breathing at low lung volumes increases the rate of stress generation in airway smooth muscle.
Adjuvant Immunization of HLA-A2–Positive Melanoma Patients With a Modified gp100 Peptide Induces Peptide-Specific CD8<sup>+</sup>T-Cell Responses
Authors: John W. Smith, Edwin B. Walker, Bernard A. Fox, Daniel Haley, Ketura P. Wisner, Teri Doran, Brenda Fisher, Lisa Justice, William Wood, John Vetto, Holden Maecker, Annemiek Dols, Sybren Meijer, Hong-Ming Hu, Pedro Romero, W. Gregory Alvord, Walter J. Urba
Journal: Journal of Clinical Oncology (2003)

Purpose: To measure the CD8 + T-cell response to a melanoma peptide vaccine and to compare an every-2-weeks with an every-3-weeks vaccination schedule. Patients and Methods: Thirty HLA-A2–positive patients with resected stage I to III melanoma were randomly assigned to receive vaccinations every 2 weeks (13 vaccines) or every 3 weeks (nine vaccines) for 6 months. The synthetic, modified gp100 peptide, g209–2M, and a control peptide, HPV16 E7, were mixed in incomplete Freund’s adjuvant and injected subcutaneously. Peripheral blood mononuclear cells obtained before and after vaccination by leukapheresis were analyzed using a fluorescence-based HLA/peptide-tetramer binding assay and cytokine flow cytometry. Results: Vaccination induced an increase in peptide-specific T cells in 28 of 29 patients. The median frequency of CD8 + T cells specific for the g209–2M peptide increased markedly from 0.02% before to 0.34% after vaccination (P &lt; .0001). Eight patients (28%) exhibited peptide-specific CD8 + T-cell frequencies greater than 1%, including two patients with frequencies of 4.96% and 8.86%, respectively. Interferon alfa-2b–treated patients also had significant increases in tetramer-binding cells (P &lt; .0001). No difference was observed between the every-2-weeks and the every-3-weeks vaccination schedules (P = .59). Conclusion: Flow cytometric analysis of HLA/peptide-tetramer binding cells was a reliable means of quantifying the CD8 + T-cell response to peptide immunization. This assay may be suitable for use in future trials to optimize different vaccination strategies. Concurrent interferon treatment did not inhibit the development of a peptide-specific immune response and vaccination every 2 weeks, and every 3 weeks produced similar results.
Tumor Necrosis Factor Receptor 1/c-Jun-NH2-Kinase Signaling Promotes Human Neoplasia
Authors: Jennifer Y. Zhang, Amy E. Adams, Todd W. Ridky, Shiying Tao, Paul A. Khavari
Journal: Cancer Research (2007)

Abstract The tumor necrosis factor α receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH2-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers. [Cancer Res 2007;67(8):3827–34]
Financial conflicts should be included in online abstracts
Authors: M F. Freshwater
Journal: BMJ (2009)

There should be not only data transparency but also financial transparency.1 Most major medical journals have made financial disclosure mandatory. Yet, now that the internet allows free access to any biomedical abstract, readers of abstracts may be blinded to papers’ relevant financial disclosure unless they have a paid subscription to the journal.

I reviewed the ICMJE uniform requirements, the author instructions for 20 journals, including …
Pericardial Effusion, a Manifestation of Systemic Lupus Erythematosus
Authors: STANLEY S. BERGEN
Journal: Circulation (1960)

Four cases of systemic lupus erythematosus with pericardial effusion as a prominent manifestation are reported. Lack of awareness of this finding as a not infrequent part of the disease entity led to misdiagnosis in 2 instances and incorrect treatment in 1. The literature on the subject is reviewed and suggestions are offered for diagnosis.