tbuckley/cabot-search huggingface dataset:
Glucagon-stimulable adenylyl cyclase in rat liver. Effects of chronic uremia and intermittent glucagon administration.
Authors: R R Dighe, F J Rojas, L Birnbaumer, A J Garber
Journal: Journal of Clinical Investigation (1984)

The effects of chronic uremia and glucagon administration on glucagon-stimulable adenylyl cyclase in rat liver were assessed by determinations of adenylyl cyclase activities, specific iodoglucagon binding, and the activity of the stimulatory regulatory component of adenylyl cyclase. Glucagon-stimulated adenylyl cyclase was reduced in uremia to 75-80% of control levels (P less than 0.05), in the presence or absence of saturating levels of guanosine triphosphate (GTP) and 5'-guanylylimidodiphosphate [GMP-P(NH)P]. Although these changes were accompanied by a concomitant 20% reduction in sodium fluoride-stimulated activity, basal, GTP-, GMP-P(NH)P-, and manganese-dependent adenylyl cyclase activities were unchanged. Using [125I-Tyr10]monoiodoglucagon as a receptor probe, the number of high affinity glucagon-binding sites was reduced 28% (P less than 0.01) in uremic as compared with control liver membranes. However, the affinity of these binding sites was unaltered. The S49 cyc- -reconstituting activity with respect to both GMP-P(NH)P- and isoproterenol plus GTP-stimulable adenylyl cyclase was unaltered in membranes from uremic as compared with control rats. Intermittent glucagon (80-100 micrograms) injections administered at 8-h intervals to normal rats reproduced all of the above described effects of chronic experimental uremia on the adenylyl cyclase system. It is concluded that changes in the hormone-stimulable adenylyl cyclase complex in uremia and with glucagon treatment result primarily from a decrease in the number of hormone-specific receptor sites in hepatic plasma membranes. Since the changes in liver adenylyl cyclase are qualitatively and quantitatively the same in glucagon-treated and uremic rats, it is suggested that these may be the result of the hyperglucagonemia of uremia. Further, the data reveal an unexpected dissociation between guanine nucleotide and sodium fluoride stimulation of adenylyl cyclase. Possible causes for this dissociation based on the known subunit composition of cyclase coupling proteins are discussed.
Multidrug resistance emerging in North London outbreak
Authors: H Maguire
Journal: Thorax (2006)

We write on behalf of the Outbreak Control Committee (OCC) investigating an outbreak of isoniazid monoresistant tuberculosis (TB) affecting over 260 cases (222 in London) to alert clinicians about recent transmission of a multidrug resistant (MDRTB) component with unusual characteristics.

A unique genetic fingerprint on Restriction Fragment Length Polymorphism (RFLP) typing1 at the Health Protection Agency Mycobacterium Reference Unit (HPA MRU) has …
Plasma Clearance Rates and Renal Clearance of 3H-labeled Cyclic AMP and 3H-labeled Cyclic GMP in the Dog
Authors: Lawrence Blonde, Robert E. Wehmann, Alton L. Steiner
Journal: Journal of Clinical Investigation (1974)

Previously, in an attempt to understand the mechanisms involved in the regulation of plasma cyclic nucleotides, we measured concentrations of adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5'-monophosphate (cGMP) in plasma from selected blood vessels of anesthetized dogs. The observation that the renal venous plasma concentrations of both cyclic nucleotides were less than arterial concentrations suggested that the kidney might be an important site for the elimination of these compounds from plasma and prompted further investigation of the renal handling of these compounds. Tracer doses of either [(3)H]cAMP or [(3)H]cGMP were administered to anesthetized dogs by constant intravenous infusion, and metabolic clearance rates were determined. Concentrations of endogenous cyclic nucleotide and of cyclic nucleotide radioactivity were measured in aortic and renal venous plasma as well as in urine. Renal venous plasma [(3)H]cGMP was 39% and [(3)H]cAMP was 65% of the concentration in arterial plasma. Endogenous cyclic nucleotide levels showed a similar relationship. The plasma clearance rates (PCR) were 271+/-27 ml/min (mean+/-SE) for cGMP and 261+/-17 for cAMP. The total kidney clearance (calculated as the renal plasma flow x renal cyclic nucleotide extraction ratio) accounted for 52+/-4% and 30+/-2% of the PCR for cGMP and cAMP, respectively. Only about two-thirds of the total kidney clearance of each cyclic nucleotide could be accounted for by urinary excretion, the remainder presumably being the result of renal metabolism. The urinary clearances of (3)H-labeled cGMP (40.9+/-4.2 ml/min) and endogenous cGMP (45.0+/-2.3 ml/min) were not significantly different from each other. Both were approximately 50% greater than the glomerular filtration rate, which was 27.1+/-2.0 ml/min, indicating that a significant amount of urinary cGMP is derived from plasma by tubular secretion. In contrast, the urinary clearances of (3)H-labeled cAMP (23.7+/-1.9 ml/min) and endogenous cAMP (27.2+/-2.6 ml/min) were nearly equal both to each other and to the glomerular filtration rate, which was 24.6+/-1.7 ml/min. Thus, in the dog, glomerular filtration of plasma cAMP appears to be responsible for most of the cAMP found in urine. Renla production of cAMP, which in humans contributes from a third to a half of the urinary cAMP, was quantitatively of minor importance in the dog.Thus, under the conditions of these experiments in dogs, renal elimination appears to be responsible for half of the PCR of cGMP and about a third of the PCR of cAMP. About a third of the renal elimination of both cyclic nucleotides appears to be due to metabolic degradation within the kidney, and the balance is due to excretion in the urine.
Osteoprotogerin plasma concentrations is correlate with forced expiratory volume at 1 second (FEV1) in patients with COPD
Authors: Levent Cem Mutlu, Mustafa Oran, Savas Güzel, Okan Avci, Banu Çiçek Yalçin, Volkan Küçükyalçin
Journal: European Respiratory Journal (2013)

Background  Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation and inflammation of the respiratory tract which causes significant morbidity and mortality. Several inflammatory biomarkers have been evaluated in stable and during exacerbations of the disease. Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family which reported to be expressed in lung and macrophages.  Aim:  The objective of the study was to evaluate the serum level of OPG and its corellation with forced expiratory volume at 1 second (FEV1) in patients with COPD and healthy volunteers.  Methods  The study was conducted between June 2011 and October 2012 in the pulmonology outptient clinic of the medical school in Namik Kemal University. The main inclusion criteria for COPD patients were; age of ≥ 40 years; experience smoking ≥ 10 pack/years and no other clinically significant disease. Control group were selected from non-smoking gender- and age-matched healthy volunteers.  Results  A total of 70 subjects (47 patients with COPD aged 61,9 ± 9,5 years and 23 healthy nonsmokers aged 58,4 ± 8,7) were recruited into study. Plasma OPG concentrations with COPD patients (8,61±4,4,78 ng/ml) were higher than healthy control group (6,29±1,36 ng/ml), the difference was found statically significant p   Conclusion:  Although we have found OPG levels higher in COPD patients and correlated with FEV1. larger and longitudinal studies will be required to use OPG as a biomarker of lung function in COPD patients.
Can the “Right” EGFR-Specific mAb Dramatically Improve EGFR-Targeted Therapy?
Authors: Francesco Sabbatino, Soldano Ferrone
Journal: Clinical Cancer Research (2013)

EGF receptor (EGFR)-specific monoclonal antibodies (mAb) display limited therapeutic efficacy in EGFR-positive solid tumors. To overcome this limitation, the significant improvement of the antibody-dependent cell-mediated cytotoxicity-mediated antitumor activity of a novel EGFR-specific mAb is described. Its potential impact on the efficacy of immunotherapy for EGFR-positive solid tumors is discussed.
Is the carbon monoxide transfer factor diminished in the presence of diabetic retinopathy in patients with insulin-dependent diabetes mellitus?
Authors: J Britton
Journal: European Respiratory Journal (1988)

Impaired carbon monoxide gas transfer has been demonstrated in patients with insulin-dependent diabetes mellitus (IDDM), but no relationship has been documented between impairment of gas transfer and the presence of other clinical evidence of diabetic microangiopathy. This study set out to determine whether carbon monoxide gas transfer was related to the presence of microangiopathy by measuring the carbon monoxide transfer coefficient (KCO) in twenty patients with IDDM complicated by retinopathy, and in twenty patients without retinopathy. The patients were reasonably matched for age (mean 47 yrs in the retinopathy group, 41 yrs in the non-retinopathy group) but those with retinopathy had a longer mean duration of diabetes (23 yrs vs 13 yrs). Carbon monoxide transfer coefficient was normal in both groups, with no significant difference between them. Values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were lower than predicted in the retinopathy group (92 (SEM 3.6%) and 91 (SEM 4.0%) respectively, p less than 0.05) but were not significantly different from those in the non-retinopathy group. This study demonstrates normal lung function in IDDM, with no relationship between impairment of gas transfer and the presence of microangiopathy elsewhere.
Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain
Authors: Frederick P Bellinger, Miyoko T Bellinger, Lucia A Seale, Andrea S Takemoto, Arjun V Raman, Takanori Miki, Amy B Manning-Boğ, Marla J Berry, Lon R White, G Ross
Journal: Molecular Neurodegeneration (2011)

Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.
Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis
Authors: Song Li, Baolu Wang, Yan Xu, Junjie Zhang
Journal: Molecular Cancer (2011)

Abstract Background Autotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown. Results In the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis. Conclusions We have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer.
Lung mucosal immunity: immunoglobulin‐A revisited
Authors: C Pilette, Y Ouadrhiri, V Godding, J P Vaerman, Y Sibille
Journal: European Respiratory Journal (2002)

Mucosal defence mechanisms are critical in preventing colonization of the respiratory tract by pathogens and penetration of antigens through the epithelial barrier. Recent research has now illustrated the active contribution of the respiratory epithelium to the exclusion of microbes and particles, but also to the control of the inflammatory and immune responses in the airways and in the alveoli. Epithelial cells also mediate the active transport of polymeric immunoglobulin-A from the lamina propria to the airway lumen through the polymeric immunoglobulin receptor. The role of IgA in the defence of mucosal surfaces has now expanded from a limited role of scavenger of exogenous material to a broader protective function with potential applications in immunotherapy. In addition, the recent identification of receptors for IgA on the surface of blood leukocytes and alveolar macrophages provides an additional mechanism of interaction between the cellular and humoral immune systems at the level of the respiratory tract.
Chronic stress at work and the metabolic syndrome: prospective study
Authors: Tarani Chandola, Eric Brunner, Michael Marmot
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objectives</b> To investigate the association between stress at work and the metabolic syndrome. <b>Design</b> Prospective cohort study investigating the association between work stress and the metabolic syndrome. <b>Participants</b> 10 308 men and women, aged 35-55, employed in 20 London civil service departments at baseline (the Whitehall II study); follow-up was an average of 14 years. <b>Main outcome measures</b> Work stress based on the iso-strain model, measured on four occasions (1985-99). Biological measures of the metabolic syndrome, based on the National Cholesterol Education Program definition, measured in 1997-9. <b>Results</b> A dose-response relation was found between exposure to work stressors over 14 years and risk of the metabolic syndrome, independent of other relevant risk factors. Employees with chronic work stress (three or more exposures) were more than twice as likely to have the syndrome than those without work stress (odds ratio adjusted for age and employment grade 2.25, 95% confidence interval 1.31 to 3.85). <b>Conclusions</b> Stress at work is an important risk factor for the metabolic syndrome. The study provides evidence for the biological plausibility of the link between psychosocial stressors from everyday life and heart disease.
Gemcitabine intercellular diffusion mediated by gap junctions: new implications for cancer therapy
Authors: Sylvine Cottin, Karim Ghani, Pedro Otavio de Campos-Lima, Manuel Caruso
Journal: Molecular Cancer (2010)

Abstract Background Solid tumors are often poorly vascularized, with cells that can be 100 μm away from blood vessels. These distant cells get less oxygen and nutrients and are exposed to lower doses of chemotherapeutic agents. As gap junctions allow the passage of small molecules between cells, we tested the possibility that the chemotherapeutic agent gemcitabine can diffuse through gap junctions in solid tumors. Results We first showed with a dye transfer assay that the glioblastoma and the osteosarcoma cells used in this study have functional gap junctions. These cells were genetically engineered to express the herpes simplex virus thymidine kinase (TK), and induced a "bystander effect" as demonstrated by the killing of TK-negative cells in presence of the nucleoside analogue ganciclovir (GCV). The ability of gemcitabine to induce a similar bystander effect was then tested by mixing cells treated with 3 μM gemcitabine for 24 hours with untreated cells at different ratios. In all cell lines tested, bystander cells were killed with ratios containing as low as 5% treated cells, and this toxic effect was reduced in presence of α-glycyrrhetinic acid (AGA), a specific gap junction inhibitor. We also showed that a 2- or a 24-hour gemcitabine treatment was more efficient to inhibit the growth of spheroids with functional gap junctions as compared to the same treatment made in presence of AGA. Finally, after a 24-hour gemcitabine treatment, the cell viability in spheroids was reduced by 92% as opposed to 51% in presence of AGA. Conclusion These results indicate that gemcitabine-mediated toxicity can diffuse through gap junctions, and they suggest that gemcitabine treatment could be more efficient for treating solid tumors that display gap junctions. The presence of these cellular channels could be used to predict the responsiveness to this nucleoside analogue therapy.
Intrinsic Mechanism of Estradiol-Induced Apoptosis in Breast Cancer Cells Resistant to Estrogen Deprivation
Authors: Joan S. Lewis, Kathleen Meeke, Clodia Osipo, Eric A. Ross, Noman Kidawi, Tianyu Li, Eric Bell, Navdeep S. Chandel, V. Craig Jordan
Journal: JNCI Journal of the National Cancer Institute (2005)

We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process.Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided.MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P < .001], 85% [95% CI = 90% to 80%, P < .001], and 40% [95% CI = 45% to 35%, P < .001], respectively, whereas blockade of FasL by siRNA had no effect. Estradiol caused complete regression of MCF-7:5C tumors in vivo.The mitochondrial pathway of apoptosis plays a critical role in estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.
GLP-1–Based Therapy for Diabetes: What You Do Not Know Can Hurt You
Authors: Peter C. Butler, Sarah Dry, Robert Elashoff
Journal: Diabetes Care (2010)

According to the Oxford Dictionary of Proverbs , the oldest written version of the saying “What you don't know can't hurt you” comes from Petit Palace , written in 1576 by G. Pettie: “So long as I know it not, it hurteth mee not.”

In this issue of Diabetes Care , Drucker et al. (1) conclude that the safety profile of the newly available glucagon-like peptide 1 (GLP-1) class of drugs is favorable in comparison to their benefits as therapy, and the class of drugs might be considered as next in line after metformin for treatment for type 2 diabetes. The purpose of this counterpoint is to suggest such a conclusion is premature. History has taught us that enthusiasm for new classes of drugs, heavily promoted by the pharmaceutical companies that market them, can obscure the caution that should be exercised when the long-term consequences are unknown. Of perhaps greatest concern in the case of the GLP-1–based drugs, including GLP-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, is preliminary evidence to suggest the potential risks of asymptomatic chronic pancreatitis and, with time, pancreatic cancer.

The GLP-1–related drugs arrived in clinical practice with much fanfare and anticipation. As summarized in the article by Drucker et al., it is a class of drugs that has potential benefits in the treatment of type 2 diabetes. The concept of gut-related factors that enhance glucose-mediated insulin secretion, the incretin effect, has been recognized for many years (2). Once it was demonstrated that an intravenous infusion of GLP-1 could decrease blood glucose concentrations in patients with type 2 diabetes, the race was on to exploit the properties of this action. Many millions of dollars have been invested by the pharmaceutical industry in developing products, the first of which are now in clinical practice. Many millions of dollars …