tbuckley/cabot-search huggingface dataset:
Relationship between Sigma-like site and progesterone-binding site of adult male rat liver microsomes
Authors: Morio Yamada, Takashi Nishigami, Keiji Nakasho, Yukiyasu Nishimoto, Hideki Miyaji
Journal: Hepatology (1994)

An increasing amount of evidence suggests that the sigma (sigma) sites, putative targets for a variety of psychotomimetic and antipsychotic drugs, exist not only in the brain but also in various peripheral organs. However, there are many ambiguities as to their biological roles, subcellular distributions, endogenous ligands and so on. We therefore performed our study for clarification of some of these ambiguities. As a result, we demonstrated that adult male rat liver microsomes, especially smooth endoplasmic reticulum, possessed a saturable haloperidol-binding site closely resembling the sigma site, with a high affinity (Kd 1.0 +/- 0.3 nmol/L) and high capacity (Bmax 9.3 +/- 1.5 pmol/mg protein) and with the rank order of affinity of the ligands: haloperidol > reduced haloperidol > clorgyline > ifenprodil > 1,3-di(2-tolyl)guanidine, (-)-butaclamol > GBR-12909 > SKF-525A > progesterone > 5 alpha-dihydrotestosterone > R(+)-3- (hydroxyphenyl)-N-propylpiperidine > testosterone >> corticosteroids, estradiol-17 beta, cholesterol and neuroactive compounds displaying high affinities for other neurotransmitter receptors such as dopamine D2, serotonin (5-HT1A and 5-HT2) and alpha 1-adrenergic and GABAA receptors. This rank order showed a high correlation (r = 0.908) with that of a large portion (approximately 85%) of specific progesterone-binding site (Kd 31.0 +/- 3.5 nmol/L, Bmax 5.7 +/- 0.2 pmol/mg protein) of the same source. Therefore, these two sites were suggested to be the same or closely related. Furthermore, we provide a strong suggestion that these sites neither are identical with some subforms of the microsomal cytochromes P-450 or other steroid/drug-metabolizing enzymes nor participate universally and directly in the progesterone-metabolizing processes.
Effects of a Diet Higher in Carbohydrate/Lower in Fat Versus Lower in Carbohydrate/Higher in Monounsaturated Fat on Postmeal Triglyceride Concentrations and Other Cardiovascular Risk Factors in Type 1 Diabetes
Authors: Irene Strychar, Jeffrey S. Cohn, Geneviève Renier, Michèle Rivard, Nahla Aris-Jilwan, Hugues Beauregard, Sara Meltzer, André Bélanger, Richard Dumas, Alain Ishac, Farouk Radwan, Jean-François Yale
Journal: Diabetes Care (2009)

OBJECTIVE To compare the effects of a eucaloric diet higher in carbohydrate/lower in fat versus lower in carbohydrate/higher in monounsaturated fat on postmeal triglyceride (TG) concentrations and other cardiovascular disease risk factors in nonobese subjects with type 1 diabetes and in good glycemic control. RESEARCH DESIGN AND METHODS In a parallel group design study, 30 subjects were randomly assigned and completed one of the two eucaloric diets. Assessments included: BMI, blood pressure, A1C, plasma lipids, and markers of oxidation, thrombosis, and inflammation. At 6 months, subjects were hospitalized for 24 h to measure plasma TG excursions. RESULTS There were no significant differences between groups other than decreased plasminogen activator inhibitor 1 (PAI-1) levels and weight gain in the lower-carbohydrate/higher–monounsaturated fat group. During the 24-h testing, the lower-carbohydrate/higher–monounsaturated fat group had a lower plasma TG profile. CONCLUSIONS A diet lower in carbohydrate/higher in monounsaturated fat could offer an appropriate choice for nonobese type 1 diabetic individuals with good metabolic and weight control.
A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice
Authors: Rebecca Kinkade, Piyali Dasgupta, Adam Carie, Daniele Pernazza, Melanie Carless, Smitha Pillai, Nicholas Lawrence, Said M. Sebti, Srikumar Chellappan
Journal: Cancer Research (2008)

Abstract Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251–mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810–8]
Novel fibrinogen γ375 Arg→Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia
Authors: Stephen O. Brennan, Ghassan Maghzal, Benjamin L. Shneider, Ronald Gordon, Margret S. Magid, Peter M. George
Journal: Hepatology (2002)

The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti-fibrinogen antisera; on electron-microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG→TGG mutation at codon 375 of the fibrinogen γ chain gene. This novel γ375 Arg→Trp substitution segregated with hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse-phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal γ chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed hypofibrinogenemia. Whereas the mutation site, γ375, is located in the γD domain at the jaws of the primary E-to-D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.
AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency
Authors: Kathy Jaworski, Maryam Ahmadian, Robin E Duncan, Eszter Sarkadi-Nagy, Krista A Varady, Marc K Hellerstein, Hui-Young Lee, Varman T Samuel, Gerald I Shulman, Kee-Hong Kim, Sarah de Val, Chulho Kang, Hei Sook Sul
Journal: Nature Medicine (2009)
Reducing the toll of road traffic accidents
Authors: C. D R Dunn, A. S Christophersen
Journal: Journal of the Royal Society of Medicine (2003)

Rodger Charlton and Gary Smith (October 2003 JRSM1) draw attention to several modifiable factors that might reduce the toll of road traffic accidents, but overlook another that may be under-recognized in the UK— prescription and over-the-counter medicines and illicit drugs. In addition to the well-known side-effects of the antidepressants, over a hundred medicines (antihistamines, opioids, muscarinic antagonists) have been recognized as impairing performance.2 While the incidence of involvement of medicines in UK accidents has been reported to be fairly static at 6%,2 studies in Scandinavia (where the adverse potential of medicines seems to have a higher profile) suggest medicines and/or illicit drugs may be implicated in more than 20% of single-vehicle fatal accidents.3 Although the total number of apprehensions by Norwegian police for accidents, dangerous or erratic driving due to a suspicion of influence by alcohol or medicines and/or illicit drugs has remained relatively constant since 1983, those associated with alcohol have declined, with an increase in cases linked to medicines and/or drugs.4,5 Furthermore, compared with 'drunk' drivers, those arrested for 'drugged' driving have a higher standardized mortality ratio6 and are more likely to re-offend.7 Impaired driving during the morning after taking a hypnotic (barbiturate, benzodiazepine, or zopiclone) returned to 'control' levels in the afternoon.8 In Canada, compared with 'undrugged' drivers, those taking a hypnotic for the first time had an odds ratio of 9.1 for acquiring a road-accident-related injury during the initial week, and 13.5 while taking an anxiolytic.9 These ratios declined to 3.9 and 2.5, respectively, after four weeks.
HER-2/neu Status Is a Determinant of Mammary Aromatase Activity <i>In vivo</i>: Evidence for a Cyclooxygenase-2-Dependent Mechanism
Authors: Kotha Subbaramaiah, Louise R. Howe, Elisa R. Port, Edi Brogi, Jack Fishman, Catherine H. Liu, Timothy Hla, Clifford Hudis, Andrew J. Dannenberg
Journal: Cancer Research (2006)

Abstract Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Given the significance of estrogen synthesis in hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 expression. The main objective of this study was to define the interrelationship between HER-2/neu, cyclooxygenase-2 (COX-2), and aromatase in mammary tissue. Mammary aromatase activity and prostaglandin E2 (PGE2) levels were increased in mice with mammary-targeted expression of a COX-2 transgene. In vitro, overexpressing COX-2 caused both increased PGE2 production and aromatase activity, effects that were suppressed by celecoxib, a selective COX-2 inhibitor. Previously, we found that overexpression of HER-2/neu was associated with increased levels of COX-2 in human breast cancers. Here, we show that overexpression of HER-2/neu is also associated with increased aromatase activity. These results suggested the possibility that COX-2 was the functional intermediate linking HER-2/neu and aromatase. Consistent with this idea, COX-2 deficiency led to a gene dose-dependent reduction in mammary aromatase activity in a HER-2/neu transgenic mouse model. Complementary in vitro studies showed that HER-2/neu–mediated induction of PGE2 synthesis and aromatase activity were suppressed by inhibiting COX-2. Collectively, our data indicate that COX-2 is the functional intermediate linking HER-2/neu and aromatase and suggest that inhibitors of PGE2 synthesis will suppress estrogen biosynthesis in breast tissue. (Cancer Res 2006; 66(10): 5504-11)
The Chronic Kidney Disease Initiative
Authors: Thomas F. Parker, Roland Blantz, Thomas Hostetter, Jonathan Himmelfarb, Alan Kliger, Michael Lazarus, Allen R. Nissenson, Brian Pereira, James Weiss
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The Chronic Kidney Disease Initiative was implemented at the request of the Council of American Kidney Societies to formulate a plan of action to solve many of the perceived problems associated with identifying, caring for, and attaining the best outcomes for patients with chronic kidney disease. With the assistance of a community of stakeholders and a formalized workshop and process, the Chronic Kidney Disease Initiative identified the barriers to solving this complicated problem. Barriers were given hierarchal significance, and solutions and action plans to the barriers were formulated. This article describes the process, the barriers encountered, and the solutions required to fully identify and manage this large and complicated population of patients.
Non-Nicotinic Therapies for Smoking Cessation
Authors: Eric C.K. Siu, Rachel F. Tyndale
Journal: The Annual Review of Pharmacology and Toxicology (2007)

Cigarette smoking is the primary cause of numerous preventable diseases; as such, the goals of smoking cessation are both to reduce health risks and to improve the quality of life. Currently, the first-line smoking cessation therapies include nicotine replacement products and bupropion. The nicotinic receptor partial agonist varenicline has recently been approved by the FDA for smoking cessation. A newer product currently under development and seeking approval by the FDA are nicotine vaccines. Clonidine and nortriptyline have demonstrated some efficacy but side effects may limit their use to second-line therapeutic products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine receptor D3 antagonists. Inhibitors of nicotine metabolism are also promising candidates for smoking reduction and cessation. In conclusion, promising new therapeutic products are emerging and they will provide smokers additional options to assist in achieving smoking cessation.
Second Primary Malignances (Spms) in Patients (P) with Gastrointestinal Stromal Tumors (Gists) – a Coincidence or an Effect of Imatinib?
Authors: A. Estival, O. Etxaniz, J.L. Cuadra Urteaga, M. Romeo, I. Blanco, M. Gil, S. Ahlal, I. Ojanguren, A. Indacochea, L. Vila, C. Balana
Journal: Annals of Oncology (2014)
<i>Stenotrophomonas maltophilia</i> in Cystic Fibrosis
Authors: Valerie Waters, Yvonne Yau, Sudha Prasad, Annie Lu, Eshetu Atenafu, Ian Crandall, Stephanie Tom, Elizabeth Tullis, Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Stenotrophomonas maltophilia is one of the more common multidrug-resistant organisms isolated from the respiratory tract of patients with cystic fibrosis (CF), but the effect of chronic S. maltophilia infection on CF lung disease is unknown.To determine the impact of chronic S. maltophilia infection on lung disease in CF.We developed a serologic assay specific for S. maltophilia and in a cross-sectional study, measured serum antibodies to S. maltophilia in patients with CF to determine if a definition of chronic S. maltophilia isolation based on culture results corresponded to an immunologic response (serologic study). We then used this validated definition to examine the effect of chronic S. maltophilia on the severity of lung disease in a retrospective cohort study using the Toronto CF Database from 1997-2008 (cohort study).Serum antibody levels to S. maltophilia were measured in 179 patients with CF. Patients with chronic S. maltophilia had significantly higher mean antibody levels to S. maltophilia flagellin (P < 0.0001) and whole cell (P = 0.0004) compared with patients with intermittent or no S. maltophilia. The cohort study included 692 patients with an average follow-up of 8.3 years. In an adjusted log linear model, patients with chronic S. maltophilia infection had a significantly increased risk of pulmonary exacerbation requiring hospitalization and antibiotics compared with patients who had never had S. maltophilia (relative risk = 1.63; P = 0.0002).Chronic S. maltophilia infection in patients with CF is associated with a specific immune response to this organism and is an independent risk factor for pulmonary exacerbations.
Regulation of class switch recombination and somatic mutation by AID phosphorylation
Authors: Kevin M. McBride, Anna Gazumyan, Eileen M. Woo, Tanja A. Schwickert, Brian T. Chait, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2008)

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching.
Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer
Authors: Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Petri Bono, Tuomo Alanko, Vesa Kataja, Raija Asola, Tapio Utriainen, Riitta Kokko, Akseli Hemminki, Maija Tarkkanen, Taina Turpeenniemi-Hujanen, Sirkku Jyrkkiö, Martti Flander, Leena Helle, Seija Ingalsuo, Kaisu Johansson, Anna-Stina Jääskeläinen, Marjo Pajunen, Mervi Rauhala, Jaana Kaleva-Kerola, Tapio Salminen, Mika Leinonen, Inkeri Elomaa, Jorma Isola
Journal: New England Journal of Medicine (2006)

We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment.We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival.Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure.Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).
A National Cancer Institute of Canada Clinical Trials Group phase II study of eniluracil (776C85) and oral 5-fluorouracil in patients with advanced squamous cell head and neck cancer
Authors: M. Knowling, G. Browman, L. Siu, K. Khoo, A. Cooke, I. Tannock, D. Klaassen, G. Cripps, G. Goss, S. Matthews, R. Clarke, L. Seymour
Journal: Annals of Oncology (2001)
Double tracer gas single breath washout – Comparison with conventional lung function tests in children with and without cystic fibrosis
Authors: Florian Singer, Chiara Abbas, Georgette Stern, Elisabeth Kieninger, Oliver Fuchs, Nicolas Regamey, Per Gustafsson, Carmen Casaulta, Urs Frey, Philipp Latzin
Journal: European Respiratory Journal (2011)

A tidal single breath washout (SBW) has been shown to have potential as new lung function test. We calculated indices describing the shape of the SBW curve, and investigated their variability and association with conventional lung function tests in cystic fibrosis (CF) and healthy children.  70 CF children, mean (SD) age 11.7 (3.5) years, and 42 healthy children aged 11.5 (3.9) years performed nitrogen multiple breath washout (MBW) and helium and sulfur hexafluoride SBW using a side-stream ultrasonic flowmeter (Eco Medics AG). 8 CF children and 10 controls performed MBW and SBW on a second day. Molar mass (MM) SBW curves were plotted vs. expired volume. MM-slopes of tidal phase II and III (MM_SII; MM_SIII), and area under the MM curve (AUC) were calculated. Mean (SD) between-test coefficient of variation (CV%) for MM_SIII, MM_SII, and AUC was 15.5 (13.3)%, 15.3 (11.4)%, and 8.7 (6.5)%, respectively. All three CV% were similar between CF and healthy children. MM_SIII was associated with expired tidal volume (TV) and mean tidal flow (MTEF), and MM_SII with TV. MM_SIII and MM_SII differed significantly between CF and healthy children. MM_SIII and MM_SII were associated with the lung clearance index (p  We identified double tracer gas SBW indices reliably characterizing ventilation inhomogeneity (VI) and separating healthy from CF children despite considerable overlap. More detailed analyses are needed to better understand underlying pathophysiological phenomena and to obtain additional yet unknown information on VI from this test.
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials
Authors: Kausik K Ray, Sreenivasa Rao Kondapally Seshasai, Shanelle Wijesuriya, Rupa Sivakumaran, Sarah Nethercott, David Preiss, Sebhat Erqou, Naveed Sattar
Journal: The Lancet (2009)
Implantable cardioverter defibrillator therapy in a patient with cardiac amyloidosis
Authors: Mitsuru Itoh, Konosuke Ohmori, Kenichiro Yata, Hideho Wada, Tetsuo Tsuchiya, Noriko Okahashi, Sohei Hamanaka, Kiyoshi Yoshida, Kazuo Tanemoto, Takashi Sugihara
Journal: American Journal of Hematology (2006)

To the Editor: Various hematological malignancies