tbuckley/cabot-search huggingface dataset:
Abstract 4486: 5-Hydroxymethyl-2’-deoxyuridine, but not temozolomide, enhances the selective synthetic lethality in BRCA1 and BRCA2-deficient cells caused by PARP inhibition.
Authors: Jean Clement, Jun Nakamura
Journal: Cancer Research (2013)

Abstract Inhibition of poly(ADP-ribose) polymerase (PARP) has been determined as an attractive chemotherapeutic treatment for homologous recombination (HR)-deficient tumors. PARP is involved in repairing DNA single strand breaks (SSBs) via the base excision repair (BER) pathway; therefore, PARP inhibitor (PARPi) leads to an accumulation of DNA double strand breaks (DSBs) at the sites of SSBs during DNA replication. While the cytotoxic effect of PARPi was demonstrated to be potentiated by addition of genotoxic alkylating agent temozolomide (TMZ), it is not clear that this combined treatment further increases selectivity to cause cell death in HR-deficient cells, such as BRCA-deficient cells, over HR-proficient cells. TMZ randomly increases SSBs at scattered locations in the genome; in contrast, incorporation of 5-hydroxymethyl-2’-deoxyuridine (5-HmedU) in DNA has a potential to cause multiple SSBs within a short distance during BER. We hypothesized that a combination treatment of PARPi and 5-hmedU could increase selectivity of PARPi-mediated cytotoxicity in HR-deficient cells more so than the PARPi and TMZ combination. Here we show that in single chemical treatment experiments, the IC50 of 5-HmedU was eight times lower in BRCA1-/- and BRCA2-/- mutant cells, but in TMZ treatments the IC50 was only two times lower compared HR-proficient cells. Furthermore, the 5-HmedU and PARPi agent Olaparib combination enhanced a synergistic cell killing effect in BRCA1-/- and BRCA2-/- mutant cells with higher selectivity than the PARPi and TMZ combination. Advantages of the 5-HmedU and PARPi combination is as follows: 1] 5-HmedU causes DNA damage through vast genome incorporation in highly proliferating cells. Thus, 5-HmedU is more effective at selecting highly proliferating tumor cells; 2] 5-HmedU single treatment more selectively targeted BRCA1-/- and BRCA2-/- mutant cells than TMZ. This selectivity could be due to more efficient DSB formation by 5-HmedU through accumulation of clustered SSBs; and 3] combination treatment of 5-HmedU and PARPi produces a synergistic selectivity to kill HR-deficient BRCA1-/- and BRCA2-/- mutant cells whereas TMZ and PARPi combination does not. A possible mechanism of the selective cell killing effect by 5-HmedU and PARPi could result from an accumulation of closely located DSBs with PARP-DNA strand break complexes in HR-deficient cells. Citation Format: Jean Clement, Jun Nakamura. 5-Hydroxymethyl-2’-deoxyuridine, but not temozolomide, enhances the selective synthetic lethality in BRCA1 and BRCA2-deficient cells caused by PARP inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2013-4486
Institute proposes programme to meet the health needs of older people
Authors: M. Gould
Journal: BMJ (2008)

An old age version of the Sure Start programme for children, which brings together health, social care, and support, is vital to halt a decline in mental health and wellbeing among people aged over 65, says an influential left leaning think tank.

The Institute for Public Policy Research concludes that older people’s health and wellbeing is “severely neglected” and policies focus on the young. It says depressive illness is under-recognised in older people despite the fact that a recorded 2.4 million older people have a depressive illness that impairs their quality of life and is a major reason for admission to nursing …
Immunological studies on mice exposed subacutely to methyl isocyanate.
Authors: A N Tucker, J R Bucher, D R Germolec, M T Silver, S J Vore, M I Luster
Journal: Environmental Health Perspectives (1987)

The immunotoxicity of methyl isocyanate (MIC) was evaluated in female B6C3F1 mice exposed via inhalation to 0, 1, or 3 ppm for 6 hr per day on 4 consecutive days. The antibody response to sheep erythrocytes and natural killer cell activity were found to be unaffected by MIC exposure. Although lymphoproliferative responses to mitogens were moderately suppressed by MIC, the differences were not statistically significant. The response of splenic lymphocytes to allogeneic leukocytes in a mixed leukocyte response (MLR) was suppressed in a dose-related fashion and was significantly different from the control response at the 3 ppm level. This effect was thought to be secondary and a result of general toxicity, rather than a direct effect of MIC on the immune system. Furthermore, resistance to the infectious agents Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to transplantable tumor cells was not compromised by MIC exposure. Thus, the immune system does not appear to be a primary target for MIC toxicity.
Antithrombotic Effects of Orally Active Synthetic Antagonist of Activated Factor X in Nonhuman Primates
Authors: Toru Yokoyama, Andrew B. Kelly, Ulla M. Marzec, Stephen R. Hanson, Satoshi Kunitada, Laurence A. Harker
Journal: Circulation (1995)

Background Since activated factor X (FXa) has a central role in hemostasis and thrombosis, it is an attractive target for antithrombotic strategies. Accordingly, we evaluated the relative antihemostatic and antithrombotic effects of an orally active amidinoaryl propanoic acid inhibitor of FXa, APAP, in baboons. Methods and Results With a two-component thrombogenic device that induced the concurrent formation of both arterial-type platelet-rich and venous-type fibrin-rich thrombus when interposed in chronic exteriorized arteriovenous (AV) femoral shunts flowing at 40 mL/min, thrombus formation was compared for oral versus parenteral APAP by measurement of 111 In-platelet deposition, 125 I-fibrin accumulation, thrombotic obstruction of flow, and circulating levels of blood biochemical markers of thrombosis. The direct infusion of APAP (120 μg/min) into AV shunts proximal to thrombogenic devices for 1 hour achieved local drug levels of 4.3±0.4 mg/L and substantially reduced the accumulation of platelets and fibrin in the formation of venous-type fibrin-rich thrombus ( P &lt;.01) but not in the formation of platelet-rich arterial-type thrombus ( P &gt;.1). APAP was subsequently removed from plasma with plasma clearance rates of T 50 α of 6.3 minutes and T 50 β of 99 minutes. The oral administration of APAP (50 mg/kg) produced peak plasma levels of 3.7±1.4 μg/mL at 30 minutes and gradually declining plasma levels over about 6 to 8 hours, with bioavailability estimated to be approximately 5% to 12%. Oral APAP decreased platelet deposition ( P &lt;.01) and fibrin accumulation ( P &lt;.05) in venous-type thrombus but failed to decrease platelet or fibrin accumulation in arterial-type thrombus ( P &gt;.1 in both cases). Oral and infused APAP prolonged the activated partial thromboplastin time and prevented thrombus-dependent elevations in plasma fibrinopeptide A, thrombin–antithrombin III complex, β-thromboglobulin, and platelet factor 4 levels. Additionally, APAP produced dose-dependent inhibition of FXa bound to thrombus on segments of vascular graft interposed in exteriorized AV shunts for 15 minutes. Conclusions An oral synthetic antagonist of FXa, APAP, inhibits the formation of venous-type fibrin-rich thrombus by inactivating bound and soluble FXa without impairing platelet hemostatic function.
Role of membrane permeabilities (calcium, chloride, and potassium) in the genesis of the notch observed on simian and prosimian cardiac action potentials
Authors: P. KREHER
Journal: Cardiovascular Research (1978)

The effect of temperature reduction on monkey ventricular action potentials has been studied. Under this condition the genesis of a notch separating the AP spike from the AP plateau has been related either to a conduction phenomenon or to a delay in the activation of the slow inward current. It is observed that the development of a notch at the beginning of the plateau depends both on the presence of a large outward, repolarising current, carried by chloride and/or potassium ions, and on the presence of a slow inward calcium current large enough to depolarise the membrane as the chloride current deactivates.
Age as a Risk Factor for Inadequate Treatment
Authors: Vittorina Zagonel, Umberto Tirelli
Journal: JAMA (1988)

<h3>To the Editor.</h3> —We don't agree with Dr Wetle<sup>1</sup>that "elders tolerate [chemotherapy] as well as or better than younger patients." In contrast to Dr Wetle's interpretation, the preliminary Eastern Cooperative Oncology Group data reported in 1983 by Begg and Carbone<sup>2</sup>actually did show increased toxic reactions in elderly patients with eight different solid cancers who had received methotrexate or lomustine. In addition, as acknowledged by the authors, there had been some selection bias against elderly patients in these studies and the median age had not been reported. These results therefore cannot be considered as being representative of the total elderly population with cancer. Other studies on the treatment of elderly patients with cancer suggest that chemotherapy-related toxic reactions occur more often than in younger patients. Armitage and Potter<sup>3</sup>retrospectively evaluated the outcome of 20 patients 70 years of age or older with diffuse histiocytic lymphoma, predominantly
Calculating the number needed to treat for trials where the outcome is time to an event
Authors: D. G Altman, P. K. Andersen
Journal: BMJ (1999)

Although many patients with disseminated nontuberculous mycobacterial disease have molecular defects in the IFN-γ/IL-12 axis, recent case reports have shown autoantibodies against IFN-γ associated with severe nontuberculous mycobacterial infections. To check this finding in an independent population, we screened 35 patients with either disseminated or pulmonary nontuberculous mycobacterial infections for whom no molecular defect was known. We identified high-titer-neutralizing anti-IFN-γ IgG in the plasma of six patients. All six patients were female, parous, of East Asian descent, and had disseminated infection, predominantly with rapidly growing mycobacteria. The anti-IFN-γ IgG had in vitro biological activity on the IFN-γ-dependent phosphorylation of STAT-1 as well as on the IFN-γ-dependent up-regulation of TNF-α and IL-12. In contrast, this anti-IFN-γ Ab had no effect on IFN-α-dependent STAT-1 phosphorylation. These patients confirm a novel syndrome linking autoimmunity and immunodeficiency.
Retrospective Analysis of Renal Function in Patients with Advanced Biliary Tract Cancer Treated by GC
Authors: M. Toyoda, Y. Imamura, M. Nishimura, Y. Funakoshi, H. Tomioka, T. Shimada, N. Chayahara, N. Kiyota, T. Mukohara, H. Minami
Journal: Annals of Oncology (2013)
Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes
Authors: Concetta Quintarelli, Juan F. Vera, Barbara Savoldo, Greta M. P. Giordano Attianese, Martin Pule, Aaron E. Foster, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Gianpietro Dotti
Journal: Blood (2007)
Where should health services go: local authorities versus the NHS?
Authors: A. M Pollock
Journal: BMJ (1995)

The Association of Metropolitan Authorities has recently proposed that responsibility for the NHS should pass from health authorities to local authorities.One of the fiercest debates at the outset of the NHS was whether the hospitals should be run by local authorities.In the end the minister for health, Aneurin Bevan, decided against local democracy and in favour of a national health service.His arguments included the fact that equality of treatment could not be guaranteed iffacilities varied with local finances and that even the largest authorities were not big enough to pool risks and expertise.All these arguments still apply today, and the recent changes in community care provide an insight into how a market model oflocal authority control might work.The changes have been accompanied by a shift from public to private sector provision and the introduction of charges for services that the NHS once provided free.As important, the willingness and ability of local authorities to raise extra revenue from local taxes and charges affect the service they can provide, so leading to inequalities of provision.Local authorities have yet to make the case that they can preserve the fundamental principles and benefits ofthe NHS, including its reliance on central taxation and unified funding formulas.
Intake of a Diet High in <i>Trans</i> Monounsaturated Fatty Acids or Saturated Fatty Acids: Effects on postprandial insulinemia and glycemia in obese patients with NIDDM
Authors: Erik Christiansen, Sibylle Schnider, Birthe Palmvig, E Tauber-Lassen, Oluf Pedersen
Journal: Diabetes Care (1997)

OBJECTIVE High intake of trans fatty acids and saturated fatty acids (SFAs) is known to increase the risk of coronary heart disease. We studied the effects of diets enriched in various fatty acids on postprandial insulinemia and fasting serum levels of lipids and lipoproteins in obese patients with NIDDM. RESEARCH DESIGN AND METHODS Sixteen obese NIDDM patients were studied in a free-living outpatient regimen. After a run-in period, the patients received three different isocaloric diets for 6 weeks using a randomized crossover design. The patients were instructed to keep the energy intake from carbohydrate and protein constant at 50 and 20 E% (percent of energy intake), respectively, on all three diets. The fat composition of the diets differed: saturated fat (SAT) diet (20 E% SFAs, 5 E% polyunsaturated fatty acids [PUFAs], and 5 E% monounsaturated fatty acids [MUFAs]) versus cis monounsaturated fatty acid (CMUFA) diet (20 E% cis-MUFAs, 5 E% PUFAs, and 5 E% SFAs) versus trans monounsaturated fatty acid (TMUFA) diet (20 E% trans-MUFAs, 5 E% PUFAs, and 5 E% SFAs). Fasting serum levels of lipids and lipoproteins were measured at baseline and in the fasting state before meal tolerance tests at the end of each study period. Insulin secretion was assessed from incremental serum insulin and C-peptide responses during the meal tests. RESULTS BMI, waist-to-hip ratio, and glycemic control remained stable throughout the study. After meal stimulation, postprandial glycemic responses were similar on all diets; however, serum insulin and C-peptide responses were greater following the TMUFA and SAT diets than following the baseline or CMUFA diets (P &amp;lt; 0.05). No statistical difference was found in fasting levels of serum lipids (total cholesterol, triglyceride, phospholipid, and nonesterified fatty acids) or lipoproteins of HDL cholesterol, VLDL cholesterol, LDL cholesterol, and apolipoprotein B between diets. CONCLUSIONS In the presence of unchanged glycemia, both dietary trans fatty acids and SFAs induce an increase in postprandial insulinemia in obese patients with NIDDM.
Vasoreactivity of the culprit lesion in unstable angina.
Authors: P Bogaty, D Hackett, G Davies, A Maseri
Journal: Circulation (1994)

Although abnormal vasoconstriction may be involved in the pathogenesis of the acute coronary syndromes, the vasoreactivity of the lesion responsible for unstable angina (culprit lesion) has not been directly investigated. It is also unknown if enhanced vasoreactivity is found downstream to this lesion or extends to uninvolved coronary arteries.We studied seven unstable angina patients whose condition had sufficiently stabilized to allow ergometric bicycle exercise and a cold pressor test to be performed as provocative stimuli during coronary arteriography. We measured the luminal diameter of the culprit lesion, a normal-appearing distal segment, and the segment of an uninvolved coronary artery using quantitative coronary angiography. Seven stable angina patients served as controls. Antianginal medications were tapered and interrupted. The culprit lesion constricted significantly with exercise and the cold pressor test compared with a stable angina control lesion. The culprit lesion measured 1.41 +/- 0.07 mm at baseline and diminished to 1.09 +/- 0.07 mm with exercise (P = .001). It measured 1.26 +/- 0.07 mm before the cold pressor test and diminished to 1.09 +/- 0.03 mm with this test (P = .015). In contrast, the profile of the stable lesion in the stable angina control group differed significantly (P = .006). Its luminal diameter measured 1.42 +/- 0.17 mm at baseline and 1.48 +/- 0.21 mm with exercise (P = NS). It measured 1.57 +/- 0.18 mm before and 1.55 +/- 0.18 mm with the cold pressor test (P = NS). There were no significant changes to these stimuli in the uninvolved coronary artery segments in unstable angina and in the distal segments in both unstable and stable angina patients.This study demonstrates increased vasoreactivity of the culprit lesion in unstable angina compared with a control lesion in stable angina. The lack of an effect either in the uninvolved coronary artery or downstream to the culprit lesion suggests that systemic neurohumoral or seeding mechanisms are not operative. This abnormal vasoreactivity might predispose to, or be a marker for, the recurrence of acute ischemia at this site.
An assay for the detection of xenoestrogens based on a promoter containing overlapping EREs.
Authors: C Massaad, R Barouki
Journal: Environmental Health Perspectives (1999)

Xenoestrogens could be implicated in the decrease of male fertility and in the increased incidence of testicular and breast cancers in humans. To predict their deleterious effects, various in vivo or in vitro tests have been proposed to assay the xenoestrogenic activity. We have designed an assay for the detection of xenoestrogens based on a novel estrogen responsive unit formed by two overlapping estrogen response elements (overEREs). This construct is able to mediate a synergistic activation of transcription by 17ss-estradiol. We have used the overERE unit to assay the estrogenic activity of synthetic compounds, mostly organochlorine compounds. By using the overERE construct, we were able to detect the estrogenic activity of compounds at concentrations 10- to 100-fold lower than a single ERE (i.e., we detected the estrogenic effect of endosulfan at a concentration of 10(-5) M with ERE, whereas the overERE unit allowed us to detect a significant estrogenic activity of endosulfan at a lower concentration (10(-6) M). Some compounds did not exhibit any estrogenic activity when tested with a classical ERE, whereas they were potent xenoestrogens when the overERE was used (i.e., Betanal). The assays we have developed are very sensitive and can be performed quickly. Moreover, because the promoter that we used contains only an overlapping ERE as a regulatory unit, the interference of the tested molecules with other regulatory pathways can be avoided.
Effect of aging on the pluripotential capacity of human CD105<sup>+</sup> mesenchymal stem cells
Authors: Santiago Roura, Jordi Farré, Carolina Soler‐Botija, Anna Llach, Leif Hove‐Madsen, Jordi J. Cairó, Francesc Gòdia, Juan Cinca, Antoni Bayes‐Genis
Journal: European Journal of Heart Failure (2006)
Working with the Family Doctor: A Programme for Mental Health
Authors: D. Anderson
Journal: BMJ (1972)

A new type of assessment for mental health in four Scottish counties has been based on multidisciplinary teams comprising psychiatrists, psychiatric social worker, nursing administrator, and a secretary. Each team collaborated with 15 to 20 family doctors and they established four main patterns of contact: around an outpatient clinic; by informal availability; by administrative and teaching seminars; or by regular consultation sessions. This improved contact was found to help both the team and the family doctors and reduced the number of patients admitted to hospital and the length of their stay and the number of urgent referrals. It emphasizes the need for team work in mental health care and that the hospital needs to remain in touch with the outside community.
The Significance of the Transitional Object for Psychosomatic Thinking
Authors: M. Mitscherlich
Journal: Psychotherapy and Psychosomatics (1977)

Research Articles| February 16 2010 The Significance of the Transitional Object for Psychosomatic Thinking Subject Area: Psychiatry and Psychology M. Mitscherlich M. Mitscherlich Düsseldorf Search for other works by this author on: This Site PubMed Google Scholar Psychother Psychosom (1977) 28 (1-4): 272–277. https://doi.org/10.1159/000287072 Article history Published Online: February 16 2010 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation M. Mitscherlich; The Significance of the Transitional Object for Psychosomatic Thinking. Psychother Psychosom 31 December 1977; 28 (1-4): 272–277. https://doi.org/10.1159/000287072 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsPsychotherapy and Psychosomatics Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. 1977Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.
Use of Intravenous Mannitol in Postperfusion Oliguria-Anuria
Authors: SAFUH ATTAR, FRANCIS J. BORGES, R. ADAMS COWLEY, WILLIAM G. ESMOND, NORMAN HOLLINGSWORTH, EMIL BLAIR
Journal: Circulation (1963)

We have applied the principle of acute functional renal failure in the management of the oliguric-anuric state encountered in 19 of 158 patients undergoing open-heart operations. Mannitol was administered to nine patients who experienced acute renal failure, with successful diuresis and restoration of kidney function in eight.