tbuckley/cabot-search huggingface dataset:
Abstract A40: New approaches to target mevalonate biosynthesis
Authors: Cinzia Casella, Alexander S. Brodsky
Journal: Clinical Cancer Research (2013)

Abstract To support rapid growth, tumors need to synthesize lipids and cholesterol, and stopping production of these metabolites can inhibit tumors. Statins are among the most prescribed and well-tolerated drugs in the world to treat cardiovascular disease by inhibiting cholesterol synthesis. Statins are known to be toxic to cancer cells and have attracted renewed attention because of the increased appreciation of the importance of the regulation of metabolism in tumors. Statins have not progressed beyond clinical trials because some patients significantly benefit, while others do not in a range of cancers. Our strategy is to improve our understanding of the mechanisms of tumor responses to statins and thereby enhance statin toxicity to cancer cells. We have found that combining statins with oxysterols synergistically enhances statin toxicity by 10-fold. Oxysterols are oxidized cholesterol metabolites that naturally occur during cholesterol synthesis. We hypothesize that oxysterols inhibit the expression of cholesterol synthesis through a master regulator of metabolism, SREBP-2, making cells more sensitive to statins. We find that oxysterols enhance statin induced apoptosis and suppress the expression of SREBP-2 along with SREBP-2 targets including HMGCR. We have tested a number of oxysterols that work with a range of efficacies in seven representative ovarian cancer cell lines. P53 status is not a major factor in mediating oxysterol activity. Oxysterols inhibit expression of SREBP-2 leading to lower expression of the statin target, HMGCR, along with lower expression of most of the mevalonate and cholesterol biosynthesis pathways. These observations suggests that the cell's response to statins and not initial expression levels may be most critical to determine which patients may benefit from statin therapy. Current studies are testing the combination in mouse models and evaluating the function and regulation of SREBP-2 in ovarian cancer. In summary, we have discovered an approach to suppress cancer cell's response to statins leading to greatly improved statin efficacy highlighting the importance of the mevalonate and cholesterol pathways in mediating growth and survival. Citation Format: Cinzia Casella, Alexander S. Brodsky. New approaches to target mevalonate biosynthesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A40.
The Theatre of Life and Death
Authors: J. Marshall
Journal: BMJ (2003)

An exhibition at the Boerhaave Museum, Leiden, the Netherlands, until 21 September 2003 http://www.museumboerhaave.nl/ Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Having freed itself from the Spanish empire, the Republic of the Seven United Provinces of the Netherlands was by the 17th century a superpower to rival Britain. Known primarily through its art, the Dutch Golden Age was also a period of great scientific and medical advance. The new ideas of the Italian renaissance filtered north, driving out the medieval superstitions, including those related to health … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
The Human Value of Behavior Therapy
Authors: Joseph Wolpe
Journal: Psychotherapy and Psychosomatics (1978)

Case Reports| February 16 2010 The Human Value of Behavior Therapy Subject Area: Psychiatry and Psychology Joseph Wolpe Joseph Wolpe Temple University Medical School and Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pa. Search for other works by this author on: This Site PubMed Google Scholar Psychother Psychosom (1978) 29 (1-4): 58–64. https://doi.org/10.1159/000287101 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 Joseph Wolpe; The Human Value of Behavior Therapy. Psychother Psychosom 31 December 1978; 29 (1-4): 58–64. https://doi.org/10.1159/000287101 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 1978Copyright / 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.
Estimation of non-autonomic and autonomic components of iliac bed vascular resistance in renal hypertensive rabbits
Authors: M. J. WEST, J. A. ANGUS, P. I. KORNER
Journal: Cardiovascular Research (1975)

Iliac bed vascular resistance (IVR) was measured before and after pharmacological block of the autonomic effectors in unanaesthetized renal hypertensive and normotensive rabbits with previously implanted Doppler flowmeters. This permitted partitioning the resting IVR into a non-autonomic component (ie, steady-state IVR after block) and an autonomic component (ie, resting IVR minus non-autonomic IVR). When IVR was measured at the same mean arterial pressure (MAP) before and after block in each animal, the increase in estimated non-autonomic IVR accounted entirely for the rise in resting IVR in renal hypertensive rabbits. However, if IVR measurements after block were made at a lower MAP than before block, the estimated non-autonomic and autonomic components were both significantly increased in renal hypertensive rabbits. It is concluded that in the latter experiment non-autonomic IVR in renal hypertension was underestimated, whilst the autonomic component was overestimated. The rise in non-autonomic IVR in renal hypertension was partly due to structural changes in the iliac bed, since IVR remained higher in hypertensive than in normotensive rabbits after abolishing smooth muscle tone with vasodilator drugs.
Neuropsychological consequences of volatile substance abuse: a population based study of secondary school pupils.
Authors: O. Chadwick, R. Anderson, M. Bland, J. Ramsey
Journal: BMJ (1989)

OBJECTIVE--To examine the effects of volatile substance abuse on neuropsychological functioning. DESIGN--A sample of index children and matched controls were identified by a two stage procedure. Firstly, over 5000 secondary school pupils completed a screening questionnaire, and, secondly, a sample of those who acknowledged volatile substance abuse and a matched sample of those who denied the practice were assessed in detail by means of (a) individually conducted interviews and (b) toxicological examination of breath samples (to exclude those intoxicated at the time of testing). SETTING--16 Local education authority secondary schools in London. SUBJECTS--160 Pupils aged 13-16: 80 index children who had abused volatile substances to the point of intoxication at least once (confirmed by interview) and 80 controls (confirmed by interview) matched for school year, sex, and ethnic background. MEASUREMENTS AND MAIN RESULTS--Neuropsychological functioning tests provided 35 main outcome measures and were administered blind. Data on educational test performance before substance abuse began were obtained retrospectively. Information on potentially confounding social factors, such as number of siblings, tenure of housing, and parents9 socioeconomic and employment state was also obtained. The index children performed significantly less well than the controls in tests of vocabulary, verbal intelligence quotient, full scale intelligence quotient, and a measure of impulsivity. When background social disadvantage was taken into account these differences were no longer significant. There were no significant associations between performance on psychological testing and frequency of abuse, and relations with other aspects of the children9s history of abuse were generally weak or unsystematic. Comparisons between the results of these tests and of educational tests taken before substance abuse produced equivocal findings. CONCLUSION--Volatile substance abuse, as commonly practised by secondary school pupils, is unlikely to result in neuropsychological impairment.
Radiographic benefit and maintenance of clinical benefit with intravenous golimumab therapy in patients with active rheumatoid arthritis despite methotrexate therapy: results up to 1 year of the phase 3, randomised, multicentre, double blind, placebo controlled GO-FURTHER trial
Authors: Michael E Weinblatt, Rene Westhovens, Alan M Mendelsohn, Lilianne Kim, Kim Hung Lo, Shihong Sheng, Lenore Noonan, Jiandong Lu, Zhenhua Xu, Jocelyn Leu, Daniel Baker, Clifton O Bingham
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). <h3>Methods</h3> Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15–25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; &lt;10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here. <h3>Results</h3> Significant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p&lt;0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a 'good' or 'moderate' response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections. <h3>Conclusions</h3> In patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year. <h3>ClinicalTrials.gov</h3> NCT00973479, EudraCT 2008–006 064–11.
Neutrophil and eosinophil involvement of the small bowel affected by chronic alcoholism.
Authors: J F Colombel, R Hallgren, P Venge, B Mesnard, J C Rambaud
Journal: Gut (1988)

Excessive ethanol intake may affect the intestinal mucosa functionally and morphologically. The ethanol effect could partly be the result of inflammatory mechanisms, possibly reflected by an enhanced local granulocyte turnover. This study investigated habitual alcoholics by segmental perfusion of the jejunum and analysed the perfusion fluid content of granulocyte granule constituents. The mean jejunal secretion rate of myeloperoxidase (MPO), a neutrophil granule constituent, was 152 (26) (SE) ng/min/40 cm jejunal segment in the controls (n = 16). The MPO secretion rate in non-cirrhotic habitual alcoholics (n = 7) was on average 450 (103) ng/min and significantly increased compared with controls (p less than 0.001). In contrast alcoholics with cirrhosis (n = 6) had normal MPO secretion rate. The mean secretion rate of eosinophil cationic protein (ECP), an eosinophil granule constituent, was in the controls 77 (15) ng/min/40 cm jejunal segment. Corresponding values in non-cirrhotic and cirrhotic alcoholics were 141 (38) and 130 (93) ng/min, respectively (ns). The data suggest an enhanced neutrophil granulocyte turnover in the jejunum in alcoholics, possibly contributing to the ethanol induced affection of the small bowel. The lack of increased neutrophil activity in cirrhotic alcoholics may reflect a role of the liver for granulocyte activity.
Abstract 283: OOPs: Novel HIF-1α mimics
Authors: Ivan V. Grishagin, Bogdan Z. Olenyuk, Brooke Bullock, Paramjit S. Arora
Journal: Cancer Research (2012)

Abstract Alpha subunit of the hypoxia-inducible factor 1 (HIF-1α) is an important transcriptional regulator of hypoxia-inducible genes responsible for tumor proliferation and metastasis, and therefore HIF-1α is a valuable therapeutic target. In turn, the interaction between C-terminal activation domain (C-TAD) of HIF-1α and the cysteine-histidine rich domain (CH1) of its coactivator p300 is known to play the key role in the HIF-1 pathway. However, to date very few compounds have been reported to disrupt HIF-1α/p300 complex. We have rationally designed and synthesized non-peptidic mimics of HIF-1α CTAD αA-helix with novel oligooxopiperazine backbone (OOPs). These mimics exhibit relatively low toxicity and substantially downregulate expression levels of selected hypoxia-inducible genes (VEGF, c-MET, LOX, GLUT1, CXCR4) in cellulo in a dose-dependent manner. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 283. doi:1538-7445.AM2012-283
Leptin Signaling and Obesity
Authors: Ronghua Yang, Lili A. Barouch
Journal: Circulation Research (2007)

Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease.
Take real world issues into account
Authors: A. Zermansky, R. Khatib
Journal: BMJ (2011)

Pink and colleagues’ analysis of the economics of dabigatran is flawed by several real world issues that were not considered.1

Firstly, the price of dabigatran will fall as competitive drugs are licensed. 

Secondly, the cost of stopping international normalised ratio (INR) monitoring depends on whether warfarin clinics continue to run but …
Efficacy and Safety of Erlotinib Monotherapy for Japanese Patients with Advanced Non-small Cell Lung Cancer: A Phase II Study
Authors: Kaoru Kubota, Yutaka Nishiwaki, Tomohide Tamura, Kazuhiko Nakagawa, Kaoru Matsui, Koshiro Watanabe, Toyoaki Hida, Masaaki Kawahara, Nobuyuki Katakami, Koji Takeda, Akira Yokoyama, Kazumasa Noda, Masahiro Fukuoka, Nagahiro Saijo
Journal: Journal of Thoracic Oncology (2008)
Commentary: child mental health services are not medical empires
Authors: A. Hall
Journal: BMJ (1997)

Child mental health: who is responsible?The labelling of all childhood ills as mental health problems diverts doctors into child welfare work that is more properly the province of social services or education, argues child psychiatrist Robert Goodman.The result, he claims, is that many children who could have benefited from medical assessment and treatment for their emotional and behavioural problems do not get that help.We asked another child psychiatrist, an educational psychologist, and a social worker to respond to Dr Goodman's challenge. An overextended remit Robert GoodmanParents and teachers are seriously dissatisfied with the behaviour of many children.Other children experience considerable stress, misery, or anxiety.Epidemiological studies suggest that roughly 20% of all children and teenagers are maladjusted or distressed, 1 with some estimates being substantially higher. 2 In the child psychiatric literature and government strategy documents these maladjusted and distressed children are referred to as having psychiatric disorders or mental health problems. 3 4I believe that this medicalisation of all maladjustment and distress is a serious "own goal" for the health service, generating unrealistic expectations of what child mental health services can deliver and diverting health professionals from their areas of expertise.The medicalisation of maladjustment and distress is enshrined in the contemporary psychiatric classifications of the World Health Organisation and the American Psychiatric Association. 5 6Perhaps both these classifications were overinfluenced by the World Health Organisation's otherworldly definition of health as "a state of complete physical, mental and social wellbeing, and not merely the absence of disease and infirmity" 7 ; falling short of this ideal is then a lack of health, and it is only a small step to define any serious shortfall as a disease.Cynics will also note that the medicalisation of maladjustment and distress generates employment for doctors and persuades health insurers to foot at least some of the bill.An overinclusive notion of child mental health may have encouraged health providers to fill the vacuum as successive funding crises have led social services and education to withdraw from much of their traditional child and family guidance work.Antisocial behaviour in adults is usually seen as a social problem: similar behaviour in children is often categorised as a mental health problem
Effects of Abciximab, Ticlopidine, and Combined Abciximab/Ticlopidine Therapy on Platelet and Leukocyte Function in Patients Undergoing Coronary Angioplasty
Authors: Becky J. Fredrickson, Nancy A. Turner, Neal S. Kleiman, Nikki Graziadei, Kelly Maresh, Mary Ann Mascelli, Mark B. Effron, Larry V. McIntire
Journal: Circulation (2000)

Background —Abciximab and ticlopidine reduce adverse cardiovascular events after percutaneous transluminal coronary angioplasty (PTCA). The goal of the current study was to determine if combined abciximab/ticlopidine therapy inhibits arterial thrombosis more effectively than either treatment alone. The effect of each therapy on platelet-leukocyte interactions was also investigated. Methods and Results —Whole blood samples from 14 patients undergoing PTCA who received abciximab therapy, ticlopidine therapy, or both treatments were evaluated using dynamic experimental systems. Mural thrombus formation under arterial shear conditions (1500 s −1 ) was determined in a parallel plate flow chamber. Shear-induced platelet aggregation was evaluated using a cone-and-plate viscometer at a shear rate of 3000 s −1 . Of the 3 treatments, combined abciximab/ticlopidine therapy produced the most consistent reduction in shear-induced platelet aggregation and the most prolonged inhibition of mural thrombosis. Three days after PTCA, abciximab/ticlopidine treatment decreased mural thrombus formation to ≈50% of baseline values. Abciximab treatment alone inhibited mural thrombosis for only 1 day after PTCA, whereas ticlopidine treatment alone had no significant effect. Two hours after PTCA, abciximab therapy significantly decreased the number of circulating platelet-neutrophil aggregates but significantly enhanced P-selectin–mediated leukocyte adhesion on the collagen/von Willebrand factor–platelet surface. Conclusions —Combined therapy with abciximab and ticlopidine has a prolonged inhibitory effect on mural thrombosis formation relative to either treatment alone. Further, we demonstrated an unexpected effect of abciximab in enhancing P-selectin–mediated leukocyte adhesion.
Cascaded Photoinduced Drug Delivery to Cells from Multifunctional Core–Shell Mesoporous Silica
Authors: Axel Schloßbauer, Anna M. Sauer, Valentina Cauda, Alexandra Schmidt, Hanna Engelke, Ulrich Rothbauer, Kourosh Zolghadr, Heinrich Leonhardt, Christoph Bräuchle, Thomas Bein
Journal: Advanced Healthcare Materials (2012)

Different bioactive molecules are released into living cells from lipid-covered mesoporous silica nanoparticles. The release is triggered by light, as the particles feature covalently attached photosensitizers as membrane-opening agents. It is demonstrated that the particles achieve endosomal escape and that they release their cargo into the cytosol. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.