tbuckley/cabot-search huggingface dataset:
Small molecule inhibitors of protein kinase D inhibit cancer cell growth through inhibition of growth factor-stimulated proliferation and induction of apoptosis.
Authors: Azadeh Bagherzadeh, Stephen Jamieson, Kevin Stewart, Jonathon Travers, Mark Charles, Gregoire Pave, Julia Gilliatt, Maria Notaridou, Sonia Eckersley, Luc Dasnois, Matthew Trickett, Fiona Smart, Lloyd Kelland, Tim Hammonds, Tony Raynham, Caroline Foxton
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3256 

Protein kinase D (PKD) lies at the crossroads of the DAG and PKC signalling network, which is frequently deregulated in cancer. PKD has been shown to play a role in many of the biological processes that lead to tumor growth, including cell proliferation, survival, epithelial-to-mesenchymal transition and invasion. Thus PKD represents a potential therapeutic target for intervention. siRNA was used to dissect the role of specific PKD isoforms (PKD1, PKD2 and PKD3) in cancer cells. siRNA-mediated depletion of PKD1, PKD2 and PKD3 expression (≈70%) revealed a role for PKD1 in cell proliferation and PKD2 in cellular resistance to apoptosis. Small molecule inhibitors of PKD were then identified by high throughput screening and characterized with respect to their potential as anti-cancer agents. A series of ATP-competitive PKD inhibitors was developed with good physicochemical and in vitro ADME properties. A lead compound was selected (CRT0059359) which had potent (sub nanomolar IC50) and selective activity against PKD in biochemical assays. CRT0059359 also caused potent (low micromolar IC50) inhibition of PKD activity in a variety of cancer cell lines in vitro (e.g. PANC-1, A549, MDA-MB-435), as determined by modulation of phorbol ester-stimulated PKD-Ser916 autophosphorylation. In addition, treatment of PANC-1 cells in vitro with CRT0059359 inhibited growth-factor-stimulated proliferation to basal levels, and caused a 12-fold increase in Caspase 3/7 activity, a biomarker of apoptosis. Pharmacokinetic studies in mice demonstrated that plasma levels of CRT0059359 in excess of those required to inhibit PKD in vitro are achievable; in vivo efficacy studies are being initiated. Collectively, these data validate PKD as a target for therapeutic intervention in cancer and demonstrate the utility of potent PKD inhibitors as anti-cancer agents.
Abstract #5548: Involvement of E2F1 in down-regulation of homologous recombination repair genes upon histone deacetylase inhibition in prostate cancer
Authors: Sushant Kachhap, Spencer Collis, Madeleine Kortenhorst, Shabana Shabbeer, Luigi Marchionni, Jianqing Lin, Theodore Deweese, Michael Carducci
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Epigenetic regulation of gene expression is thought to be brought about by both chromatin modulators, such as histone decaetylase (HDACs), that modify N-terminal tails of histones and DNA methylating enzymes that methylate CpG clusters in promoter regions of eukaryotic genomes. We performed microarray analysis to understand global changes in gene expression in DU-145 and PC3 prostate cancer (PCA) cell lines using two different types of HDAC inhibitor, Valproate (VPA) and vorinostat. Our analysis revealed key genes of the homologous recombination (HR) repair pathway downregulated in both the cell lines. Gene Set Enrichment Analysis revealed BRCA1 and E2F1 associated proteins are negatively modulated by HDACi. VPA was shown to radiosensitize PCA cell lines DU-145 and LNCaP cells which indicated a defective DNA repair. Persistence of H2AX staining in VPA treated and irradiated PCA cells indicated that the repair proteins were unable to recruit on the damaged sites and efficiently repair the DSBs after irradiation. HR repair genes were downregulated both at the transcript and protein level upon VPA treatment and remained downregulated even upon irradiation. The activator transcription factor E2F1 was downregulated in VPA treated cells both at the transcript and protein level while E2F4 and 6 were not affected. In order to investigate the status of these factors at the promoters of HR genes chromatin immunoprecipitation (ChIP) analysis performed in a subset of HR gene promoters. ChIP analysis revealed that E2F1 occupancy was lower in the promoters of these genes upon VPA treatment, however the repressive E2Fs (E2F4 and 6) were not recruited to the promoters in the absence of E2F1. This indicates that downregulation of HR genes upon VPA treatment, in part, is brought about by decrease recruitment of activator E2F and not increased recruitment of repressive E2Fs. Acetylation status of downregulated gene promoters by ChIP analysis indicated a decrease in H3 acetylation suggesting repressed chromatin at the proximal region of the promoters. Our data provides mechanistic insights into downregulation of repair genes upon HDAC inhibition and implicates the E2F1 transcription factors as one of the mediators. Knowledge about the molecular mechanism by which various HDAC isozyme causes a downregulation of repair proteins will help in developing a target driven therapy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5548.
The Risk of Systemic Lupus Erythematosus Associated With Vaccines: An International Case‐Control Study
Authors: Lamiae Grimaldi‐Bensouda, Veronique Le Guern, Isabelle Kone‐Paut, Elodie Aubrun, Olivier Fain, Michel Ruel, Laurent Machet, Jean‐François Viallard, Nadine Magy‐Bertrand, Eric Daugas, Michel Rossignol, Lucien Abenhaim, Nathalie Costedoat‐Chalumeau
Journal: Arthritis & Rheumatology (2014)

Studies have suggested that systemic lupus erythematosus (SLE) may be triggered by vaccinations. We undertook this study to investigate the relationship between vaccination and onset of SLE.This international case-control study was conducted between April 2008 and June 2012 in 36 specialist referral centers (34 in France and 2 in Quebec, Canada) and recruited patients ≤60 years old recently diagnosed as having either definite SLE (meeting ≥4 American College of Rheumatology [ACR] criteria including at least 1 immunologic criterion) or probable SLE (meeting 3 ACR criteria including at least 1 immunologic criterion). Controls were recruited from general practice settings through a closely monitored protocol and matched to patients by age, sex, region of residence, and date of recruitment. Vaccinations and other potential risk factors for SLE were assessed using a standardized telephone interview. We compared proportions of patients and controls who were vaccinated 12 and 24 months before the index date (date of first clinical symptom presented by the patient) using odds ratios (ORs) from conditional logistic regression.We assessed 105 patients (89 with definite SLE and 16 with probable SLE) and 712 controls. Twenty-two of the 105 patients (21.0%) and 181 of the 712 controls (25.4%) had received at least 1 vaccination within 24 months before the index date (adjusted OR 0.9 [95% confidence interval 0.5-1.5]). The proportions of patients and controls vaccinated within the previous 12 months were also similar.Our study showed no association between exposure to vaccination and risk of developing SLE.
Comparison of roflumilast, an oral anti‐inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma
Authors: J. Bousquet, M. Aubier, J. Sastre, J. L. Izquierdo, L. M. Adler, P. Hofbauer, K.‐D. Rost, U. Harnest, B. Kroemer, A. Albrecht, D. Bredenbröker
Journal: Allergy (2005)

Background: Roflumilast is an oral, once‐daily phosphodiesterase 4 inhibitor with anti‐inflammatory activity in development for the treatment of asthma. Roflumilast was compared with inhaled beclomethasone dipropionate (BDP) in patients with asthma. Methods: In a double blind, double‐dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV 1 ] = 50–85% predicted) received roflumilast 500 μ g once daily or BDP 200 μ g twice daily (400 μ g/day) for 12 weeks. Lung function and adverse events were monitored. Results: Roflumilast and BDP significantly improved FEV 1 by 12% (270 ± 30 ml) and 14% (320 ± 30 ml), respectively ( P &lt; 0.0001 vs baseline). Roflumilast and BDP also significantly improved forced vital capacity (FVC) ( P &lt; 0.0001 vs baseline). There were no significant differences between roflumilast and BDP with regard to improvement in FEV 1 and FVC. Roflumilast and BDP showed small improvements in median asthma symptom scores (–0.82 and −1.00, respectively) and reduced rescue medication use (−1.00 and −1.15 median puffs/day, respectively; P &lt; 0.0001 vs baseline). These small differences between roflumilast and BDP were not considered clinically relevant. Both agents were well tolerated. Conclusions: Once daily, oral roflumilast 500 μ g was comparable with inhaled twice‐daily BDP (400 μ g/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.
For the Record, by P D Clayton, W E Boebbert, G H DeFriese, S P Howell, M L Fennell, K A Frawley, J Glaser, R A Kemmerer, C E Landwehr, T C Rindfleisch, S A Ryan, B J Sams, P Szolovitz, R G Trussel, E Ward, P M Schwartz Privacy and Health Research, by William W Lowrance
Authors: R. Anderson
Journal: BMJ (1998)

P D Clayton, W E Boebbert, G H DeFriese, S P Howell, M L Fennell, K A Frawley, J Glaser, R A Kemmerer, C E Landwehr, T C Rindfleisch, S A Ryan, B J Sams, P Szolovitz, R G Trussel, E Ward, P M Schwartz National Academy Press, £24.95, pp 264 ISBN 0 309 05697 7

William W Lowrance US Department of Health and Human Services, pp 80

The recent debate between the Department of Health and the BMA about medical privacy has not been a phenomenon local to Britain. Much the same issues exercise doctors, patients, administrators, and activists in several other countries, and two recent publications have been influential in driving policy in the United States.

For the Record was commissioned by the US National Research Council on the general topic of privacy and security in healthcare informatics. It was written by a committee of 15 people drawn from government, providers of healthcare information systems, …
Troponin-T and N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality Benefit From Coronary Revascularization in Acute Coronary Syndromes
Authors: Stefan K. James, Johan Lindbäck, Johanna Tilly, Agneta Siegbahn, Per Venge, Paul Armstrong, Robert Califf, Maarten L. Simoons, Lars Wallentin, Bertil Lindahl
Journal: Journal of the American College of Cardiology (2006)
THE CAUSE OF DEATH OF PATIENTS WITH ORGANIC HEART DISEASE SUBJECTED TO SURGICAL OPERATION
Authors: W. K. Purks
Journal: Annals of Internal Medicine (1934)

Article1 January 1934THE CAUSE OF DEATH OF PATIENTS WITH ORGANIC HEART DISEASE SUBJECTED TO SURGICAL OPERATIONW. K. PURKS, M.D.W. K. PURKS, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-7-7-885 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAn evaluation of the ability of the patient with organic heart disease to withstand operation is a matter of great importance and also of great difficulty. In 1930, Butler, Feeney and Levine1wrote on the cardiac patient as a surgical risk. They reviewed 414 cases with organic heart disease who had been subjected to operation. Their study, contrary to some previous reports, indicated that these patients tolerate operation reasonably well. In their series, comprising 494 operations, there were 60 deaths, a mortality of 12.1 per cent. If those patients whose cardiac condition was such as to have produced death regardless...1. BUTLERFEENEYLEVINE SNSA: The patient with heart disease as a surgical risk; review of 414 cases, Jr. Am. Med. Assoc., 1930, xcv, 85-91. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Massachusetts*Received for publication October 13, 1933.From the Medical Clinic of the Peter Bent Brigham Hospital, Boston, Massachusetts. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1934Volume 7, Issue 7Page: 885-894KeywordsCardiovascular therapyHospitalsMortality ePublished: 1 December 2008 Issue Published: 1 January 1934 PDF downloadLoading ...
859. A Skin-Restricted Conditionally Expressing Mouse Model of Pompe Disease for Assessment of Gene and Enzyme Replacement Therapies
Authors: Kerry O. Cresawn, Nina Raben, Paul H. Plotz, Christina Pacak, Adam Glick, Barry J. Byrne
Journal: Molecular Therapy (2004)

Gene therapies and recombinant enzyme replacement therapies (ERT) are currently under investigation as therapeutic options for several lysosomal storage diseases (LSDs) including Pompe disease, a lysosomal storage disease caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Both ERT and gene therapeutic approaches to Pompe disease will require careful evaluation of potential immunologic responses to proposed therapies. Because of the unique intercellular trafficking of lysosomal enzymes, we propose to use hepatic gene delivery and subsequent GAA secretion as a platform for systemic correction of affected tissues, notably the heart, skeletal, and respiratory muscles.
NNMT: A Bad Actor in Fat Makes Good in Liver
Authors: Samuel A.J. Trammell, Charles Brenner
Journal: Cell Metabolism (2015)

High adipose expression of NNMT, an enzyme that converts nicotinamide to 1-methyl-nicotinamide, correlates with adiposity. Though murine NNMT knockdown in fat and liver prevents weight gain on high-fat diet, Hong et al. (2015) now show that high hepatic expression of NNMT improves lipid parameters via SIRT1 stabilization.
Palliative and Hospice Care Needed for Children With Life-Threatening Conditions
Authors: J Stephenson
Journal: JAMA (2000)

WHEN CHILDREN IN THE UNITED States are stricken with a serious illness or injury, few question the medical community’s focus on aggressive intervention aimed at curing or extending young lives. But what is all too often overlooked, say experts, is that children who die—along with many others who ultimately triumph over life-threatening conditions— often suffer needlessly because of lack of palliative and hospice care. Such care not only addresses the physical needs of the child, such as managing pain and other symptoms, but also brings together a team of physicians, nurses, social workers, therapists, clergy, volunteers, and others to provide psychological, social, and spiritual support for children and their families. Although pediatric palliative care is more generally accepted in some industrialized countries, seriously ill children in the United States often are not offered this kind of help. The United Kingdom, Australia, and Canada have done a better job in providing such services, says Marcia Levetown, MD, of the University of Texas Medical Branch, Galveston. But there are encouraging signs that the issue is gaining new prominence in the United States. A few months ago, the American Academy of Pediatrics (AAP) issued care guidelines for children with lifethreatening and terminal conditions (Pediatrics. 2000;106:351-357) that include a number of recommendations to help make palliative care and respite programs more widely available to children and families who need them. And earlier this year, for the first time, Congress allocated $1 million to develop children’s hospice care demonstration programs in Florida, Kentucky, New York, Utah, and Virginia.
A new method to measure cough pressure in intubated patients. Validity and usefulness as a predictor of extubation failure in ICU patients having succeded a spontaneous breathing trial
Authors: Manuel Baz, Estrella Echavarria, Pedro Alzugaray, Alberto Biestro, Mario Cancela, Julio Cabrera
Journal: European Respiratory Journal (2013)

We aimed to validate a new equipment and method to measure cough pressure developed at the tube cuff as a predictor of successful extubation in a Burn ICU. Methods: once extubation criteria met and a spontaneous breathing trial succeded, we measured: cough pressure with a new device (mmHg)(CPd), cough pressure with a commercial handheld dynamometry (mmHg)(CPhhd), and used a BICORE to measure Cough Peak Flow (L/sec)(CpF), Maximal Inspiratory Pressure (mmHg)(MIP), Tidal Volume (mL)(Vt), Respiratory Rate (RR). Extubation failure expressed the reintubation within the 48 hours. We measured morphine dose 4 hours prior extubation and clinical characteristics. T test (Bonferroni corrected), Pearson correlation, Bland Altmann agreement and multiple regression analysis were used.  Results: We studied 40 patients, 39,5 ± 25,7 years old. Admission criteria: inhalation injury in 38 cases and polyvalent disease in 2 cases. 4 patients failed extubation (10%). CPd vs CPhhd comparaison showed a significant correlation (r=0,91) and a Bland – Altmann plot analysis of the differences showed significant agreement. CPd and CPF showed a significant correlation. Patients succeded vs failed showed: Ve 2.9 ± 0.99 vs 2.4 ± 0.28 (*), CPF 1.47 ± 0.13 vs 1.23 ± 0.15 (*), MIP 38.2 ± 3.36 vs 31.0 ± 2.94 (*). CPd 54.5 ± 9.3 vs 23.0 ± 3.5 (*). CPd best related to extubation success (*). Dose of morphine (mg) was 1,20 ± 0,77 vs 2,60 ± 0,66 (*). (*) means p minor 0,05.  Conclusions: We could perform and validate the method, and CPd was the best extubation success predictor. A hypodynamic scenario was due to sedative agents.
Functional analysis of human tumor response to signal transduction inhibitors: <i>Ex vivo</i> analysis of programmed cell death (EVA-PCD) in 1° culture microspheroids
Authors: Robert A. Nagourney, Kaylee R. Kenyon, Eric Frederico, Paula Bernard, Steven S. Evans
Journal: Clinical Cancer Research (2010)

Abstract Advances in cancer therapy increasingly reflect the application of genomics and proteomics to target tumor-specific phenomena. Several insights have accelerated this process including the primacy cell survival signals in carcinogenesis and drug resistance and the growing appreciation of tumor biology as contextual. Ex vivo analysis of programmed cell death (EVA/PCD™) addresses both issues by measuring metabolic and morphologic features of drug induced cell death (apoptotic and non-apoptotic) using native state 1° cultures isolated from surgical specimens and cytologically (+) fluids. The predictive validity of the EVA/PCD™ established for cytotoxics, e.g,. 2CDA in hairy cell leukemia; purine-alkylator synergy in NHL (Nagourney et al, B.J. Cancer, ‘93) and platin-gemcitabine activity/synergy in breast and gynecologic cancers (Nagourney et al, Deoxynucleoside analogs in cancer therapy, Humana Press, 2006) has led to this platforms current focus on signal transduction with a growing emphasis on NSCLC. A recent report in NSCLC provided an ORR of 62%, med TTP of 9.5 mos and med OS of 22.3 mos, including the identification of durable responders to EGFr-TKIs (Nagourney RA Proc ASCO, 2010). An EVA/PCD™ exploration of “vertical” and “horizontal” signal inhibition (Nagourney et al Proc AACR, 2010) favored “horizontal” strategies in NSCLC providing very durable clinical responses with dual EGFr/VEGFr and clinical response for dual EGFr/mTOR salvage following single agent EGFr-TKI failure. By expanding beyond current FDA-approved drugs into the new agents that target PI3K, AKT, TORC1&amp;2, MEK/ERK and c-MET, the EVA/PCD™ can facilitate developmental therapeutics. Analyses are now examining the activity and synergy of EGFr-TKIs with VEGF, mTOR, MEK/ERK, PI3K, AKT and c-MET inhibitors in NSCLC and other diseases as will be reported. Supported in part by a research grant from Biophysica, Ltd, the Vanguard Cancer Foundation and The Nagourney Institute.
Opportunities for doctors in the prison service
Authors: J Bilkhu, M. Longfield, P J Keavney
Journal: BMJ (1999)

# The director of health care in prisons, Mike Longfield, explains the range and scope of the service for those who serve at Her Majesty's pleasure {#article-title-2}

Medical practice in prison is, perhaps by its nature, little known and poorly understood outside the confines of the prison service. Only 225 doctors work in prisons in England and Wales (of whom 133 are full time and 92 part time), but their potential to influence the health of some of the most disadvantaged people in society is considerable. Last year around 65,500 prisoners were in custody at any one time, a number that has been rising steadily for about five years. That number is deceptive: in the latest year for which statistics are available, around 200,000 people spent some time in prisons in England and Wales because the vast majority of prisoners spend comparatively short periods in custody. All of these people will come into contact with a prison doctor during their time in custody, and this contact offers prisoners the opportunity for consistent health care, which may well have been absent from their lives outside prison.

Opposite, Patrick Keavney argues that prison medical officers are general practitioners who need even more vision, tenacity, and common sense than their non-prison counterparts, in work with a group of patients who are more likely to need some form of mental care.

I would like to add to that by first putting the role of the prison medical officer within the judicial context of the Prison Act (1952). This is the basic legal constitution for the work of the prison service and requires, among other things, that “every prison shall have a governor, a chaplain and a medical officer and such other officers as may be necessary.” This legal context underscores the fact that prison medical officers are required not only to “have the care of the health, mental and physical, of the prisoners in that prison,” as stated in the prison …