tbuckley/cabot-search huggingface dataset:
Improved Statistical Modeling of Tumor Growth and Treatment Effect in Preclinical Animal Studies with Highly Heterogeneous Responses <i>In Vivo</i>
Authors: Teemu D. Laajala, Jukka Corander, Niina M. Saarinen, Katja Mäkelä, Saija Savolainen, Mari I. Suominen, Esa Alhoniemi, Sari Mäkelä, Matti Poutanen, Tero Aittokallio
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated. Experimental design: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses. Results: When applied to four tumor growth experiments, the modeling framework was shown to (i) improve the detection of subtle treatment effects in the presence of high within-group tumor variability; (ii) reveal hidden tumor subgroups associated with established or novel biomarkers, such as ERβ expression in a MCF-7 breast cancer model, which remained undetected with standard statistical analysis; (iii) provide guidance on the selection of sufficient sample sizes and most informative treatment periods; and (iv) offer flexibility to various cancer models, experimental designs, and treatment options. Model-based testing of treatment effect on the tumor growth rate (or slope) was shown as particularly informative in the preclinical assessment of treatment alternatives based on dietary interventions. Conclusions: In general, the modeling framework enables identification of such biologically significant differences in tumor growth profiles that would have gone undetected or had required considerably higher number of animals when using traditional statistical methods. Clin Cancer Res; 18(16); 4385–96. ©2012 AACR.
Systemic lupus erythematosus and Klinefelter's syndrome.
Authors: M.A French, P Hughes
Journal: Annals of the Rheumatic Diseases (1983)

A case of Klinefelter's syndrome presenting with systemic lupus erythematosus while receiving androgen replacement therapy is described. The association of systemic lupus erythematosus with Klinefelter's syndrome is discussed, particularly in terms of the effect of sex hormones.
GRB10 Imprinting Is Eutherian Mammal Specific
Authors: Jessica M. Stringer, Shunsuke Suzuki, Andrew J. Pask, Geoff Shaw, Marilyn B. Renfree
Journal: Molecular Biology and Evolution (2012)

GRB10 is an imprinted gene differently expressed from two promoters in mouse and human. Mouse Grb10 is maternally expressed from the major promoter in most tissues and paternally expressed from the brain-specific promoter within specific regions of the fetal and adult central nervous system. Human GRB10 is biallelically expressed from the major promoter in most tissues except in the placental villus trophoblast where it is maternally expressed, whereas the brain-specific promoter is paternally expressed in the fetal brain. This study characterized the ortholog of GRB10 in a marsupial, the tammar wallaby (Macropus eugenii) to investigate the origin and evolution of imprinting at this locus. The protein coding exons and predicted amino acid sequence of tammar GRB10 were highly conserved with eutherian GRB10. The putative first exon, which is located in the orthologous region to the eutherian major promoter, was found in the tammar, but no exon was found in the downstream region corresponding to the eutherian brain-specific promoter, suggesting that marsupials only have a single promoter. Tammar GRB10 was widely expressed in various tissues including the brain but was not imprinted in any of the tissues examined. Thus, it is likely that GRB10 imprinting evolved in eutherians after the eutherian–marsupial divergence approximately 160 million years ago, subsequent to the acquisition of a brain-specific promoter, which resides within the imprinting control region in eutherians.
Rapid tumoritropic accumulation of systemically injected plateloid particles and their biodistribution
Authors: Anne L. van de Ven, Pilhan Kim, O'Hara Haley, Jean R. Fakhoury, Giulia Adriani, Jeffrey Schmulen, Padraig Moloney, Fazle Hussain, Mauro Ferrari, Xuewu Liu, Seok-Hyun Yun, Paolo Decuzzi
Journal: Journal of Controlled Release (2011)
Accuracy of Conflict-of-Interest Disclosures Reported by Physicians
Authors: Kanu Okike, Mininder S. Kocher, Erin X. Wei, Charles T. Mehlman, Mohit Bhandari
Journal: New England Journal of Medicine (2009)

The recent public reporting of payments made to physicians by manufacturers of orthopedic devices provides an opportunity to assess the accuracy of physicians' conflict-of-interest disclosures.We analyzed the reports of payments made to physicians by five manufacturers of total hip and knee prostheses in 2007. For each payment recipient who was an author of a presentation or served as a committee member or board member at the 2008 annual meeting of the American Academy of Orthopaedic Surgeons, the disclosure statement was reviewed to determine whether the payment had been disclosed. To ascertain the reasons for nondisclosure, a survey was administered to physicians who had received payments that were not disclosed.The overall rate of disclosure was 71.2% (245 of 344 payments). For payments that were directly related to the topic of the presentation at the meeting, the rate was 79.3% (165 of 208); for payments that were indirectly related, the rate was 50.0% (16 of 32); and for payments that were unrelated, the rate was 49.2% (29 of 59) (P=0.008). In the multivariate analysis, payments were also more likely to have been disclosed if they exceeded $10,000 (P<0.001), were directed toward an individual physician rather than a company or organization (P=0.04), or included an in-kind component (P=0.002). Among the 36 physicians who responded to the survey regarding reasons for nondisclosure (response rate, 39.6%), the reasons most commonly given for nondisclosure were that the payment was unrelated to the topic of presentation at the annual meeting (38.9% of respondents) and that the physician had misunderstood the disclosure requirements (13.9%); 11.1% reported that the payment had been disclosed but was mistakenly omitted from the program.In this study of self-reported conflict-of-interest disclosure by physicians at a large annual meeting, the rate of disclosure was 79.3% for directly related payments and 50.0% for indirectly related payments.
Survival in treated hypertension: follow up study after two decades
Authors: O. K Andersson, T. Almgren, B. Persson, O. Samuelsson, T. Hedner, L. Wilhelmsen
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective</b>: To compare survival and cause specific mortality in hypertensive men with non-hypertensive men derived from the same random population, and to study mortality and morbidity from cardiovascular diseases in the hypertensive men in relation to effects on cardiovascular risk factors during 22-23&nbsp;years of follow up. <b>Design</b>: Prospective, population based observational study. <b>Subjects and methods</b>: 686&nbsp;hypertensive men aged 47-55&nbsp;at screening compared with 6810&nbsp;non-hypertensive men. The hypertensive men were having stepped care treatment with eitherβ&nbsp;adrenergic blocking drugs, thiazide diuretics, or combination treatment. Mortality, morbidity, and adverse effects were registered at yearly examinations and from death certificates. <b>Main outcome measures</b>: All cause mortality and cause specific mortality. <b>Results</b>: Treated hypertensive men had significantly impaired probability of total survival as well as survival from coronary heart disease and stroke. All cause mortality as well as coronary heart disease and stroke mortality were very similar in hypertensive men and normotensive men during the first decade, but increased steadily thereafter despite continuous good blood pressure control. Smoking, signs of target organ damage, and high serum cholesterol levels, but not blood pressure at screening, were significantly related to the incidence of coronary heart disease during follow up. In time dependent Cox9s regression analysis, the incidence of coronary heart disease was significantly related only to serum cholesterol concentrations in the study. Cancer mortality was almost similar in treated hypertensive men (61/686, 8.9%) and non-hypertensive men (732/6810, 10.8%). <b>Conclusion</b>: Treated hypertensive men had impaired survival and increased mortality from cardiovascular disease compared with non-hypertensive men of similar age. These differences were observed during the second decade of follow up. During an observation period of 22-23&nbsp;years —about 15&nbsp;000 patient years—hypertensive men receiving diuretics and β &nbsp;blockers had no increased risk of cancer or non-cardiovascular disease.
Endothelium, Nitric Oxide, and Atherosclerosis
Authors: Richard N. Channick
Journal: Annals of Internal Medicine (2000)

Medical Writings: Book Notes6 June 2000Endothelium, Nitric Oxide, and AtherosclerosisRichard N. Channick, MDRichard N. Channick, MDUniversity of California San Diego Medical Center, San Diego, California. (Channick)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-11-200006060-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Panza JA, Cannon RO, eds. 336 pages. Armonk, NY: Futura; 1999. $75.00. ISBN 0879934360. Order phone 800-877-8761.Field of medicine: Cardiology and vascular medicine.Format: Hardcover book.Audience: Primarily clinicians and investigators in cardiovascular medicine.Purpose: To trace the role of nitric oxide (NO) in vascular biology and the atherosclerotic process.Content: The first of four sections discusses historical aspects of the discovery of NO, then turns to its basic properties and regulation. The second section highlights mechanisms of endothelial dysfunction. The third section is more clinically oriented and covers the role of NO and endothelial dysfunction in specific cardiovascular ... Author, Article, and Disclosure InformationAffiliations: University of California San Diego Medical Center, San Diego, California. (Channick) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 6 June 2000Volume 132, Issue 11Page: 931KeywordsCardiology and cardiovascular diseasesCardiovascular diseasesEndotheliumHeart failureHypertensionLungsNitric oxideSoftware toolsStable coronary artery diseaseVascular medicine ePublished: 15 August 2000 Issue Published: 6 June 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Understanding the role of mirror neurons in action understanding will require more than a domain-general account
Authors: Alia Martin, Laurie R. Santos
Journal: Behavioral and Brain Sciences (2014)

Abstract Cook et al. propose that mirror neurons emerge developmentally through a domain-general associative mechanism. We argue that experience-sensitivity does not rule out an adaptive or genetic argument for mirror neuron function, and that current evidence suggests that mirror neurons are more specialized than the authors' account would predict. We propose that future work integrate behavioral and neurophysiological techniques used with primates to examine the proposed functions of mirror neurons in action understanding.
Effects of Androgen Administration in Men with the AIDS Wasting Syndrome
Authors: S Grinspoon, C Corcoran, H Askari, D Schoenfeld, L Wolf, B Burrows, M Walsh, D Hayden, K Parlman, E Anderson, N Basgoz, A Klibanski
Journal: Annals of Internal Medicine (1998)

Background: Development of successful anabolic strategies to reverse the loss of lean body mass is of critical importance to increase survival in men with the AIDS wasting syndrome. Hypogonadism, an acquired endocrine deficiency state characterized by loss of testosterone, occurs in more than half of all men with advanced HIV disease. It is unknown whether testosterone deficiency contributes to the profound catabolic state and loss of lean body mass associated with the AIDS wasting syndrome. Objective: To investigate the effects of physiologic testosterone administration on body composition, exercise functional capacity, and quality of life in androgen-deficient men with the AIDS wasting syndrome. Design: Randomized, double-blind, placebo-controlled study. Setting: University medical center. Patients: 51 HIV-positive men (age 42 ± 8 years) with wasting (body weight < 90% of ideal body weight or weight loss > 10% of baseline weight) and a free testosterone level less than 42 pmol/L (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]). Intervention: Patients were randomly assigned to receive testosterone enanthate, 300 mg, or placebo intramuscularly every 3 weeks for 6 months. Measurements: Change in fat-free mass was the primary end point. Secondary clinical end points were weight, lean body mass, muscle mass, exercise functional capacity, and change in perceived quality of life. Virologic variables were assessed by CD4 count and viral load. Results: Compared with patients who received placebo, testosterone-treated patients gained fat-free mass ( −0.6 kg and 2.0 kg; P = 0.036), lean body mass (0.0 kg and 1.9 kg; P = 0.041), and muscle mass ( −0.8 kg and 2.4 kg; P = 0.005). The changes in weight, fat mass, total-body water content, and exercise functional capacity did not significantly differ between the groups. Patients who received testosterone reported benefit from the treatment (P = 0.036), feeling better (P = 0.033), improved quality of life (P = 0.040), and improved appearance (P = 0.021). Testosterone was well tolerated in all patients. Conclusions: Physiologic testosterone administration increases lean body mass and improves quality of life among androgen-deficient men with the AIDS wasting syndrome.
Continuous ambulatory peritoneal dialysis as a therapeutic alternative in patients with advanced congestive heart failure
Authors: Julio Núñez, Miguel González, Gema Miñana, Rafael Garcia‐Ramón, Juan Sanchis, Vicent Bodí, Eduardo Núñez, Maria Jesús Puchades, Patricia Palau, Pilar Merlos, Angel Llàcer, Alfonso Miguel
Journal: European Journal of Heart Failure (2012)
Prenatal Diagnosis for "Minor" Genetic Abnormalities is Ethical
Authors: Robert J. Boyle, Julian Savulescu
Journal: The American Journal of Bioethics (2003)

Is it justified to detect minor genetic aberrations before birth and terminate pregnancies based upon such information? We present the case of a woman who wanted Prenatal Diagnosis (PND) to detect whether her female fetus was a Haemophilia mutation carrier. Such carriers are usually healthy. She wished to eradicate the Haemophilia mutation from her family to avoid future generations being affected and to protect her children from having to go through PND themselves. We explore existing guidelines, public attitudes and possible objections to providing PND for minor abnormalities. We argue that in a society where couples have considerable autonomy relating to decisions about the fetus at least until viability, the routine restriction of PND for minor genetic abnormalities would be an unjust infringement of individual liberty.
Association of ACE Inhibitors and Angiotensin Receptor Blockers with Keratinocyte Cancer Prevention in the Randomized VATTC Trial
Authors: J. B. Christian, K. L. Lapane, A. L. Hume, C. B. Eaton, M. A. Weinstock
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundThe observation that angiotensin II is a potent angiogenic and growth factor raises the possibility that blocking its effects could reduce the incidence of cancer. We evaluated associations between use of angiotensin-converting enzyme (ACE) inhibitors and of angiotensin receptor blockers (ARBs) and keratinocyte cancer incidence in a population at high risk of the disease.
The Phosphatase Inhibitor Menadione (Vitamin K3) Protects Cells from EGFR Inhibition by Erlotinib and Cetuximab
Authors: Roman Perez-Soler, Yiyu Zou, Tianhong Li, Yi He Ling
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Skin toxicity is the main side effect of epidermal growth factor receptor (EGFR) inhibitors, often leading to dose reduction or discontinuation. We hypothesized that phosphatase inhibition in the skin keratinocytes may prevent receptor dephosphorylation caused by EGFR inhibitors and be used as a new potential strategy for the prevention or treatment of this side effect. Experimental Design: Menadione (Vitamin K3) was used as the prototype compound to test our hypothesis. HaCat human skin keratinocyte cells and A431 human squamous carcinoma cells were used. EGFR inhibition was measured by Western blotting and immunofluorescence. Phosphatase inhibition and reactive oxygen species (ROS) generation were measured by standard ELISA and fluorescence assays. Results: Menadione caused significant and reversible EGFR activation in a dose-dependent manner starting at nontoxic concentrations. EGFR activation by menadione was associated with reversible protein tyrosine phosphatase inhibition, which seemed to be mediated by ROS generation as exposure to antioxidants prevented both menadione-induced ROS generation and phosphatase inhibition. Short-term coincubation of cells with nontoxic concentrations of menadione and the EGFR inhibitors erlotinib or cetuximab prevented EGFR dephosphorylation. Seventy-two–hour coincubation of cells with the highest nontoxic concentration of menadione and erlotinib provided for a fourfold cell growth inhibitory protection in HaCat human keratinocyte cells. Conclusions: Menadione at nontoxic concentrations causes EGFR activation and prevents EGFR dephosphorylation by erlotinib and cetuximab. This effect seems to be mediated by ROS generation and secondary phosphatase inhibition. Mild oxidative stress in skin keratinocytes by topical menadione may protect the skin from the toxicity secondary to EGFR inhibitors without causing cytotoxicity. Clin Cancer Res; 17(21); 6766–77. ©2011 AACR.
Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries
Authors: Florian Blaschke, Olli Leppanen, Yasunori Takata, Evren Caglayan, Joey Liu, Michael C. Fishbein, Kai Kappert, Keiichi I. Nakayama, Alan R. Collins, Eckart Fleck, Willa A. Hsueh, Ronald E. Law, Dennis Bruemmer
Journal: Circulation Research (2004)

The liver X receptors α and β (LXRα and LXRβ) are important regulators of cholesterol homeostasis in liver and macrophages. Synthetic LXR ligands prevent the development of atherosclerosis in murine models; however, the potential functional relevance of LXRs in vascular smooth muscle cells (VSMCs) has not been investigated. In the present study, we demonstrate that LXRs are expressed and functional in primary human coronary artery VSMCs (CASMCs). LXR ligands inhibited mitogen-induced VSMC proliferation and G 1 →S phase progression of the cell cycle. Inhibition of G 1 exit by LXR ligands was accompanied by a dose-dependent inhibition of retinoblastoma protein (Rb) phosphorylation, which functions as the key switch for G 1 →S cell cycle progression. LXR ligands suppressed mitogen-induced degradation of the cyclin-dependent kinase inhibitor p27 Kip1 , attenuated cyclin D1 and cyclin A expression, and inhibited the expression of S phase-regulatory minichromosome maintenance protein 6. Stabilization of p27 kip1 by LXR ligands was mediated by supressing the transcriptional activation of the S phase kinase–associated protein 2 (Skp2), an F-box protein that targets p27 Kip1 for degradation. Inhibition of Rb phosphorylation and G 1 →S cell cycle progression by LXR ligands was reversed in VSMCs overexpressing Skp2, indicating that Skp2 as an upstream regulator of p27 Kip1 degradation plays a central role in LXR ligand–mediated inhibition of VSMC proliferation. Furthermore, adenovirus-mediated overexpression of the S phase transcription factor E2F, which is released after Rb phosphorylation, reversed the inhibitory effect of LXR ligands on VSMC proliferation and S phase gene expression, suggesting that the primary mechanisms by which LXR ligands inhibit VSMC proliferation occur upstream of Rb phosphorylation. Finally, neointima formation in a model of rat carotid artery balloon injury was significantly attenuated after treatment with the LXR ligand T1317 compared with vehicle-treated animals. These data demonstrate that LXR ligands inhibit VSMC proliferation and neointima formation after balloon injury and suggest that LXR ligands may constitute a novel therapy for proliferative vascular diseases. The full text of this article is available online at http://circres.ahajournals.org.
A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer
Authors: Richard M. Goldberg, Daniel J. Sargent, Roscoe F. Morton, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Henry C. Pitot, Steven R. Alberts
Journal: Journal of Clinical Oncology (2003)

Purpose Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. Patients and Methods Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. Results A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. Conclusion The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.