tbuckley/cabot-search huggingface dataset:
Insulin Dose and Cardiovascular Mortality in the ACCORD Trial
Authors: Elias S. Siraj, Daniel J. Rubin, Matthew C. Riddle, Michael E. Miller, Fang-Chi Hsu, Faramarz Ismail-Beigi, Shyh-Huei Chen, Walter T. Ambrosius, Abraham Thomas, William Bestermann, John B. Buse, Saul Genuth, Carol Joyce, Christopher S. Kovacs, Patrick J. O'Connor, Ronald J. Sigal, Sol Solomon
Journal: Diabetes Care (2015)

OBJECTIVE In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality. RESEARCH DESIGN AND METHODS We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment. RESULTS More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P &amp;lt; 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation. CONCLUSIONS These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.
Neurite Extension and Malignancy of Neuroblastoma Cells After Treatment With Prostaglandin E 1 and Papaverine 2
Authors: John S. Lazo, Raymond W. Ruddon
Journal: JNCI Journal of the National Cancer Institute (1977)

Cultured murine neuroblastoma cells (NB4 line) were treated with the cyclic AMP-elevating agents prostaglandin E1 and papaverine to determine the effect of these agents on the state of differentiation and malignancy of the cells. Morphologic differentiation, determined by the appearance of neurite extensions greater than 50µ, occurred in 75–80% of the cells within the first 3 hours after treatment with 1µg prostaglandin E1/ml and 25µg papaverine/ml. The percentage of cells with neurites began to decrease within 24 hours after initiation of treatment, even in the continued presence of drugs. Moreover, neurite extensions were reversible even after 4 days of continuous drug exposure. Although NB4 cells and a number of clones derived from them contain acetylcholine and choline acetyltransferase activity, acetylcholine content and transferase activity were not significantly altered after treatment with prostaglandin E1 and papaverine. Cultures of NB4 cells treated with 1µg prostaglandin E1/ml and 25µg papaverine/ml stopped proliferating. Treated cultures had a prolonged population doubling time compared to control cultures for the initial 48 hours after replating in drug-free medium. After 144 hours, cultures from treated cells attained a cell density that was not statistically different from that of control cultures. The initially prolonged population doubling time in the treated cell cultures was due to a decrease in the number of dividing cells rather than to a prolonged cell cycle time. The tumorigenicity of treated cells was less than that of control cells. Fourfold more treated than control cells were needed to produce tumors in 50% of inoculated mice. Animals inoculated with treated cells had an increased mean latent period for the development of a palpable tumor mass and an increased survival time. Decreased malignancy of the treated cell population appeared to result from the loss of proliferative capacity without a concomitant irreversible change in the state of differentiation.
Tumor Metabolism and Blood Flow Changes by Positron Emission Tomography: Relation to Survival in Patients Treated With Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer
Authors: Lisa K. Dunnwald, Julie R. Gralow, Georgiana K. Ellis, Robert B. Livingston, Hannah M. Linden, Jennifer M. Specht, Robert K. Doot, Thomas J. Lawton, William E. Barlow, Brenda F. Kurland, Erin K. Schubert, David A. Mankoff
Journal: Journal of Clinical Oncology (2008)

Purpose Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome. Patients and Methods Fifty-three women with primary LABC underwent dynamic [ 18 F]fluorodeoxyglucose (FDG) and [ 15 O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K 1 ) parameters were calculated; BF was estimated from the [ 15 O]water study. Associations between BF, MRFDG, FDG K 1 , and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. Results Patients with persistent or elevated BF and FDG K 1 from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K 1 changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P &lt; .001). Conclusion LABC patients with limited or no decline in BF and FDG K 1 experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [ 15 O]water or indirectly by dynamic FDG predict DFS and OS.
Determinants and outcomes of physical activity in patients with COPD: a systematic review
Authors: Elena Gimeno-Santos, Anja Frei, Claudia Steurer-Stey, Jordi de Batlle, Roberto A Rabinovich, Yogini Raste, Nicholas S Hopkinson, Michael I Polkey, Hans van Remoortel, Thierry Troosters, Karoly Kulich, Niklas Karlsson, Milo A Puhan, Judith Garcia-Aymerich
Journal: Thorax (2014)

<h3>Background</h3> The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed. Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD. <h3>Methods</h3> We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012. Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence. <h3>Results</h3> 86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both. Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence. Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low. As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence. Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV<sub>1</sub> but based on cross-sectional studies and low to very low quality evidence. <h3>Conclusions</h3> Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment.
Psychopathy as a Clinical and Empirical Construct
Authors: Robert D. Hare, Craig S. Neumann
Journal: Annual Review of Clinical Psychology (2007)

In this review, we focus on two major influences on current conceptualizations of psychopathy: one clinical, with its origins largely in the early case studies of Cleckley, and the other empirical, the result of widespread use of the Hare Psychopathy Checklist-Revised (PCL-R) for assessment purposes. Some investigators assert that the PCL-R, ostensibly based on Cleckley's work, has "drifted" from the construct described in his Clinical Profile. We evaluate this profile, note its basis in an unrepresentative sample of patients, and suggest that its literal and uncritical acceptance by the research community has become problematical. We also argue that the idea of construct "drift" is irrelevant to current conceptualizations of psychopathy, which are better informed by the extensive empirical research on the integration of structural, genetic, developmental, personality, and neurobiological research findings than by rigid adherence to early clinical formulations. We offer some suggestions for future research on psychopathy.
Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications
Authors: Nicholas Mitsiades, Constantine S. Mitsiades, Vassiliki Poulaki, Dharminder Chauhan, Paul G. Richardson, Teru Hideshima, Nikhil C. Munshi, Steven P. Treon, Kenneth C. Anderson
Journal: Blood (2002)
The answer is 17 years, what is the question: understanding time lags in translational research
Authors: Zoë Slote Morris, Steven Wooding, Jonathan Grant
Journal: Journal of the Royal Society of Medicine (2011)

This study aimed to review the literature describing and quantifying time lags in the health research translation process. Papers were included in the review if they quantified time lags in the development of health interventions. The study identified 23 papers. Few were comparable as different studies use different measures, of different things, at different time points. We concluded that the current state of knowledge of time lags is of limited use to those responsible for R&D and knowledge transfer who face difficulties in knowing what they should or can do to reduce time lags. This effectively 'blindfolds' investment decisions and risks wasting effort. The study concludes that understanding lags first requires agreeing models, definitions and measures, which can be applied in practice. A second task would be to develop a process by which to gather these data.
Kinetics of the long-term antibody response after meningococcal C vaccination in patients with juvenile idiopathic arthritis: a retrospective cohort study
Authors: Susanne P Stoof, Marloes W Heijstek, Karen M Sijssens, Fiona van der Klis, Elisabeth A M Sanders, Peter F M Teunis, Nico M Wulffraat, Guy A M Berbers
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> The kinetics of the antibody response induced by meningococcal serogroup C (MenC) conjugate vaccination was analysed in patients with juvenile idiopathic arthritis (JIA) to assess their long-term protection against MenC disease. <h3>Methods</h3> In The Netherlands, a nationwide catch-up campaign was performed in 2002 during which children aged 1–19 years, including JIA patients, received the MenC conjugate vaccination. From 127 JIA patients, IgG antibody concentrations against MenC-polysaccharide were determined by a fluorescent-bead-based immunoassay in 402 serum samples collected between 2002 and 2010. Using a hierarchical linear regression model, the 8 years course of MenC-specific antibodies was analysed in four age groups (13–19, 9–12.9, 5–8.9 and 1–4.9 years), and in patients starting with methotrexate or biologicals. In 65 randomly selected samples, the correlation of MenC-specific IgG concentrations with serum bactericidal assay (SBA) titres was assessed. MenC-specific IgG concentrations at 4.2 years after vaccination were compared with those of 1527 age-matched healthy controls. <h3>Results</h3> MenC-specific IgG concentrations postvaccination were highest in patients aged 13–19 years at time of vaccination. Antibodies gradually waned over time in patients, but their estimated concentrations at 4.2 years postvaccination were similar to those measured in controls. MenC-specific IgG concentrations correlated well with SBA titres (r=0.72, p&lt;0.001). By contrast with methotrexate, starting treatment with biologicals induced a trend towards accelerated decline of MenC-specific antibodies. <h3>Conclusions</h3> Persistence of MenC-specific IgG antibodies in JIA patients is similar to healthy controls, but treatment with biologicals may induce accelerated antibody waning, resulting in unprotected patients who may need revaccination.
Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation
Authors: Madeleine E. Gentle, Shaolin Shi, Ilse Daehn, Taoran Zhang, Haiying Qi, Liping Yu, Vivette D. D’Agati, Detlef O. Schlondorff, Erwin P. Bottinger
Journal: Journal of the American Society of Nephrology (2013)

TGFβ signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFβ signaling, however, limiting conclusions about the direct role of TGFβ in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFβ receptor type 1 (TβR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter. In this model, activation of TGFβ signaling in the tubular epithelium alone was sufficient to cause AKI characterized by marked tubular cell apoptosis and necrosis, oxidative stress, dedifferentiation and regenerative cell proliferation, reduced renal function, and interstitial accumulation of inflammatory cells. This tubular injury was associated with mitochondrial-derived generation of reactive oxygen species (ROS), but cell damage and apoptosis were partially independent of mitochondrial-derived ROS. TβR1 signaling-induced tubular injury also associated with significant leukocyte infiltration consisting of F4/80(+) macrophages, CD11c(+) F4/80(+) dendritic cells, CD11c(+) F4/80(-) Ly6C(high) dendritic cells/monocytes, and T cells. Inhibition of mitochondrial-derived ROS significantly reduced accumulation of CD11c(+) F4/80(+) dendritic cells and T cells, suggesting a role for ROS in the activation and recruitment of the adaptive immune response to tubular injury. Taken together, these results suggest that TGFβ signaling in the tubular epithelium alone is sufficient to cause acute tubular injury and inflammation; therefore, TGFβ may be a mechanistic link between acute injury and chronic progression of kidney disease.
Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma
Authors: Qiwei Yang, Yufeng Tian, Shuqing Liu, Rana Zeine, Alexandre Chlenski, Helen R. Salwen, Jack Henkin, Susan L. Cohn
Journal: Cancer Research (2007)

Abstract In the pediatric cancer neuroblastoma, clinically aggressive disease is associated with increased levels of angiogenesis stimulators and high vascular index. We and others have hypothesized that blocking angiogenesis may be effective treatment for this pediatric malignancy. However, little is known about the efficacy of antiangiogenic agents in pediatric malignancies. Recently, promising results have been reported in an adult phase I study of ABT-510, a peptide derivative of the natural angiogenic inhibitor thrombospondin-1. Histone deacetylase inhibitors, such as valproic acid (VPA), have also been shown to have antiangiogenic activity in several cancer models. In this study, we evaluated the effects of ABT-510 and VPA on neuroblastoma tumor growth and angiogenesis. Although only VPA was capable of blocking the proliferation of neuroblastoma cells and inducing neuroblastoma cell apoptosis in vitro, treatment with VPA or ABT-510 alone significantly suppressed the growth of neuroblastoma xenografts established from two different MYCN-amplified cell lines. Combination therapy more effectively inhibited the growth of small neuroblastoma xenografts than single-agent treatment, and in animals with large xenografts, total cessation of tumor growth was achieved with this treatment approach. The microvascular density was significantly reduced in the xenografts treated with combination therapy compared with controls or tumors treated with single agents. In addition, the number of structurally abnormal vessels was reduced, suggesting that these agents may “normalize” the tumor vasculature. Our results indicate that ABT-510 combined with VPA may be an effective antiangiogenic treatment strategy for children with high-risk neuroblastoma. [Cancer Res 2007;67(4):1716–24]
Assessment of Substitution Model Adequacy Using Frequentist and Bayesian Methods
Authors: Jennifer Ripplinger, Jack Sullivan
Journal: Molecular Biology and Evolution (2010)

In order to have confidence in model-based phylogenetic methods, such as maximum likelihood (ML) and Bayesian analyses, one must use an appropriate model of molecular evolution identified using statistically rigorous criteria. Although model selection methods such as the likelihood ratio test and Akaike information criterion are widely used in the phylogenetic literature, model selection methods lack the ability to reject all models if they provide an inadequate fit to the data. There are two methods, however, that assess absolute model adequacy, the frequentist Goldman–Cox (GC) test and Bayesian posterior predictive simulations (PPSs), which are commonly used in conjunction with the multinomial log likelihood test statistic. In this study, we use empirical and simulated data to evaluate the adequacy of common substitution models using both frequentist and Bayesian methods and compare the results with those obtained with model selection methods. In addition, we investigate the relationship between model adequacy and performance in ML and Bayesian analyses in terms of topology, branch lengths, and bipartition support. We show that tests of model adequacy based on the multinomial likelihood often fail to reject simple substitution models, especially when the models incorporate among-site rate variation (ASRV), and normally fail to reject less complex models than those chosen by model selection methods. In addition, we find that PPSs often fail to reject simpler models than the GC test. Use of the simplest substitution models not rejected based on fit normally results in similar but divergent estimates of tree topology and branch lengths. In addition, use of the simplest adequate substitution models can affect estimates of bipartition support, although these differences are often small with the largest differences confined to poorly supported nodes. We also find that alternative assumptions about ASRV can affect tree topology, tree length, and bipartition support. Our results suggest that using the simplest substitution models not rejected based on fit may be a valid alternative to implementing more complex models identified by model selection methods. However, all common substitution models may fail to recover the correct topology and assign appropriate bipartition support if the true tree shape is difficult to estimate regardless of model adequacy.
Maternal transmission of duck hepatitis B virus in pedigree pekin ducks
Authors: Kwesi N. Tsiquaye, Thomas F. McCaul, Arie J. Zuckerman
Journal: Hepatology (1985)

A 14-month old female Pekin duck experimentally infected as an embryo with duck hepatitis B virus via the amniotic route has been a chronic carrier of duck hepatitis B virus with very high (P/N) values of DNA polymerase activity since hatching. All the progeny were, on evaluation for congenital infection, found to be duck hepatitis B virus positive by endogenous DNA polymerase reaction and electron microscopy. These offspring remained persistently viremic throughout the study. Maternal transmission therefore bred true to a total of 49 offspring--24 ducklings (less than 24 hr old) and 25 ducks--studied. Six of these 25 ducks matched for age and sex and bled weekly for 6 weeks exhibited fluctuating plasma levels of DNA polymerase activity. Higher DNA polymerase activity was detected in newly hatched ducklings than in older viremic ducks. This observation was corroborated with the results of electron microscopic examination of thin sections of liver. Duck hepatitis B virus particles, located within vesicles of rough endoplasmic reticulum in the cytoplasm of hepatocytes, were more abundant, and therefore more readily observed, in ducklings than in older ducks.
Neutral Endopeptidase 24.11/CD10 Suppresses Progressive Potential in Ovarian Carcinoma <i>In vitro</i> and <i>In vivo</i>
Authors: Hiroaki Kajiyama, Kiyosumi Shibata, Mikio Terauchi, Takanori Morita, Kazuhiko Ino, Shigehiko Mizutani, Fumitaka Kikkawa
Journal: Clinical Cancer Research (2005)

Abstract Recently, numerous studies have shown that endothelin-1 (ET-1) is expressed in ovarian carcinoma and that ET-1 selectively acts as an autocrine or paracrine growth factor through the endothelin A receptor (ETAR), and is involved in cell proliferation, invasiveness, neovascularization, and prevention of apoptosis. Neutral endopeptidase 24.11 (NEP) is a cell surface aminopeptidase with a ubiquitous expression and is capable of degrading a number of bioactive peptides including ET-1. Our previous report showed that stromal NEP expression in ovarian carcinoma was down-regulated as the histologic grade advanced. Here, we confirmed that NEP was expressed in tumor cells as well as stromal tissues in ovarian carcinoma, and investigated the functions of NEP in this carcinoma. We showed that there was a significant decrease in cell proliferation and invasiveness with a reduction in the concentration of ET-1 in the conditioned medium on the NEP overexpression of NEP in ovarian carcinoma cells. In addition, the overexpression of NEP enhanced susceptibility to paclitaxel, resulting in an increased occurrence of apoptotic morphologic change. Furthermore, tumorigenesis was reduced in vivo with the overexpression of NEP, down-regulation of both matrix metalloproteinase-2, and vascular endothelial growth factor expression. This evidence suggests that NEP functionally suppresses the progression of ovarian carcinoma and further study of this enzyme may reveal an effective way to target ET-1 for the treatment of this carcinoma.