tbuckley/cabot-search huggingface dataset:
A Phase I Clinical-Pharmacodynamic Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Proteasome Inhibitor Bortezomib in Advanced Acute Leukemias
Authors: Jeffrey E. Lancet, Vu H. Duong, Elliott F. Winton, Robert K. Stuart, Michelle Burton, Shumin Zhang, Christopher Cubitt, Michelle A. Blaskovich, John J. Wright, Said Sebti, Daniel M. Sullivan
Journal: Clinical Cancer Research (2011)

To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias.In a "3 + 3" design, patients received escalating doses of tipifarnib (days 1-14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMC) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-κB activity.The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-κB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and additional 5 patients had stable disease.Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance.
Acquired Resistance to Tamoxifen Is Associated with Loss of the Type I Insulin-like Growth Factor Receptor: Implications for Breast Cancer Treatment
Authors: Dedra H. Fagan, Ryan R. Uselman, Deepali Sachdev, Douglas Yee
Journal: Cancer Research (2012)

The role of the insulin-like growth factor (IGF) system in breast cancer is well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. In this study, we examined the effectiveness of IGF1R inhibitors in vitro by generating tamoxifen-resistant (TamR) cells. We found that TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and failed to respond to IGF-I-induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. The IGF1R antibody dalotuzumab inhibited IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. An IGF1R tyrosine kinase inhibitor, AEW541, with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II-stimulated effects in TamR cells. Tamoxifen-treated xenografts also had reduced levels of IGF1R, and dalotuzumab did not enhance the effect of tamoxifen. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Inhibition of IR may be necessary to manage tamoxifen-resistant breast cancer.
Electromechanical mapping for determination of myocardial contractility and viability
Authors: Andreas Keck, Klaus Hertting, Yitzhack Schwartz, Roland Kitzing, Michael Weber, Bernhard Leisner, Christian Franke, Edda Bahlmann, Carsten Schneider, Thomas Twisselmann, Michael Weisbach, Robert Küchler, Karl Heinz Kuck
Journal: Journal of the American College of Cardiology (2002)
Fifteen-Year Trends in Lower Limb Amputation, Revascularization, and Preventive Measures Among Medicare Patients
Authors: Philip P. Goodney, Massimo Tarulli, Adrienne E. Faerber, Andreas Schanzer, Robert M. Zwolak
Journal: JAMA Surgery (2014)

Although severe lower extremity peripheral arterial disease affects more than 12 million people in the United States,1,2 secular trends in the risk of amputation remain unexplored in recent years. Using national billing and survey data sets from the Centers for Medicare and Medicaid Services and the Behavioral Risk Factor Surveillance System, we examined trends in lower extremity amputation rates, diagnostic and therapeutic vascular procedures, and the use of preventive measures aimed at limiting the use of amputation procedures in the United States between 1996 and 2011.
STAT1
Authors: Michelle Thomas, Clodagh E. Finnegan, Katherine M.-A. Rogers, James W. Purcell, Anne Trimble, Patrick G. Johnston, Marion P. Boland
Journal: Cancer Research (2004)

Abstract The anthracyclines, such as doxorubicin, are widely used in the treatment of breast cancer. Previously, we showed that these drugs could activate the transcription factor, nuclear factor κB, in a DNA damage-dependent manner. We now show that these drugs can potentiate the activation of signal transducer and activator of transcription 1 (STAT1) in MDA-MB 435 breast cancer cells treated with IFN-γ. We observed that key markers of STAT1 activation, including tyrosine 701 and serine 727 phosphorylation, were enhanced in the presence of doxorubicin. This potentiation resulted in enhanced nuclear localization of activated STAT1 and led to an increase in the nuclear binding of activated STAT complexes. The observed potentiation was specific for STAT1 and IFN-γ, as no effects were observed with either STAT3 or STAT5. Furthermore, the type I IFNs (α and β) had little or no effect. The observed effects on STAT1 phosphorylation have previously been linked with maximal transcriptional activation and apoptosis. Cell viability was assessed by crystal violet staining followed by analysis with CalcuSyn to determine combination index values, a measure of synergy. We confirmed that significant synergy existed between IFN-γ and doxorubicin (combination index = 0.34) at doses lower than IC50 values for this drug (0.67 μmol/L). In support of this, we observed that apoptotic cell death was also enhanced by measuring poly(ADP-ribose) polymerase and caspase-3 cleavage. Finally, suppression of STAT1 expression by small-interfering RNA resulted in a loss of synergistic apoptotic cell death compared with cells, where no suppression of STAT1 expression was attained with scrambled small-interfering RNA control. We conclude that doxorubicin potentiates STAT1 activation in response to IFN-γ, and that this combination results in enhanced apoptosis in breast cancer cells.
Lessons from the repression of the α-fetoprotein gene in the adult liver
Authors: Bahri M. Bilir
Journal: Hepatology (1993)

The developmental regulation of the α-fetoprotein (AFP) gene in liver results in high-level expression in the fetus, followed by dramatic transcriptional repression after birth. We have examined the mouse AFP gene for transcriptional control sequences that may be involved in its postnatal repression in liver. We showed previously that removal of a DNA region between positions −250 base pairs (bp) and −838 bp of the AFP gene resulted in the persistence of expression of an AFP minigene in the postpartum liver of transgenic mice (Vacher and Tilghman, Science 250;1732-1735, 1990). This study examines the distribution of these transgene transcripts in liver using in situ hybridization. We show that there is a zonal distribution of minigene transcripts in the adult livers of these animals. Hepatocytes surrounding the central veins express high levels of minigene transcripts, while hepatocytes in the intermediate and portal areas contain few, if any, transcripts. Quantitative RNAsc protection analysis shows a decrease in transgene RNA levels after birth, consistent with repression in all but a small subset of hepatocytes. These results indicate that repression in the pericentral hepatocytes is dependent upon the presence of a cis -acting, negative-regulatory domain, which is located between the enhancers and the proximal promoter of the AFP gene. In contrast, this domain is not essential for complete repression of AFP transgenes in the intermediate zone and periportal hepatocytes.
Discovery of Genes Essential for Heme Biosynthesis through Large-Scale Gene Expression Analysis
Authors: Roland Nilsson, Iman J. Schultz, Eric L. Pierce, Kathleen A. Soltis, Amornrat Naranuntarat, Diane M. Ward, Joshua M. Baughman, Prasad N. Paradkar, Paul D. Kingsley, Valeria C. Culotta, Jerry Kaplan, James Palis, Barry H. Paw, Vamsi K. Mootha
Journal: Cell Metabolism (2009)
Why Current Publication Practices May Distort Science
Authors: Neal S Young, John P. A Ioannidis, Omar Al-Ubaydli
Journal: PLoS Medicine (2008)

The current system of publication in biomedical research provides a distorted view of the reality of scientific data that are generated in the laboratory and clinic.This system can be studied by applying principles from the field of economics.The "winners curse", a more general statement of publication bias, suggests that the small proportion of results chosen for publication are unrepresentative of scientists repeated samplings of the real world.The self-correcting mechanism in science is retarded by the extreme imbalance between the abundance of supply (the output of basic science laboratories and clinical investigations) and the increasingly limited venues for publication (journals with sufficiently high impact).This system would be expected intrinsically to lead to the misallocation of resources.The scarcity of available outlets is artificial, based on the costs of printing in an electronic age and a belief that selectivity is equivalent to quality.Science is subject to great uncertainty: we cannot be confident now which efforts will ultimately yield worthwhile achievements.However, the current system of publication abdicates to a small number of intermediates an authoritative prescience to anticipate a highly unpredictable future.In considering societys expectations and our own goals as scientists, we believe that there is a moral imperative to reconsider how scientific data are judged and disseminated.Science can be viewed from various standpoints, not only from that of epistemology: for example, we can look at it as a biological and or as a sociological phenomenon.As such, it might be described as a tool, or an instrument, comparable perhaps to some of our industrial machinery.Science may be regarded as a means of production... Karl Popper, The Logic of Scientific Discovery, 1932 (1) The central economic fact about the processes of invention and research is that they are devoted to the production of information.
Common Carotid Intima-Media Thickness and Arterial Stiffness
Authors: Petra C. G. Simons, Ale Algra, Michiel L. Bots, Diederick E. Grobbee, Yolanda van der Graaf
Journal: Circulation (1999)

Background —Common carotid intima-media thickness (IMT) and distensibility are markers of structural and functional vessel wall properties. Both parameters have been found in population-based studies to be associated with cardiovascular risk factors and prevalent cardiovascular disease. We investigated cross-sectionally whether IMT and distensibility are associated with cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors and evaluated the diagnostic ability of IMT and distensibility to discriminate between low- and high-risk patients. Methods and Results —IMT and distensibility (change of diameter) of the left and right common carotid arteries were measured in the first 570 patients (537 for distensibility) enrolled in the Second Manifestations of ARTerial disease (SMART) study, a cohort study among patients with a manifestation of vascular disease or cardiovascular risk factors. Three risk scores were used to classify each patient’s vascular risk. Areas under the curve (AUCs) of receiver-operating characteristic curves were calculated for IMT and distensibility after the patients were dichotomized on the median of the risk scores as the outcome. Risk scores increased nearly linearly with increasing IMT and decreasing distensibility. The AUCs for IMT predicting high-risk patients were 0.77, 0.73, and 0.77 based on the 3 risk scores. The AUCs for distensibility were 0.65, 0.62, and 0.66. Conclusions —Common carotid IMT and distensibility are clear markers of cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors. IMT appears to discriminate between low- and high-risk patients better than distensibility.
Rapid Magnetic Resonance Imaging vs Radiographs for Patients With Low Back Pain
Authors: Jeffrey G. Jarvik, William Hollingworth, Brook Martin, Scott S. Emerson, Darryl T. Gray, Steven Overman, David Robinson, Thomas Staiger, Frank Wessbecher, Sean D. Sullivan, William Kreuter, Richard A. Deyo
Journal: JAMA (2003)

Context Faster magnetic resonance imaging (MRI) scanning has made MRI a potential cost-effective replacement for radiographs for patients with low back pain. However, whether rapid MRI scanning results in better patient outcomes than radiographic evaluation or a cost-effective alternative is unknown. Objective To determine the clinical and economic consequences of replacing spine radiographs with rapid MRI for primary care patients. Design, Setting, and Patients Randomized controlled trial of 380 patients aged 18 years or older whose primary physicians had ordered that their low back pain be evaluated by radiographs. The patients were recruited between November 1998 and June 2000 from 1 of 4 imaging centers in the Seattle, Wash, area: a university-based teaching program, a nonuniversity-based teaching program, and 2 private clinics. Intervention Patients were randomly assigned to receive lumbar spine evaluation by rapid MRI or by radiograph. Main Outcome Measures Back-related disability measured by the modified Roland questionnaire. Secondary outcomes included Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), pain, preference scores, satisfaction, and costs. Results At 12 months, primary outcomes of functional disability were obtained from 337 (89%) of the 380 patients enrolled. The mean back-related disability modified Roland score for the 170 patients assigned to the radiograph evaluation group was 8.75 vs 9.34 for the 167 patients assigned the rapid MRI evaluation group (mean difference, −0.59; 95% CI, −1.69 to 0.87). The mean differences in the secondary outcomes were not statistically significant : pain bothersomeness (0.07; 95% CI −0.88 to 1.22), pain frequency (0.12; 95% CI, −0.69 to 1.37), and SF-36 subscales of bodily pain (1.25; 95% CI, −4.46 to 4.96), and physical functioning (2.73, 95% CI −4.09 to 6.22). Ten patients in the rapid MRI group vs 4 in the radiograph group had lumbar spine operations (risk difference, 0.34; 95% CI, −0.06 to 0.73). The rapid MRI strategy had a mean cost of $2380 vs $2059 for the radiograph strategy (mean difference, $321; 95% CI, −1100 to 458). Conclusions Rapid MRIs and radiographs resulted in nearly identical outcomes for primary care patients with low back pain. Although physicians and patients preferred the rapid MRI, substituting rapid MRI for radiographic evaluations in the primary care setting may offer little additional benefit to patients, and it may increase the costs of care because of the increased number of spine operations that patients are likely to undergo.
Paraspinal muscle fibrosis: a specific pathological component in ankylosing spondylitis.
Authors: R G Cooper, A J Freemont, R Fitzmaurice, S M Alani, M I Jayson
Journal: Annals of the Rheumatic Diseases (1991)

The histological appearance of percutaneous superficial paraspinal muscle biopsy specimens from eight patients with ankylosing spondylitis was compared with that of biopsy specimens from 13 control patients with similar degrees of disability and spinal immobility due to severe, chronic mechanical back pain. In both groups marked type II muscle fibre atrophy was shown. Additionally, in patients with ankylosing spondylitis there were obvious increases in perifibre connective tissue in association with central migration of cell nuclei but without evidence of inflammation. Qualitative electromyography failed to show denervation changes in either group. Paraspinal muscle fibrosis, occurring over and above atrophic changes due to disuse, seems to be a specific pathological component of ankylosing spondylitis which may be of particular importance in early disease as it may contribute towards back stiffness and weakness.
Clinical Importance of Obesity Versus the Metabolic Syndrome in Cardiovascular Risk in Women
Authors: Kevin E. Kip, Oscar C. Marroquin, David E. Kelley, B. Delia Johnson, Sheryl F. Kelsey, Leslee J. Shaw, William J. Rogers, Steven E. Reis
Journal: Circulation (2004)

Background— Obesity and the metabolic syndrome frequently coexist. Both are associated with cardiovascular disease (CVD). However, the contribution of obesity to cardiovascular risk, independent of the presence of the metabolic syndrome, remains controversial. Methods and Results— From the WISE study, 780 women referred for coronary angiography to evaluate suspected myocardial ischemia were classified by body mass index (BMI; &lt;24.9=normal, n=184; ≥25.0 to ≤29.9=overweight, n=269; ≥30.0=obese, n=327) and presence (n=451) or absence (n=329) of the metabolic syndrome, further classified by diabetes status. Prevalence of significant angiographic coronary artery disease (CAD; ≥50% stenosis) and 3-year risk of CVD were compared by BMI and metabolic status. The metabolic syndrome and BMI were strongly associated, but only metabolic syndrome was associated with significant CAD. Similarly, unit increases in BMI (normal to overweight to obese) were not associated with 3-year risk of death (adjusted hazard ratio [HR] 0.92, 95% CI 0.59 to 1.51) or major adverse cardiovascular event (MACE: death, nonfatal myocardial infarction, stroke, congestive heart failure; adjusted HR 0.95, 95% CI 0.71 to 1.27), whereas metabolic status (normal to metabolic syndrome to diabetes) conferred an approximate 2-fold adjusted risk of death (HR 2.01, 95% CI 1.26 to 3.20) and MACE (HR 1.88, 95% CI 1.38 to 2.57). Levels of C-reactive protein (hs-CRP) were more strongly associated with metabolic syndrome than BMI but were not independently associated with 3-year risk of death or MACE. Conclusions— The metabolic syndrome but not BMI predicts future cardiovascular risk in women. Although it remains prudent to recommend weight loss in overweight and obese women, control of all modifiable risk factors in both normal and overweight persons to prevent transition to the metabolic syndrome should be considered the ultimate goal.
Cytokine Preconditioning Promotes Codifferentiation of Human Fetal Liver CD133 <sup>+</sup> Stem Cells Into Angiomyogenic Tissue
Authors: Sergey V. Shmelkov, Sarah Meeus, Nelson Moussazadeh, Pouneh Kermani, William K. Rashbaum, Sina Y. Rabbany, Marilee A. Hanson, William J. Lane, Ryan St. Clair, Kathryn A. Walsh, Sergio Dias, Jason T. Jacobson, Barbara L. Hempstead, Jay M. Edelberg, Shahin Rafii
Journal: Circulation (2005)

CD133 (AC133) is a surface antigen that defines a broad population of stem cells, including myogenic and endothelial progenitors. CD133+ cells are rare in adult tissues, and the factors that support their differentiation into mature angiomyogenic cells are not known. These hurdles have hampered the use of CD133+ cells for therapeutic purposes. Because human fetal liver is a rich source of CD133+ cells, we sought to identify the growth factors that promote codifferentiation of these cells into angiogenic and myogenic cells.Human fetal liver CD133+ and CD133- cell subpopulations were cultured with 5'-azacytidine or vascular endothelial growth factor (VEGF165) and/or brain-derived nerve growth factor (BDNF). CD133+ but not CD133- cells from human fetal liver codifferentiated into spindle-shaped cells, as well as flat adherent multinucleated cells capable of spontaneous contractions in culture. The resulting spindle-shaped cells were confirmed to be endothelial cells by immunohistochemistry analysis for von Willebrand factor and by acetylated LDL uptake. Multinucleated cells were characterized as striated muscles by electron microscopy and immunohistochemistry analysis for myosin heavy chain. Presence of VEGF165 and BDNF significantly enhanced angiomyogenesis in vitro. Inoculation of cells derived from CD133+ cells, but not CD133- cells, into the ear pinna of NOD/SCID mice resulted in the formation of cardiomyocytes, as identified by immunostaining with cardiac troponin-T antibody. These cells generated electrical action potentials, detectable by ECG tracing.CD133 defines a population of human fetal liver cells capable of differentiating into both angiogenic and myogenic cells. Preconditioning of these CD133+ cells with VEGF165 and BDNF enhances the angiomyogenesis. CD133+ fetal liver cells ultimately may be used for therapeutic angiomyogenesis.
Spontaneous and cytokine regulated c-fos gene expression in rheumatoid synovial cells: resistance to cytokine stimulation when the c-fos gene is overexpressed
Authors: K Shimizu
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To study the effect of cytokines on the transactivation of the c<i>-fos</i> gene in relation to the contribution of overexpression of c-<i>fos</i>/AP-1 in rheumatoid joint destruction. <h3>METHODS</h3> The promoter region (−447 to +109) of the human c<i>-fos</i>gene was integrated upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, and the effect of cytokines on the expression of the c<i>-fos</i> gene was studied in the rheumatoid synovial cells of early (3–4) or late (14–18) passages, in the presence or absence of cytokines, by the transient transfection assay. <h3>RESULTS</h3> Expression of c<i>-fos</i> gene was enhanced by tumour necrosis factor α (TNFα) and interleukin 6 (IL6) in the synovial cells of early passage, whereas it was not enhanced in the synovial cells of late passage. The c<i>-fos</i> gene expression was also enhanced by 13-<i>O</i>-tetradecanoyl phorbol-13-acetate (TPA) in early passage but was somewhat suppressed in the late passage. It was found that the c-<i>fos</i> gene and c-Fos protein were both increased in the synovial cells of late passage. Similarly, c<i>-fos</i> gene expression was also not increased by TPA or cytokine stimulation in the stable<i>c-fos</i> transformants (fos-pH8) or H-ras transformed NIH3T3 cells (NIH H-ras cells) that constitutively expressed c-<i>fos</i> genes. <h3>CONCLUSIONS</h3> Although TNFα and IL6 augmented c<i>-fos</i> gene expression of rheumatoid synovial cells, transactivation of c<i>-fos</i> gene became resistant against cytokine stimulation under prolonged expression of c<i>-fos</i> gene, which may impart a tumour-like characteristic to rheumatoid synovial cells.