tbuckley/cabot-search huggingface dataset:
Transcriptional and structural impact of TATA-initiation site spacing in mammalian core promoters.
Authors: Jasmina Ponjavic, Boris Lenhard, Chikatoshi Kai, Jun Kawai, Piero Carninci, Yoshihide Hayashizaki, Albin Sandelin
Journal: Genome biology (2006)

The TATA box, one of the most well studied core promoter elements, is associated with induced, context-specific expression. The lack of precise transcription start site (TSS) locations linked with expression information has impeded genome-wide characterization of the interaction between TATA and the pre-initiation complex.Using a comprehensive set of 5.66 x 10(6) sequenced 5' cDNA ends from diverse tissues mapped to the mouse genome, we found that the TATA-TSS distance is correlated with the tissue specificity of the downstream transcript. To achieve tissue-specific regulation, the TATA box position relative to the TSS is constrained to a narrow window (-32 to -29), where positions -31 and -30 are the optimal positions for achieving high tissue specificity. Slightly larger spacings can be accommodated only when there is no optimally spaced initiation signal; in contrast, the TATA box like motifs found downstream of position -28 are generally nonfunctional. The strength of the TATA binding protein-DNA interaction plays a subordinate role to spacing in terms of tissue specificity. Furthermore, promoters with different TATA-TSS spacings have distinct features in terms of consensus sequence around the initiation site and distribution of alternative TSSs. Unexpectedly, promoters that have two dominant, consecutive TSSs are TATA depleted and have a novel GGG initiation site consensus.In this report we present the most comprehensive characterization of TATA-TSS spacing and functionality to date. The coupling of spacing to tissue specificity at the transcriptome level provides important clues as to the function of core promoters and the choice of TSS by the pre-initiation complex.
Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro
Authors: Mei Chang, Peggy A. Nakagawa, Shirley A. Williams, Michael R. Schwartz, Karen L. Imfeld, Jeffrey S. Buzby, Diane J. Nugent
Journal: Blood (2003)
Aortic Stenosis, von Willebrand Factor, and Bleeding
Authors: J. Evan Sadler
Journal: New England Journal of Medicine (2003)

Some patients with aortic stenosis have recurrent bleeding into their skin or gastrointestinal tract. Several studies suggest that this bleeding is caused by an acquired defect in von Willebrand factor and that replacement of the aortic valve restores the normal structure of von Willebrand factor and restores normal hemostasis. However, we know little about the prevalence of symptomatic defects in von Willebrand factor in patients with aortic stenosis. In this issue of the Journal, Vincentelli and colleagues (pages 343–349) address this question and provide new information about the response of such hemostatic abnormalities to valve replacement.Von Willebrand factor circulates . . .
Medical Clinics Versus Usual Care for Patients With Both Diabetes and Hypertension
Authors: David Edelman
Journal: Annals of Internal Medicine (2010)

Background: Group medical clinics (GMCs) are widely used in the management of diabetes and hypertension, but data on their effectiveness are limited. Objective: To test the effectiveness of GMCs in the management of comorbid diabetes and hypertension. Design: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00286741) Setting: 2 Veterans Affairs Medical Centers in North Carolina and Virginia. Patients: 239 patients with poorly controlled diabetes (hemoglobin A1c [HbA1c] level ≥7.5%) and hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg). Intervention: Patients were randomly assigned within each center to either attend a GMC or receive usual care. Clinics comprised 7 to 8 patients and a care team that consisted of a primary care general internist, a pharmacist, and a nurse or other certified diabetes educator. Each session included structured group interactions moderated by the educator. The pharmacist and physician adjusted medication to manage each patient's HbA1c level and blood pressure. Measurements: Hemoglobin A1c level and systolic blood pressure, measured by blinded research personnel at baseline, study midpoint (median, 6.8 months), and study completion (median follow-up, 12.8 months). Linear mixed models, adjusted for clustering within GMCs, were used to compare HbA1c levels and systolic blood pressure between the intervention and control groups. Results: Mean baseline systolic blood pressure and HbA1c level were 152.9 mm Hg (SD, 14.2) and 9.2% (SD, 1.4), respectively. At the end of the study, mean systolic blood pressure improved by 13.7 mm Hg in the GMC group and 6.4 mm Hg in the usual care group (P = 0.011 by linear mixed model), whereas mean HbA1c level improved by 0.8% in the GMC group and 0.5% in the usual care group (P = 0.159). Limitation: Measurements of effectiveness may have been limited by concomitant improvements in the usual care group that were due to co-intervention. Conclusion: Group medical clinics are a potent strategy for improving blood pressure but not HbA1c level in diabetic patients. Primary Funding Source: U.S. Department of Veterans Affairs Health Services Research and Development Service.
Impact of <i>BRCA1</i>/<i>BRCA2</i> Counseling and Testing on Newly Diagnosed Breast Cancer Patients
Authors: Marc D. Schwartz, Caryn Lerman, Barbara Brogan, Beth N. Peshkin, Chanita Hughes Halbert, Tiffani DeMarco, William Lawrence, David Main, Clinton Finch, Colette Magnant, Marie Pennanen, Theodore Tsangaris, Shawna Willey, Claudine Isaacs
Journal: Journal of Clinical Oncology (2004)

Approximately 5% to 10% of newly diagnosed breast cancer patients carry a BRCA1 or BRCA2 mutation. Given these patients' high risk for contralateral breast cancer, bilateral mastectomy is increasingly considered a treatment option for newly diagnosed BRCA1/2 carriers. In the present study, we prospectively evaluated the impact on surgical decision-making of pretreatment genetic counseling and BRCA1/BRCA2 testing among breast cancer patients at high-risk for carrying a mutation.Participants were 194 newly diagnosed breast cancer patients who had not yet received definitive surgical treatment and who had at least a 10% prior probability of carrying a BRCA1/2 mutation. Participants were offered free genetic counseling and rapid BRCA1/2 testing. Primary analyses focused on the impact of BRCA1/2 test result on subsequent breast cancer surgical treatment.Forty-eight percent of patients who were found to carry a BRCA1/2 mutation chose bilateral mastectomy as their definitive breast cancer surgery. In contrast, 24% of patients in whom no mutation was detected and 4% of test decliners opted for bilateral mastectomy. Additional predictors of bilateral mastectomy included patients' self-reports of physician recommendations for BRCA1/2 testing and bilateral mastectomy.This study highlights patient interest in and the technical feasibility of offering presurgery BRCA1/2 testing to high-risk patients. Most importantly, these results demonstrate that BRCA1/2 test results significantly affect patients' surgical decision-making. The availability of genetic counseling and testing could serve as a valuable aid to patient decision-making for newly diagnosed breast cancer patients at high-risk for carrying a mutation.
Determinants of Rapamycin Sensitivity in Breast Cancer Cells
Authors: Woo-Chul Noh, Wallace H. Mondesire, Junying Peng, Weiguo Jian, Haixia Zhang, JinJiang Dong, Gordon B. Mills, Mien-Chie Hung, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Rapamycin inhibits the serine-threonine kinase mammalian target of rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Although rapamycin analogues show activity in clinical trials, only some of the treated patients respond. The purpose of this study is to identify determinants of rapamycin sensitivity that may assist the selection of appropriate patients for therapy. Experimental Design: Breast cancer cell lines representing a spectrum of aberrations in the mTOR signaling pathway were tested for rapamycin sensitivity. The expression and phosphorylation state of multiple components of the pathway were tested by Western blot analysis, in the presence and absence of rapamycin. Results: Cell proliferation was significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell lines. The ratio of total protein levels of 4E-BP1 to its binding partner eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In contrast, overexpression of S6K1, and phosphorylated Akt independent of phosphatase and tensin homologue deleted from chromosome 10 status, were associated with rapamycin sensitivity. Targeting S6K1 and Akt with small interfering RNA and dominant-negative constructs, respectively, decreased rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, indicating that its ability to inhibit the mTOR pathway is not sufficient to confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in rapamycin-resistant cells. Conclusions: Overexpression of S6K1 and expression of phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in breast cancer patients. Furthermore, changes in cyclin D1 levels provide a potential pharmacodynamic marker of response to rapamycin.
Migraine, Platelets, and Headache Prophylaxis
Authors: Donald J. Dalessio
Journal: JAMA (1978)

Since the late 1930s and the first demonstration by Graham and Wolff that the ergot drugs were cranial vasoconstrictors, the emphasis in migraine research has been on vasomotion. This is as it should be, and these changes have been well investigated. With the aid of regional cerebral blood-flow measurements using radioactive techniques, the classical theory of preheadache intracranial vasoconstriction and subsequent intracranial and extracranial vasodilation has been proved accurate, though the recent studies of Edmeads<sup>2</sup>and Otis et al<sup>3</sup>suggest that the vascular changes in migraine may be more persistent than heretofore suspected. Migraine is characterized by vasodilation, but vasodilation of itself does not produce painful headache. During the last decade, a series of observations has been reported that suggests that in migraine, vasoactive substances are liberated locally about painful and distended blood vessels.<sup>4</sup>This combination of vasodilation and sterile inflammation is needed if the clinical syndrome
Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer
Authors: Misun Park, Won Kyu Kim, Meiying Song, Minhee Park, Hyunki Kim, Hye Jin Nam, Sung Hee Baek, Hoguen Kim
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis. Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation. Results: We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-δ in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004). Conclusions: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ–mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT. Clin Cancer Res; 19(18); 4961–71. ©2013 AACR.
Tracing iron and transferrin in the macrophage by visual means
Authors: Farid I. Haurani, Antoinette Ryter
Journal: American Journal of Hematology (1993)

Abstract The purpose of the study was to investigate the movement of iron and transferrin in the macrophage using light and electron microscopy. First, depicted here are the phagocytosis of antibody sensitized murine red cells by the murine bone marrow derived macrophage and the formation of red cell phagosomes. Second, we show the fusion of the lysosomes with the red cell phagosome to form a lysophagosome and the lysis of the red cell using acid phosphatase as a lysosome marker. Third, by autoradiography, the presence of 55 Fe silver grains in the phagocytosed red cells and its delivery to the organelles of the macrophage are demonstrated. Fourth a transferrin species is shown in red cells of all ages, in the phagocytosed as well as the non‐phagocytosed, and in the phagocytosed as well as the non‐phagocytosed, and in the macrophage itself. Transferrin was detected using immunogold and fluorescence labelling. These studies suggest that iron, using vesicles as means of transport, moves from the effete red cells inside the macrophage to the outside possibly bound to transferrin. © 1993 Wiley‐Liss, Inc.
Heart involvement in patients with systemic sclerosis is mimicked by Fra-2 transgenic mice
Authors: P Venalis, O Distler, I E Lundberg, G Schett, J H Distler
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Intoduction</h3> Systemic sclerosis (SSc) is a systemic autoimmune disease with vascular and fibrotic components. SSc-related cardiomyopathy is increasingly recognised as a major cause of death. The pathogenesis of SSc-related cardiomyopathy is poorly understood. New therapies as well as platforms for testing are needed. There, the authors characterise different murine models of SSc and identify the best animal model for SSc-related cardiomyopathy. <h3>Methods</h3> Six patients with definite SSc were enrolled in the project. Three systemic disease models of scleroderma were chosen: Fra-2 transgenic mice (Fra-2), sclerodermatous chronic Graft versus Host disease (cGvHD) and tight skin 1 mutation (Tsk-1) models. Heart sections were stained for α-SMA, CD31, active caspase3, picrosirius, haematoxylin/eosin. <h3>Result</h3> Significant accumulation of collagen was observed in hearts of SSc patients. Fibrotic area was increased in 8.8±2.3 folds compared to controls (p&lt;0.001). Same pattern was found in Fra-2 mice with 8.9±2.8 fold increase (p=0.0002). No significant fibrosis observed in cGvHD and Tsk-1 mice. SSc samples presented with increased numbers of myofibroblasts 2.5±0.6 vs. 0.5±0.8 (p=0.01) per high power field in controls. Same pattern found in all models of SSc, though highest mimicry observed in Fra-2 model (3.0±1.1 vs 0.5±0.6 p=0.0005). Slight increases in myofibroblast numbers were also obtained in cGvHD and Tsk-1 models. CD31 staining revealed significant loss of capillaries in SSc hearts (2.16±0.17 fold change vs controls p&lt;0.0001). Similar capillary loss was observed in Fra-2 tg and in cGvHD models (2.0±0.2 and 2.1±0.3 respectively, p&lt;0.0001). No changes observed in Tsk-1 mice. Endothelial apoptosis was increased in Fra-2 tg mice versus controls (2.5±0.9 vs 0.17±0.43 p=0.0001). Apoptosis was observed in cGvHD mice though it was also elevated in controls (2.6±0.7 vs 1.2±0.5 p=0.003). No apoptosis detected in Tsk-1 mice. Endothelial apoptosis was also elevated in SSc hearts with 1.2±0.4 versus 0.2±0.4 in controls (p=0.0018). Detected higher numbers of perivascular leucocytes in SSc patients (5.8±1.8 fold change, p=0.0001), strengthened the hypothesis of vascular damage. <h3>Conclusion</h3> The typical features of cardiac disease in SSc-loss of capillaries due to endothelial apoptosis and fibrosis- are closely mimicked by Fra-2 tg mice. In contrast, the changes in cGvHD and Tsk-1 mice were less representative. Thus, Fra-2 tg mice are a promising preclinical model to study the mechanisms and therapeutic approaches of scleroderma heart involvement.
Comparison of Gemcitabine Versus the Matrix Metalloproteinase Inhibitor BAY 12-9566 in Patients With Advanced or Metastatic Adenocarcinoma of the Pancreas: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: M.J. Moore, J. Hamm, J. Dancey, P.D. Eisenberg, M. Dagenais, A. Fields, K. Hagan, B. Greenberg, B. Colwell, B. Zee, D. Tu, J. Ottaway, R. Humphrey, L. Seymour
Journal: Journal of Clinical Oncology (2003)

To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer.Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned.The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P <.001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P <.001). Quality-of-life analysis also favored gemcitabine.Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.
The prediction of maximal oxygen uptake from submaximal ratings of perceived exertion elicited during the multistage fitness test
Authors: R C Davies, A V Rowlands, R G Eston
Journal: British Journal of Sports Medicine (2008)

The purpose of this study was to assess whether maximal oxygen uptake (V.O 2max ) could be predicted from submaximal ratings of perceived exertion (RPE) elicited during the multistage fitness test (MFT). Eleven female volunteers completed three maximal exercise tests in random order; the MFT, a simulated MFT on a motorised treadmill and a graded exercise test to volitional exhaustion (GXT), also on a motorised treadmill. RPE values were recorded at the end of each 1 min stage in all three tests. Oxygen consumption (VO 2 ) was recorded continuously during the treadmill tests. Measured V.O 2max values from the GXT and simulated MFT were not significantly different (48.2 and 47.5 ml/kg/min, respectively), but they were significantly higher than V.O 2max values predicted by the MFT (41.2 ml/kg/min, p&lt;0.05). Regression of submaximal RPE values (7–17) elicited from the MFT and VO 2 values predicted by the MFT were extrapolated to RPE 20 to predict V.O 2max . The RPE-predicted V.O 2max from the MFT (47.5 ml/kg/min) was similar to measured V.O 2max . The findings suggest that submaximal RPE values can be used to provide acceptable estimates of V.O 2max which are more accurate than the published table values for the MFT. Furthermore, the use of RPE measures in conjunction with the MFT enhances the accuracy of V.O 2max prediction by the MFT.
Endothelium-derived relaxing factor released from canine femoral artery by acetylcholine cannot be identified as free nitric oxide by electron paramagnetic resonance spectroscopy.
Authors: S S Greenberg, D E Wilcox, G M Rubanyi
Journal: Circulation Research (1990)

Recent studies using chemiluminescence and spectrophotometry have shown that cultured and native endothelial cells release nitric oxide (NO). Pharmacological and biochemical evidence argue for and against the proposal that endothelium-derived relaxing factor (EDRF) is identical with free NO. In an attempt to identify EDRF as free NO, a bioassay technique was combined with an NO trap (hemoglobin bound to agarose; Ag-Hb), and electron paramagnetic resonance (EPR) spectroscopy was used to detect the resultant nitrosylhemoglobin (NO-Hb). Canine femoral arteries with or without endothelium were perfused with physiological saline solution containing superoxide dismutase and ibuprofen and were stimulated with acetylcholine. The relaxing activity of the effluent was monitored in canine coronary artery rings without endothelium (bioassay tissue) half-maximally contracted with U46619. Acetylcholine stimulated the release of EDRF from intact femoral arteries (but not from segments without endothelium), which relaxed the bioassay tissue by 63 +/- 5%. NO (approximately 1 and approximately 10 nM) infused directly over the bioassay tissue produced 34 +/- 8% and 96 +/- 3% relaxation, respectively (ED50, approximately 2 nM). Effluents were collected under vacuum in the absence of oxygen through a column containing Ag-Hb, and the samples were assayed for NO-Hb by EPR. Samples containing NO produced the triplet EPR signal characteristic of NO-Hb, but the effluent containing EDRF did not. Infusion of NO through the donor tissue in the presence of acetylcholine gave an EPR signal similar to that observed when NO had no contact with the tissue. Nitrite anion (up to 2.7 x 10(-2) M) produced no detectable NO-Hb in analogous experiments. Thus, EDRF released from the native endothelium of canine femoral artery cannot be identified as free NO. The present findings support a concept that EDRF may be a labile precursor of NO.