tbuckley/cabot-search huggingface dataset:
The Human Orthologue of <i>Drosophila</i> Ecdysoneless Protein Interacts with p53 and Regulates Its Function
Authors: Ying Zhang, Channabasavaiah B. Gurumurthy, JunHyun Kim, Ishfaq Bhat, Qingshen Gao, Goberdhan Dimri, Sam W. Lee, Hamid Band, Vimla Band
Journal: Cancer Research (2006)

Abstract Biochemical mechanisms that control the levels and function of key tumor suppressor proteins are of great interest as their alterations can lead to oncogenic transformation. Here, we identify the human orthologue of Drosophila melanogaster ecdysoneless (hEcd) as a novel p53-interacting protein. Overexpression of hEcd increases the levels of p53 and enhances p53 target gene transcription whereas hEcd knockdown has the opposite effects on p53 levels and target gene expression. Furthermore, hEcd interacts with murine double minute-2 and stabilizes p53 by inhibiting murine double minute-2–mediated degradation of p53. Thus, hEcd protein represents a novel regulator of p53 stability and function. Our studies also represent the first demonstration of a biochemical function for hEcd protein and raise the possibility that altered hEcd levels and/or function may contribute to oncogenesis. (Cancer Res 2006; 66(14): 7167-75)
Response to Comments on Inzucchi et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–149
Authors: Silvio E. Inzucchi, David R. Matthews
Journal: Diabetes Care (2015)

Mazzucchelli et al. (1) are incorrect in stating that the recently updated American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) Position Statement on the management of hyperglycemia in type 2 diabetes (2) favors newer drug classes to sulfonylureas because of lower hypoglycemia rates. The risk of hypoglycemia is important to consider, but it is merely one factor influencing optimal drug selection. Most agents that have become available over the past 15 years, including thiazolidinediones, incretin-based therapies, and sodium–glucose cotransporter 2 inhibitors, are associated with much lower hypoglycemia rates when compared with insulin or insulin secretagogues. Nonetheless, each of these classes has its own adverse effects and/or potential concerns with long-term use—issues with which clinicians and patients must also contend.

Mazzucchelli et al. also appear to minimize the risk of hypoglycemia with the sulfonylurea gliclazide. While likely to a lesser degree than certain other members of this …
Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers
Authors: Gregory N. Gan, Justin Eagles, Stephen B. Keysar, Guoliang Wang, Magdalena J. Glogowska, Cem Altunbas, Ryan T. Anderson, Phuong N. Le, J. Jason Morton, Barbara Frederick, David Raben, Xiao-Jing Wang, Antonio Jimeno
Journal: Cancer Research (2014)

Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy.
Dopamine Treatment of Postischemic Contractile Dysfunction Rapidly Induces Calcium-Dependent Pro-Apoptotic Signaling
Authors: Christof Stamm, Ingeborg Friehs, Douglas B. Cowan, Hung Cao-Danh, Yeong-Hoon Choi, Lennart F. Duebener, Francis X. McGowan, Pedro J. del Nido
Journal: Circulation (2002)

Ischemia and adrenergic stimulation of cardiomyocyte cultures have been shown to induce apoptotic cell death. We hypothesized that in a model of contractile dysfunction following ischemia, a commonly used catecholamine such as dopamine augments cardiomyocyte apoptosis via activation of calcium-dependent signaling cascades.Isolated perfused rabbit hearts were subjected to 45 minutes of normothermic ischemia with cardioplegic arrest. Hearts were reperfused for 120 minutes with unmodified perfusate (control), perfusate containing 20 nM dopamine, dopamine+2,3-butanedione monoxime (BDM), a MgATPase-inhibitor, or the calcium-sensitizing inotrope ORG 30029. Ischemia-reperfusion alone caused contractile dysfunction without significant myocardial necrosis (left ventricular pressure-volume curves; 1% triphenyltetrazolium chloride staining; creatine kinase release) or apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling [TUNEL] analysis; immunoblotting for poly(ADP-ribose) polymerase [PARP] cleavage; activation of caspases-3, -8, and -9; expression of Bax/Bcl-2). Intracellular calcium [Ca2+]i measured by rhod-2 spectrofluorometry was increased in dopamine-reperfused hearts. Although postischemic dopamine treatment improved contractility, the number of apoptotic cardiomyocytes was significantly higher than in untreated postischemic hearts (32.5+/-9 versus 5.5+/-1.6/1000 nuclei, P<0.01). Further evidence of dopamine-stimulated apoptosis included PARP cleavage, activation of mitochondrial-derived caspase-9, and the terminal effector caspase-3. Dopamine also increased cellular content of pro-apoptotic Bax while decreasing anti-apoptotic Bcl-2. Simultaneous treatment with BDM suppressed contractility without affecting [Ca2+]i and did not reduce dopamine-stimulated apoptotic markers. When contractility was increased without elevating [Ca2+]i using ORG 30029, no activation of pro-apoptotic signaling cascades was found. Dopamine infusion in nonischemic hearts did not result in cardiomyocyte apoptosis.Postischemic dopamine treatment of contractile dysfunction activates pro-apoptotic signal cascades, most likely via a calcium-dependent process and mitochondrial damage.
Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia
Authors: Gail J. Roboz, Francis J. Giles, Ellen K. Ritchie, Sandra Allen-Bard, Tania J. Curcio, Meredith A. Wilkes, S. Lani Park, Hagop M. Kantarjian, Stefan Faderl, Farhad Ravandi, Michael J. Kelner, Eric J. Feldman
Journal: Journal of Clinical Oncology (2006)

Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity.Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts.Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%.Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days.
The Relationship between Lung Inflammation and Cardiovascular Disease
Authors: Stephan Van Eeden, Jonathon Leipsic, S. F. Paul Man, Don D. Sin
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Acute and chronic lung inflammation is an underrecognized risk factor for cardiovascular disease. Yet, there are compelling epidemiological data to indicate that airway exposures to cigarette smoke, air pollution particles, and viral and bacterial pathogens are strongly related to acute ischemic events. Over the past 10 years, there have been important human and animal studies that have provided experimental evidence to support a causal link. In this article, we review the epidemiological data for the relationship between lung inflammation and cardiovascular disease and provide plausible mechanistic pathways by which acute and chronic inflammation contributes to the development of acute cardiovascular syndromes.
Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites.
Authors: L R Gottschalk, D M Giannola, S G Emerson
Journal: The Journal of Experimental Medicine (1993)

Interleukin 3 (IL-3) is a hematopoietic stem-cell growth and differentiation factor that is expressed solely in activated T and NK cells. Studies to date have identified elements 5' to the IL-3 coding sequences that regulate its transcription, but the sequences that confer T cell-specific expression remain to be clearly defined. We have now identified DNA sequences that are required for T cell-restricted IL-3 gene transcription. A series of transient transfections performed with human IL-3-chloramphenicol acetyltransferase (CAT) reporter plasmids in T and non-T cells revealed that a plasmid containing 319 bp of 5' flanking sequences was active exclusively in T cells. Deletion analysis revealed that T cell specificity was conferred by a 49-bp fragment (bp -319 to -270) that included a potential binding site for AP-1 transcription factors 6 bp upstream of a binding site for Elf-1, a member of the Ets family of transcription factors. DNaseI footprint and electrophoretic mobility shift assay analyses performed with MLA-144 T cell nuclear extracts demonstrated that this 49-bp region contains a nuclear protein binding region that includes consensus AP-1 and Elf-1 binding sites. In addition, extracts prepared from purified human T cells contained proteins that bound to synthetic oligonucleotides corresponding to the AP-1 and Elf-1 binding sites. In vitro-transcribed and -translated Elf-1 protein bound specifically to the Elf-1 site, and Elf-1 antisera competed and super shifted nuclear protein complexes present in MLA-144 nuclear extracts. Moreover, addition of anti-Jun family antiserum in electrophoretic mobility shift assay reactions completely blocked formation of the AP-1-related complexes. Transient transfection studies in MLA-144 T cells revealed that constructs containing mutations in the AP-1 site almost completely abolished CAT activity while mutation of the Elf-1 site or the NF-IL-3 site, a previously described nuclear protein binding site (bp. -155 to -148) in the IL-3 promoter, reduced CAT activity to &amp;lt; 25% of the activity given by wild-type constructs. We conclude that expression of the human IL-3 gene requires the AP-1 and Elf-1 binding sites; however, unlike other previously characterized cytokine genes such as IL-2, the AP-1 and Elf-1 factors can bind independently in the IL-3 gene.(ABSTRACT TRUNCATED AT 400 WORDS)
An increase in exhaled nitric oxide is not associated with activity in pulmonary sarcoidosis
Authors: D. Ziora, K. Kałuska, J. Kozielski
Journal: European Respiratory Journal (2004)

Exhaled nitric oxide (eNO) concentration measurement may permit the noninvasive estimation of the severity of airways inflammation in respiratory tract diseases. The aim of this study was to evaluate the correlation between eNO concentration and the activity of sarcoidosis, its radiographic staging and lung function abnormalities. eNO concentration was measured using a chemiluminescent analyser in 27 patients with sarcoidosis and 11 control subjects. The mean eNO concentration in patients with sarcoidosis was significantly higher (6.7±0.50 parts per billion (ppb)) than that in the control group (5.17±0.73 ppb). eNO concentration was similar in radiographic stage I, II and III patients (6.53, 7.32 and 6.24 ppb, respectively). No significant difference was found in eNO concentration between the patients with active and inactive disease. Nor did eNO concentration differ between the patients with and without indication for therapy. There was no significant correlation between eNO concentration and forced vital capacity or bronchoalveolar lavage fluid lymphocyte and macrophage counts. There was a weak correlation between eNO concentration and single-breath carbon monoxide diffusing capacity of the lung. Exhaled nitric oxide concentration is elevated in patients with sarcoidosis. This concentration does not depend on the radiographic staging, activity or progression of the disease.
Automated quantification of radiological patterns predicts survival in idiopathic pulmonary fibrosis
Authors: Fabien Maldonado, Teng Moua, Srinivasan Rajagopalan, Ronald A. Karwoski, Sushravya Raghunath, Paul A. Decker, Thomas E. Hartman, Brian J. Bartholmai, Richard A. Robb, Jay H. Ryu
Journal: European Respiratory Journal (2013)

Accurate assessment of prognosis in idiopathic pulmonary fibrosis remains elusive due to significant individual radiological and physiological variability. We hypothesised that short-term radiological changes may be predictive of survival. We explored the use of CALIPER (Computer-Aided Lung Informatics for Pathology Evaluation and Rating), a novel software tool developed by the Biomedical Imaging Resource Laboratory at the Mayo Clinic Rochester (Rochester, MN, USA) for the analysis and quantification of parenchymal lung abnormalities on high-resolution computed tomography. We assessed baseline and follow-up (time-points 1 and 2, respectively) high-resolution computed tomography scans in 55 selected idiopathic pulmonary fibrosis patients and correlated CALIPER-quantified measurements with expert radiologists’ assessments and clinical outcomes. Findings of interval change (mean 289 days) in volume of reticular densities (hazard ratio 1.91, p=0.006), total volume of interstitial abnormalities (hazard ratio 1.70, p=0.003) and per cent total interstitial abnormalities (hazard ratio 1.52, p=0.017) as quantified by CALIPER were predictive of survival after a median follow-up of 2.4 years. Radiologist interpretation of short-term global interstitial lung disease progression, but not specific radiological features, was also predictive of mortality. These data demonstrate the feasibility of quantifying interval short-term changes on high-resolution computed tomography and their possible use as independent predictors of survival in idiopathic pulmonary fibrosis.
NICE approval of new hepatitis drug could result in £700m bill for NHS
Authors: Nigel Hawkes
Journal: BMJ (2015)

The National Institute for Health and Care Excellence (NICE) has approved another treatment for hepatitis C, presenting NHS England with a dilemma over how to pay for it.1

NICE has now approved three new treatments as cost effective: daclatasvir (Daklinza, Bristol-Myers Squibb); ledipasvir/sofosbuvir (Harvoni, Gilead Sciences); and ombitasvir/paritaprevir/ritonavir with or without dasabuvir (Viekirax with or without Exviera, AbbVie).

All are more effective than previous treatments for hepatitis C, but they are expensive. To make them affordable for the NHS, NHS England has announced a scheme to pay for the drugs for 3500 people who have developed cirrhosis of the liver as a result of hepatitis C infection. This is a small fraction of the estimated 160 000 people in England with the virus.

Fewer than half of these people are aware that they are infected, and …
In Subjects with Persistent Allergic Rhinitis (PER) Treated with Desloratadine, Improvements in Total 5-Symptom Scores (T5SS) and Rhinoconjunctivitis Quality of Life Questionnaire-Standardized (RQLQ-S) Correlate with Disease Burden as Measured using a Simple Visual Analog Scale (VAS)
Authors: T. Zuberbier, G. Canonica, C. Bachert, J. Bousquet
Journal: Journal of Allergy and Clinical Immunology (2009)
FRI0157 The eular study group for biologic registers: initiating a combined approach to the analysis of rare outcomes
Authors: K. L. Hyrich, L. Kearsley-Fleet
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Biologic therapies have significantly improved outcomes for patients with rheumatoid arthritis (RA), but concern remains regarding the occurrence of rare adverse events. Under the auspices of EULAR, a study group of investigators representing European Biologic Registers was convened in 2012. The remit was to explore an approach to combined analysis for rare biologic-associated adverse events, as it was recognised that individually, no single register may have sufficient power to explore these events alone. <h3>Objectives</h3> The purpose of this initial analysis was to compare the baseline characteristics of patients starting a first biologic therapy across Europe and to identify a common initial dataset. <h3>Methods</h3> 17 registers across Europe were invited to participate and data from 12 are included in this initial analysis. Baseline characteristics of patients starting their first biologic between 01/01/2008 and 31/12/2008 were collected including demographics, disease and drug characteristics and comorbidities. <h3>Results</h3> In total, 4573 patients with RA initiating a first ever biologic were included from 12 registers across Europe (1676 ETN, 810 IFX, 1646 ADA, 9 ANA, 64 ABA, 349 RTX, 5 TCZ, 14 other). In 2008, almost half of the registers had limited recruitment restricted to certain biologics only. All registers collected age, gender, disease duration, seropositivity for IgM-RF, DAS28, concurrent MTX and corticosteroid use (Table 1). Less frequent items included physician global score and patient pain and fatigue. Disease severity varied across the registers with DAS28 ranging from 4.2 to 6.6 and HAQ ranging from 0.8 to 1.9. Steroid use ranged from 13 to 72%. Seven registries reported on comorbidity, with hypertension being the most frequent. The prevalence of comorbidities was relatively constant across the registers with the exception of depression, which ranged from 1.4% to 20.1%. <h3>Conclusions</h3> This initial exercise has been a success with respect to a European-wide collaboration of rheumatology biologic registers. It has identified differences in prescribing patterns, recruitment strategies to individual registers, and data items collected. These differences need to be considered when applying strategies for combined analysis and in particular, the lack of common data across Europe on co-morbidities and smoking, two potentially important confounders in both treatment decisions and risk of adverse outcomes. Moving forward it is hoped that more registries will be able to participate. <h3>Disclosure of Interest</h3> None Declared
Effects of Continuous Positive Airway Pressure on Obstructive Sleep Apnea and Left Ventricular Afterload in Patients With Heart Failure
Authors: Ruzena Tkacova, Fiona Rankin, Fabia S. Fitzgerald, John S. Floras, T. Douglas Bradley
Journal: Circulation (1998)

The objectives of this study were to determine the effects of continuous positive airway pressure (CPAP) on blood pressure (BP) and systolic left ventricular transmural pressure (LVPtm) during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). In CHF patients with OSA, chronic nightly CPAP treatment abolishes OSA and improves left ventricular (LV) ejection fraction. We hypothesized that one mechanism whereby CPAP improves cardiac function in CHF patients with OSA is by lowering LV afterload during sleep.Eight pharmacologically treated CHF patients with OSA were studied during overnight polysomnography. BP and esophageal pressure (Pes) (ie, intrathoracic pressure) were recorded before the onset of sleep and during stage 2 non-rapid eye movement sleep before, during, and after CPAP application. OSA was associated with an increase in systolic BP (from 120.4+/-7.8 to 131.8+/-10.6 mm Hg, P<0.05) and systolic LVPtm (from 124.4+/-7.7 to 137.2+/-10.8 mm Hg, P<0.05) from wakefulness to stage 2 sleep. CPAP alleviated OSA, improved oxyhemoglobin saturation, and reduced systolic BP in stage 2 sleep to 115.4+/-8.5 mm Hg (P<0.01), systolic LVPtm to 117.4+/-8.5 mm Hg (P<0.01), heart rate, Pes amplitude, and respiratory rate.In CHF patients with OSA, LV afterload increases from wakefulness to stage 2 sleep. By alleviating OSA, CPAP reduces LV afterload and heart rate, unloads inspiratory muscles, and improves arterial oxygenation during stage 2 sleep. CPAP is a nonpharmacological means of further reducing afterload and heart rate during sleep in pharmacologically treated CHF patients with OSA.
Foveal Drusen Resorption One Year after Perifoveal Laser Photocoagulation
Authors: Jesse Sigelman
Journal: Ophthalmology (1991)

"Soft" drusen maculopathy is an important precursor of exudative and atrophic macular degeneration. Resorption of soft drusen at the macula in response to laser photocoagulation has been demonstrated previously. The case described in this article is unique because it documents progression of soft drusen maculopathy prior to laser and shows a better visual and morphologic result than in previous studies. In this case, perifoveal laser photocoagulation caused the complete resorption not only of the treated drusen but also the untreated subfoveal and perifoveal drusen. Foveal morphology was restored, visual acuity improved from 20/40 to 20/20, and metamorphopsia diminished. This uniquely favorable response to photocoagulation may result from the treatment of the drusen maculopathy before atrophic, exudative, or neovascular complications. This result shows the need for establishing indications for this treatment through a prospective clinical study and for investigating its mechanism of action.