tbuckley/cabot-search huggingface dataset:
A Fiber-Modified Mesothelin Promoter–Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer
Authors: Yuko Tsuruta, Larisa Pereboeva, Martina Breidenbach, Daniel T. Rein, Minghui Wang, Ronald D. Alvarez, Gene P. Siegal, Paul Dent, Paul B. Fisher, David T. Curiel
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenoviruses (CRAd) may contain tumor-specific promoters that restrict virus replication to cancer cells. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter–based CRAd in a murine model of ovarian cancer, using noninvasive in vivo imaging. Experimental Design: We constructed a mesothelin promoter–based CRAd with a chimeric Ad5/3 fiber (AdMSLNCRAd5/3) that contains an Ad5 tail, Ad5 shaft, and an Ad3 knob. Previously, a chimeric Ad5/3 fiber has shown improved infectivity in many ovarian cancer cells. Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of AdMSLNCRAd5/3 in a murine model, bioluminescence imaging of tumor luciferase activity and survival analysis were done. Results: AdMSLNCRAd5/3 achieved up to a 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all human ovarian cancer cells, compared with wild-type Ad5. AdMSLNCRAd5/3 significantly inhibited tumor growth as confirmed by in vivo imaging (P &amp;lt; 0.05). Survival with AdMSLNCRAd5/3 was significantly enhanced when compared with no virus or with a wild-type Ad5-treated group (P &amp;lt; 0.05). Conclusions: The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLNCRAd5/3 showed that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have applied in vivo imaging that has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment.
Interaction of adriamycin in vitro with cardiac myofibrillar proteins.
Authors: W Lewis, J Kleinerman, S Puszkin
Journal: Circulation Research (1982)

Binding of the anthracycline antibiotic doxorubicin [Adriamycin (ADR)] to selected cardiac muscle contractile proteins was determined in purified canine heart actin and alpha-actinin. Adriamycin binding to these proteins in solution was measured by equilibrium dialysis and gel filtration with [14C]-labeled ADR. Adriamycin did not bind when its primary amino group was blocked. Adriamycin binding did not affect actin polymerization as detected by viscometry. Viewed under the electron microscope, however, ADR promoted formation of distinct actin filaments in the presence of microM amounts of ATP without K+ and MG++. Adriamycin-induced actin microfilaments were thicker (120 A) than those of F-actin controls (70 A) and stimulated myosin-ATPase to higher levels than the F-actin controls. It appears that ADR has a direct effect on the biophysical and biochemical properties of heart myofibril proteins in vitro.
Computed tomography and magnetic resonance imaging: past, present and future
Authors: N.L. Muller
Journal: European Respiratory Journal (2002)

The aims of this paper are to summarize the current recommendations for the use of computed tomography (CT) and magnetic resonance imaging (MRI) in the chest and to suggest some possible future developments. The main developments of CT in the chest have been the introduction of high-resolution CT (HRCT), spiral CT and, more recently, multidetector spiral CT. HRCT is defined as thin-section CT (1- to 2-mm collimation scans), optimized by using a high-spatial resolution (edge-enhancing) algorithm. Several studies have shown that HRCT closely reflects macroscopic (gross) pathological findings. HRCT currently has the best sensitivity and specificity of any imaging method used for the assessment of focal and diffuse lung diseases. The advent of spiral CT and, more recently, multidetector CT scanners, has allowed for major improvements in the imaging of airways, pulmonary and systemic vessels, and lung nodules. Spiral CT facilitates multiplanar and three-dimensional display of structures and visualization of pulmonary and systemic vessels, with a level of detail that is comparable to that of conventional angiography. With the use of graphics-based software programs, spiral CT enables depiction of the luminal surface of the airways with images that resemble those of bronchoscopy (virtual bronchoscopy) or bronchography (virtual bronchography). Several studies have shown a high sensitivity and specificity for spiral CT in the diagnosis of acute pulmonary embolism. Therefore, spiral CT is rapidly becoming the imaging modality of choice in the diagnosis of pulmonary embolism. Like the radiograph, signal intensity on computed tomography is mainly due to a single parameter: electron density. The signal intensity of the magnetic resonance image depends on four parameters: nuclear density, two relaxation times called T1 and T2, and motion of the nuclei within the imaged lung volume. Abnormal soft tissue can be identified more easily through measurement of these four parameters than through use of computed tomography. Furthermore, because the spatial orientation of the image is determined by manipulation of magnetic fields, scans can be performed in any plane. The main indications for magnetic resonance in the chest have been in the evaluation of the heart, major vessels, mediastinum, and hilar structures because of the natural contrast provided by flowing blood. Of particular interest for the respirologist has been the recent development of magnetic resonance angiography. This technique consists of three-dimensional single breath-hold images obtained using gadolinium-based contrast agents. This is a promising technique for the diagnosis of acute and chronic pulmonary embolism.
BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling
Authors: Bettina C Urban, Tracey J Collard, Catherine J Eagle, Samantha L Southern, Alexander Greenhough, Maryam Hamdollah-Zadeh, Anil Ghosh, Richard Poulsom, Christos Paraskeva, Andrew Silver, Ann C Williams
Journal: Gut (2015)

Colorectal cancer remains the fourth most common cause of cancer-related mortality worldwide. Here we investigate the role of nuclear factor-κB (NF-κB) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival.Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF-κB complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5-aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated.We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-κB p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK-3β and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells.Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy.
Portal hypertension in kala-azar
Authors: D. V. Datta, S. Saha, S. L. Grover, S. A. Singh, R. N. Chakravarti, P. N. Chhuttani
Journal: Gut (1972)

The present study records haemodynamic studies in three patients with kala-azar, a parasitic disease. All the three patients had high intrasplenic pressure, mild to moderate elevation of wedged hepatic vein pressure, and increased or normal estimated hepatic blood flow. Liver histology showed marked proliferation and swelling of Kupffer cells in the sinusoids. One patient was studied serially for nine months following treatment which showed persistent elevation of intrasplenic pressure though wedge pressure and liver blood flow touched normal levels. Liver biopsy was essentially normal at this stage. These findings may have some relevance to the role of different parasitic infections in the pathogenesis of a heterogeneous group of non-cirrhotic portal fibroses.
Association of Urinary Bisphenol A Concentration With Medical Disorders and Laboratory Abnormalities in Adults
Authors: Iain A. Lang
Journal: JAMA (2008)

<h3>Context</h3>Bisphenol A (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans.<h3>Objective</h3>To examine associations between urinary BPA concentrations and adult health status.<h3>Design, Setting, and Participants</h3>Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P &lt; .05.<h3>Main Outcome Measures</h3>Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes.<h3>Results</h3>Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P &lt; .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes γ-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P &lt; .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P = .002).<h3>Conclusion</h3>Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.Published online September 16, 2008 (doi:10.1001/jama.300.11.1303).
Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors
Authors: Anna Sjöström, Mikael Eriksson, Cristina Cerboni, Maria H. Johansson, Charles L. Sentman, Klas Kärre, Petter Höglund
Journal: The Journal of Experimental Medicine (2001)

Murine natural killer (NK) cells express inhibitory Ly49 receptors specific for major histocompatibility complex (MHC) class I molecules. We report that during interactions with cells in the environment, NK cells acquired MHC class I ligands from surrounding cells in a Ly49-specific fashion and displayed them at the cell surface. Ligand acquisition sometimes reached 20% of the MHC class I expression on surrounding cells, involved transfer of the entire MHC class I protein to the NK cell, and was independent of whether or not the NK cell expressed the MHC class I ligand itself. We also present indirect evidence for spontaneous MHC class I acquisition in vivo, as well as describe an in vitro coculture system with transfected cells in which the same phenomenon occurred. Functional studies in the latter model showed that uptake of H-2Dd by Ly49A+ NK cells was accompanied by a partial inactivation of cytotoxic activity in the NK cell, as tested against H-2Dd-negative target cells. In addition, ligand acquisition did not abrogate the ability of Ly49A+ NK cells to receive inhibitory signals from external H-2Dd molecules. This study is the first to describe ligand acquisition by NK cells, which parallels recently described phenomena in T and B cells.
A Unique Metastasis Gene Signature Enables Prediction of Tumor Relapse in Early-Stage Hepatocellular Carcinoma Patients
Authors: Stephanie Roessler, Hu-Liang Jia, Anuradha Budhu, Marshonna Forgues, Qing-Hai Ye, Ju-Seog Lee, Snorri S. Thorgeirsson, Zhongtang Sun, Zhao-You Tang, Lun-Xiu Qin, Xin Wei Wang
Journal: Cancer Research (2010)

Abstract Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (&amp;lt;5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (&amp;lt;2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation. Cancer Res; 70(24); 10202–12. ©2010 AACR.
Fluorescein-enhanced Autofluorescence Thoracoscopy in Patients with Primary Spontaneous Pneumothorax and Normal Subjects
Authors: Marc Noppen, Tom Dekeukeleire, Shane Hanon, Grigoris Stratakos, Kayvan Amjadi, Priscilla Madsen, Marc Meysman, Jan D'Haese, Walter Vincken
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: The exact site(s) and pathophysiology of air leakage in patients with primary spontaneous pneumothorax (PSP) are unknown. In one patient with PSP, fluorescein-enhanced autofluorescence thoracoscopy (FEAT) has shown areas of parenchymal abnormality unnoticed during white light thoracoscopy (WLT).Objectives: To prospectively perform and compare WLT and FEAT in patients with spontaneous pneumothorax and in normal subjects.Methods: One-time FEAT and WLT inspection with systematic mapping of semiquantified lesions in 12 consecutive patients with PSP was compared with one-time FEAT and WLT during sequential bilateral thoracoscopy in 17 control subjects.Results: WLT abnormalities (anthracosis, cobblestone malformation, and blebs/bullae) were more prevalent in PSP. FEAT, however, showed high-grade lesions in PSP only, which often were present at areas that were normal, or that only showed anthracosis at WLT. When blebs/bullae were present, bleb-associated FEAT abnormalities were only present in two. Actual fluorescein leakage was seen in two patients with PSP.Conclusions: Lungs in patients with PSP show significantly more abnormalities at WLT when compared with normal subjects. High-grade FEAT lesions were exclusively present in PSP, and predominantly at lung zones that appeared normal at white light inspection. These findings suggest that significant parenchymal abnormalities are not limited to lesions visible during WLT, such as blebs and bullae.
Mechanoelectrical Feedback
Authors: Bruce B. Lerman, Erica D. Engelstein, Daniel Burkhoff
Journal: Circulation (2001)

Background— Augmented preload increases myocardial excitability by shortening action potential duration (APD). The mechanism governing this phenomenon is unknown. Because myocardial stretch increases intracellular cAMP, we hypothesized that load-dependent changes in myocardial excitability are mediated by β-adrenergic stimulation of a cAMP-sensitive K + current. Methods and Results— The effects of propranolol on load-induced changes in electrical excitability were studied in 7 isolated ejecting canine hearts. LV monophasic APD at 50% and 90% repolarization (MAPD 50 and MAPD 90 ) and refractoriness were determined at low (9±3 mL) and high (39±4 mL) load before and after β-adrenergic blockade. During control, the MAPD 50 decreased from 193±26 to 184±26 ms with increased load, as did the MAPD 90 (238±28 to 233±28 ms), P ≤0.04. Similar changes were observed in ventricular refractoriness. Treatment with propranolol completely abolished these load-induced effects. Myocardial catecholamine depletion with reserpine in 2 hearts also abolished changes in MAPD and excitability in response to increased preload. Conclusions— Increases in ventricular load mediate a decrease in ventricular APD and refractoriness through activation of the β-adrenergic receptor. An increase in a cAMP-mediated K + current, possibly the slowly activating delayed rectifier I Ks , may account in part for this form of mechanoelectrical coupling.
Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein IIb/IIIa in an experimental angioplasty model.
Authors: M A Azrin, F S Ling, Q Chen, A Pawashe, F Migliaccio, R Homer, M Todd, M D Ezekowitz
Journal: Circulation Research (1994)

The deposition of platelets at the site of balloon angioplasty is thought to play a major role in the pathogenesis of restenosis. The antibody AZ-1, which binds to the rabbit platelet glycoprotein IIb/IIIa receptor and inhibits platelet function both in vitro and in vivo, was produced and tested in an experimental model of angioplasty. Atherosclerosis was induced by desiccation injury of the femoral artery, followed by a 28-day diet with 2% cholesterol and 6% peanut oil. Rabbits were randomized to receive an infusion of saline, a single infusion of 0.5 mg/kg of AZ-1, or an infusion of 0.6 mg/kg AZ-1 before angioplasty. The latter group received a second infusion of 0.6 mg/kg 72 hours later. Functional platelet inhibition was demonstrated by prolongation of the bleeding time in all treated animals. Angiography was performed at baseline, immediately after a standardized angioplasty, and again 28 days after angioplasty on a total of 42 vessels. There were no significant differences between the antibody-treated group and the control group in the mean angiographic minimum luminal diameter at any of the time points. There was also no difference in the initial improvement after angioplasty (acute gain), in the decrease in luminal diameter from immediately after angioplasty to 28 days after angioplasty (late loss), or in the overall improvement from before angioplasty to 28 days after angioplasty. Quantitative histological analysis confirmed the lack of a beneficial effect of AZ-1. There were no significant differences in the area of the intima, the media, or the combined intima and media between the antibody-treated groups and the control group. Thus, potent platelet inhibition for up to 6 days after balloon angioplasty using a monoclonal antibody that inhibits platelet aggregation did not reduce the response to vascular injury after balloon angioplasty in this rabbit model of experimental atherosclerosis.
Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial
Authors: Richard Gray, Natalie Ives, Caroline Rick, Smitaa Patel, Alastair Gray, Crispin Jenkinson, Emma McIntosh, Keith Wheatley, Adrian Williams, Carl E Clarke
Journal: The Lancet (2014)
Structural heterogeneity of the axonemes of respiratory cilia and sperm flagella in normal men.
Authors: L J Wilton, H Teichtahl, P D Temple-Smith, D M de Kretser
Journal: Journal of Clinical Investigation (1985)

The ultrastructure of normal human cilia and flagella was examined and quantitatively assessed to determine the normal variations in the structure of the axoneme. Ciliated respiratory epithelial cells and spermatozoa from 10 normal, nonsmoking male volunteers who had normal semen parameters were fixed for electron microscopy. Tannic acid and MgSO4 were included during fixation to enhance, in particular, axonemal components. In 75 axonemal cross sections per sample, the number of outer doublet and central singlet microtubules, outer and inner dynein arms, and radial spokes were recorded. Statistical analysis of the results showed a marked reduction, from the expected value of nine, in the numbers of inner dynein arms (mean +/- SE, cilia, 5.31 +/- 0.13; sperm, 5.38 +/- 0.16) and radial spokes (cilia, 4.95 +/- 0.22; sperm, 5.80 +/- 0.19). The ideal axoneme with all its structural components was seen in only 0.13% of cilia and 0.80% of sperm tails. Significantly more doublet microtubules (P less than 0.05) and less central microtubules (P less than 0.01) and radial spokes (P less than 0.01) were seen in cilia than in sperm tail axonemes. Between subjects there was little variation in the mean number of a structure seen per axoneme. However, within each sample, the variation was considerably higher, particularly for the inner and outer dynein arms and radial spokes. The doublet microtubules had significantly greater standard deviations in the sperm tails compared with the cilia (P less than 0.01), and furthermore, a significantly greater number of sperm tails compared with cilia showed the incorrect number of doublet microtubules (P less than 0.02). In one semen sample, with normal semen analysis, 20% of the sperm tails showed incorrect numbers of doublet microtubules, ranging from 12 + 2 to 5 + 2 compared with only 1.3% in cilia from this subject. This study has demonstrated that the ideal axoneme is rarely seen even in normal samples, probably because of the technical difficulties in resolution and visualization, and stresses the need for thorough documentation of axonemal ultrastructure. This work provides a normal data base for comparison with patients who have chronic respiratory disease and suspected infertility.