tbuckley/cabot-search huggingface dataset:
Radiosensitizing Effect of YM155, a Novel Small-Molecule Survivin Suppressant, in Non–Small Cell Lung Cancer Cell Lines
Authors: Tsutomu Iwasa, Isamu Okamoto, Minoru Suzuki, Takahito Nakahara, Kentaro Yamanaka, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Koji Ono, Kazuhiko Nakagawa
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non–small cell lung cancer (NSCLC) cell lines to γ-radiation. Experimental Design: The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation. Results: YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration- and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to γ-radiation in vitro. The combination of YM155 and γ-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone γ-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and γ-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. Conclusions: These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.
Mutation Rates and Intraspecific Divergence of the Mitochondrial Genome of Pristionchus pacificus
Authors: Ruxandra I. Molnar, Gabi Bartelmes, Iris Dinkelacker, Hanh Witte, Ralf J. Sommer
Journal: Molecular Biology and Evolution (2011)

Evolutionary reconstruction of the natural history of an organism ultimately requires knowledge about the development, population genetics, ecology, and phylogeny of the species. Such investigations would benefit from studies of mutational processes because mutations are the source of natural variation. The nematode Pristionchus pacificus has been developed as a model organism in evolutionary biology by comparing its development with Caenorhabditis elegans. Pristionchus pacificus and related species are associated with scarab beetles, and their ecology and phylogeny are well known. More than 200 P. pacificus isolates from all over the world are available for this cosmopolitan species. We generated mutation accumulation (MA) lines in P. pacificus to study spontaneous mutation rates in the mitochondrial genome and compared mutation rate estimates with natural variation between nine representative isolates of the species. The P. pacificus mitochondrial genome is 15,955 bp in length and is typical for nematodes. Pristionchus pacificus has all known mitochondrial genes and contains an unusual suppressor transfer RNA (tRNA) for the codon UAA. This has most likely influenced the spectrum of observable mutations because 6 of 12 mutations found in the 82 MA lines analyzed are nonsense mutations that can be suppressed by the suppressor tRNA. The overall mutation rate in P. pacificus is 7.6 × 10−8 per site per generation and is less than one order of magnitude different from estimates in C. elegans and Drosophila. Using this mutation rate estimate in a comparison of the mitochondrial genome of nine P. pacificus isolates, we calculate the minimum time to the most recent common ancestor at 105–106 generations. The combination of mutation rate analysis with intraspecific divergence provides a powerful tool for the reconstruction of the natural history of P. pacificus, and we discuss the ecological implication of these findings.
Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study
Authors: Frank Ulrich Weiss, Claudia Schurmann, Annett Guenther, Florian Ernst, Alexander Teumer, Julia Mayerle, Peter Simon, Henry Völzke, Dörte Radke, Andreas Greinacher, Jens-Peter Kuehn, Martin Zenker, Uwe Völker, Georg Homuth, Markus M Lerch
Journal: Gut (2014)

<h3>Objective</h3> Serum lipase activities above the threefold upper reference limit indicate acute pancreatitis. We investigated whether high lipase activity—within the reference range and in the absence of pancreatitis—are associated with genetic single nucleotide polymorphisms (SNP), and whether these identified SNPs are also associated with clinical pancreatitis. <h3>Methods</h3> Genome-wide association studies (GWAS) on phenotypes 'serum lipase activity' and 'high serum lipase activity' were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genome-wide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. <h3>Results</h3> Initial discovery GWAS detected SNPs within or near genes encoding the ABO blood group specifying transferases A/B (<i>ABO</i>), Fucosyltransferase-2 (<i>FUT2</i>), and Chymotrypsinogen-B2 (<i>CTRB2</i>), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR=1.49; p=0.012) and <i>ABO</i> blood-type-B (OR=2.48; p=7.29×10<sup>−8</sup>) with high lipase activity levels. In pancreatitis patients, significant associations were found for FUT-2 non-secretor status (OR=1.53; p=8.56×10<sup>−4</sup>) and <i>ABO</i>-B (OR=1.69, p=1.0×10<sup>−4</sup>) with chronic pancreatitis, but not with acute pancreatitis. Conversely, carriers of blood group O were less frequently affected by chronic pancreatitis (OR=0.62; p=1.22×10<sup>−05)</sup> and less likely to have high lipase activity levels (OR=0.59; p=8.14×10<sup>−05</sup>). <h3>Conclusions</h3> These are the first results indicating that ABO blood type-B as well as FUT2 non-secretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.
The Malaria Parasite's Chloroquine Resistance Transporter is a Member of the Drug/Metabolite Transporter Superfamily
Authors: R. E. Martin
Journal: Molecular Biology and Evolution (2004)

The malaria parasite's chloroquine resistance transporter (CRT) is an integral membrane protein localized to the parasite's acidic digestive vacuole. The function of CRT is not known and the protein was originally described as a transporter simply because it possesses 10 transmembrane domains. In wild-type (chloroquine-sensitive) parasites, chloroquine accumulates to high concentrations within the digestive vacuole and it is through interactions in this compartment that it exerts its antimalarial effect. Mutations in CRT can cause a decreased intravacuolar concentration of chloroquine and thereby confer chloroquine resistance. However, the mechanism by which they do so is not understood. In this paper we present the results of a detailed bioinformatic analysis that reveals that CRT is a member of a previously undefined family of proteins, falling within the drug/metabolite transporter superfamily. Comparisons between CRT and other members of the superfamily provide insight into the possible role of the protein and into the significance of the mutations associated with the chloroquine resistance phenotype. The protein is predicted to function as a dimer and to be oriented with its termini in the parasite cytosol. The key chloroquine-resistance-conferring mutation (K76T) is localized in a region of the protein implicated in substrate selectivity. The mutation is predicted to alter the selectivity of the protein such that it is able to transport the cationic (protonated) form of chloroquine down its steep concentration gradient, out of the acidic vacuole, and therefore away from its site of action.
Airway obstruction during exercise in asthma.
Authors: O E Suman, M A Babcock, D F Pegelow, N N Jarjour, W G Reddan
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Airway obstruction (AO) in exercise-induced asthma (EIA) is considered a postexercise phenomenon. However, many with EIA complain of respiratory distress during exercise. We evaluated AO in six asthmatic subjects during a short (SX = 6 min) and a long (LX = 20 min) exercise session. We measured peak expiratory flow (PEF) rate, forced expiratory volume in one second (FEV1), and forced expiratory flow at 50% of vital capacity (Vmax50) and calculated expiratory and inspiratory pulmonary resistance (RLe and RLi). Rated perceived exertion (RPE) was evaluated as a measure of dyspnea. All three indices of airflow significantly decreased following SX and LX, but RLi and RLe increased. During SX, PEF, FEV1, and Vmax50 did not decrease, but RLi decreased. During LX, PEF, FEV1, and Vmax50 decreased (20.0, 26.0, and 17.7%, respectively), whereas RLi and RLe significantly increased (74.0 and 53.0%). Rated perceived exertion correlated highly with RLi during exercise (r = 0.95). In summary, there was little or no AO during SX but a frank AO during LX in asthmatic subjects. We conclude that AO occurs during LX and that the manifestation of dyspnea is associated with AO during exercise, as well as in recovery.
Altered Gene Expression of c-myc, Epidermal Growth Factor Receptor, Transforming Growth Factor-α, and c-erb-B2 in an Immortalized Human Breast Epithelial Cell Line, HMT-3522, Is Associated with Decreased Growth Factor Requirements
Authors: Mogens Winkel Madsen, Anne E. Lykkesfeldt, Inga Laursen, Kirsten Vang Nielsen, Per Briand
Journal: Cancer Research (1992)

Activation of protooncogenes and constitutive secretion of autocrine growth factors are thought to be involved in the uncontrolled growth of cancer cells. We have attempted to elucidate the role of oncogenes and growth factors in the premalignant progression of human breast epithelial cells by using an immortalized, nontumorigenic, near-diploid human mammary epithelial cell line, HMT-3522, derived from a fibrocystic lesion and established in our laboratory. During propagation in tissue culture, the growth factor requirements of the HMT-3522 cells decreased simultaneously with an amplification and overexpression of the c- myc protooncogene. Other protooncogenes related to human breast cancer were unaltered with regard to gene copy number and expression. In passage 118, in which the most important growth factor still was epidermal growth factor (EGF), we were able to isolate an EGF-independent subline (S2). The EGF independence of S2 was accompanied by an overexpression of the mRNAs for epidermal growth factor receptor (EGF-R), transforming growth factor-α, and c- erb -B2 as compared to the EGF-dependent subline (S1). Moreover, by application of a blocking anti-EGF-R antibody, growth of S2 cells in EGF-free medium was inhibited significantly, indicating that EGF-R was involved in an autocrine loop probably with transforming growth factor-α as ligand. Neither the late passages of S1 cells nor S2 cells were tumorigenic after subcutaneous transplantation to athymic mice. Our results indicate that c- myc amplification and overexpression are correlated with a decreased requirement for growth factors. Even when these alterations are combined with immortalization and EGF independence, they are insufficient for malignant transformation of these human breast epithelial cells.
Characterization of Magnetic Viral Complexes for Targeted Delivery in Oncology
Authors: Isabella Almstätter, Olga Mykhaylyk, Marcus Settles, Jennifer Altomonte, Michaela Aichler, Axel Walch, Ernst J. Rummeny, Oliver Ebert, Christian Plank, Rickmer Braren
Journal: Theranostics (2015)

Oncolytic viruses are promising new agents in cancer therapy.Success of tumor lysis is often hampered by low intra-tumoral titers due to a strong anti-viral host immune response and insufficient tumor targeting.Previous work on the co-assembly of oncolytic virus particles (VPs) with magnetic nanoparticles (MNPs) was shown to provide shielding from inactivating immune response and improve targeting by external field gradients.In addition, MNPs are detected by magnet resonance imaging (MRI) enabling non-invasive therapy monitoring.In this study two selected core-shell type iron oxide MNPs were assembled with adenovirus (Ad) or vesicular stomatitis virus (VSV).The selected MNPs were characterized by high r 2 and r 2 * relaxivities and thus could be quantified non-invasively by 1.5 and 3.0 tesla MRI with a detection limit below 0.001 mM iron in tissue-mimicking phantoms.Assembly and cell internalization of MNP-VP complexes resulted in 81 -97 % reduction of r 2 and 35 -82 % increase of r 2 * compared to free MNPs.The relaxivity changes could be attributed to the clusterization of particles and complexes shown by transmission electron microscopy (TEM).In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model.In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies.Furthermore, our study provides first evidence of the in vivo applicability of selected MNP-VPs in cancer therapy.
Fondaparinux for the Treatment of Superficial-Vein Thrombosis in the Legs
Authors: Hervé Decousus, Paolo Prandoni, Patrick Mismetti, Rupert M. Bauersachs, Zoltán Boda, Benjamin Brenner, Silvy Laporte, Lajos Matyas, Saskia Middeldorp, German Sokurenko, Alain Leizorovicz
Journal: New England Journal of Medicine (2010)

The efficacy and safety of anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs, but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation, have not been established.In a randomized, double-blind trial, we assigned 3002 patients to receive either fondaparinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo for 45 days. The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. The main safety outcome was major bleeding. The patients were followed until day 77.The primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fondaparinux group and 88 of 1500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P<0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P<0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo.Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00443053.)
Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data
Authors: Katherine S Elliott, Kay Chapman, Aaron Day-Williams, Kalliope Panoutsopoulou, Lorraine Southam, Cecilia M Lindgren, Nigel Arden, Nadim Aslam, Fraser Birrell, Ian Carluke, Andrew Carr, Panos Deloukas, Michael Doherty, John Loughlin, Andrew McCaskie, William E R Ollier, Ashok Rai, Stuart Ralston, Mike R Reed, Timothy D Spector, Ana M Valdes, Gillian A Wallis, Mark Wilkinson, Eleftheria Zeggini
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale. Methods We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls. Results We found significant overlap between osteoarthritis and height (p=3.3×10 −5 for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10 −5 ). As expected, this signal was attenuated when we adjusted for BMI. Conclusions We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
Biochemical characterization of a second family of human Ia molecules, HLA-DS, equivalent to murine I-A subregion molecules.
Authors: S M Goyert, J E Shively, J Silver
Journal: The Journal of Experimental Medicine (1982)

In mice, two families of structurally distinct Ia molecules, one designated I-A and the other I-E, have been identified and characterized. The HLA-DR molecules represent one family of human Ia molecules equivalent to the murine I-E molecules on the basis of amino acid sequence homology. We describe the isolation and biochemical characterization of a second family of human Ia molecules, designated HLA-DS for second D-region locus, equivalent to the murine I-A molecules. The human HLA-DS molecules consist of two polypeptide chains, DS alpha (37,000 mol wt) and DS beta (29,000 mol wt), with 73% amino acid sequence identity to the murine I-A molecules. Furthermore, the HLA-DS molecules are closely linked genetically to HLA-DR molecules, a situation analogous to that observed in mice. The similarity in molecular weights of the DR and DS molecules might explain why others have failed to identify the latter in man.
Estrogen-Dependent and Estrogen-Independent Mechanisms Contribute to AIB1-Mediated Tumor Formation
Authors: Maria I. Torres-Arzayus, Jin Zhao, Roderick Bronson, Myles Brown
Journal: Cancer Research (2010)

Abstract We have previously reported the oncogenic properties of the gene amplified in breast cancer 1 (AIB1), a member of the p160 family of hormone receptor coactivators. In a transgenic mouse model, AIB1 overexpression resulted in a high incidence of tumors in various tissues, including mammary gland, uterus, lung, and pituitary. To determine whether the AIB1 oncogenicity in this model depended on its function as an estrogen receptor (ER) coactivator, we abolished ER signaling through two independent approaches, by performing ovariectomy on AIB1 transgenic (AIB1-tg) mice to prevent gonadal estrogen production and by crossing AIB1-tg mice with ERα-null mutant mice. Ovariectomized (ovx) mice, but not AIB1 × ERα−/− mice, still developed mammary gland hyperplasia and ductal carcinoma in situ. Both approaches, however, completely prevented the development of invasive mammary tumors, indicating that invasive mammary tumor formation is strictly estrogen dependent. Once developed, AIB1-induced mammary tumors can subsequently lose their dependence on estrogen: Injection of ERα(+) tumor cell lines derived from such tumors into ovx or untreated wild-type mice resulted in a similar rate of tumor growth in both groups. Surprisingly, however, ovx mice had an ∼4-fold higher rate of metastasis formation, suggesting that estrogen provided some protection from metastasis formation. Lastly, our experiments identified oncogenic functions of AIB1 that are independent of its ER coactivation, as both approaches, ovariectomy and ER−/− crosses, still resulted in a high incidence of tumors in the lung and pituitary. We therefore conclude that AIB1 can exert its oncogenicity through tissue-specific estrogen-dependent and estrogen-independent functions. Cancer Res; 70(10); 4102–11. ©2010 AACR.
Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling
Authors: Samir Fareh, Christine Villemaire, Stanley Nattel
Journal: Circulation (1998)

Rapid atrial activation causes electrical remodeling that promotes the occurrence and the maintenance of atrial fibrillation (AF). Although remodeling has been shown to alter electrophysiological variables, the spatial uniformity of these changes is unknown.Dogs subjected to rapid atrial pacing (400 bpm) for 24 hours (n=12) were compared with sham-operated dogs (instrumented but not paced, n=12). Epicardial mapping (240 bipolar electrodes) and extrastimulation at a large number of sites (mean+/-SEM, 66+/-4 per dog) were used to evaluate atrial activation and the heterogeneity of the effective refractory period (ERP), respectively. Rapid pacing increased both the percentage of sites at which AF could be induced by single premature stimuli (from 2.6+/-0.9% to 11.8+/-2.8%, P=0.007) and AF duration (from 39+/-28 to 146+/-49 seconds, P=0.03). Atrial tachycardia decreased atrial ERP (from 120+/-4 to 103+/-2 ms, P=0.003), increased the coefficient of variation of ERP (from 14.9+/-0.9% to 20.7+/-0.9%, P<0.0001), and accelerated conduction velocity (from 91+/-2 to 108+/-3 cm/s, P=0.0004), with no change in the wavelength. The increase in ERP heterogeneity was due both to interregional differences in the extent of ERP remodeling and to increased intersite variability within regions. Stepwise multilinear regression indicated that ERP heterogeneity was an independent determinant of the inducibility (P<0.0001) and duration (P<0.0001) of AF, whereas ERP per se and wavelength were not significant determinants. Combined mapping of AF induction and atrial ERP showed that premature extrastimuli induced AF at sites with short ERP by causing local conduction slowing and/or block in adjacent zones with longer ERP values.Atrial tachycardia causes nonuniform remodeling of atrial refractoriness that plays an important role in increasing atrial vulnerability to AF induction and the duration of induced AF.