tbuckley/cabot-search huggingface dataset:
Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms
Authors: Zhi Gang Li, Paul Mathew, Jun Yang, Michael W. Starbuck, Amado J. Zurita, Jie Liu, Charles Sikes, Asha S. Multani, Eleni Efstathiou, Adriana Lopez, Jing Wang, Tina V. Fanning, Victor G. Prieto, Vikas Kundra, Elba S. Vazquez, Patricia Troncoso, Austin K. Raymond, Christopher J. Logothetis, Sue-Hwa Lin, Sankar Maity, Nora M. Navone
Journal: Journal of Clinical Investigation (2008)

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.
Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer
Authors: Miquel Porta, Núria Malats, Manuel Jariod, Joan O Grimalt, Juli Rifà, Alfredo Carrato, Luisa Guarner, Antonio Salas, Mary Santiago-Silva, Josep M Corominas, Montserrat Andreu, Francisco X-Real
Journal: The Lancet (1999)
A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure.
Authors: N J Samani, D Lodwick, M Vincent, C Dubay, M A Kaiser, M P Kelly, M Lo, J Harris, J Sassard, M Lathrop
Journal: Journal of Clinical Investigation (1993)

The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension.
Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine
Authors: Kazuhiko Yamane, Timothy J. Kinsella
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purine antimetabolite, 6-thioguanine (6-TG), is an effective drug in the management of acute leukemias. In this study, we analyze the mechanisms of apoptosis associated with 6-TG treatment and casein kinase 2 (CK2 or CKII) in human tumor cells. Experimental Design: Small interfering RNA and chemical CK2 inhibitors were used to reduce CK2 activity. Control and CK2 activity–reduced cells were cultured with 6-TG and assessed by flow cytometry to measure apoptosis and cell cycle profiles. Additionally, confocal microscopy was used to assess localization of CK2 catalytic units following 6-TG treatment. Results: Transfection of small interfering RNA against the CK2 α and/or α′ catalytic subunits results in marked apoptosis of HeLa cells following treatment with 6-TG. Chemical inhibitors of CK2 also induce apoptosis following 6-TG treatment. Apoptosis induced by 6-TG is similarly observed in both mismatch repair-proficient and -deficient HCT116 and HeLa cells. Concomitant treatment with a pan-caspase inhibitor or transfection of apoptosis repressor with caspase recruitment domain markedly suppresses the apoptotic response to DNA damage by 6-TG in the CK2-reduced cells, indicating caspase regulation by CK2. CK2 α relocalizes to the endoplasmic reticulum after 6-TG treatment. Additionally, transfection of Cdc2 with a mutation at Ser39 to Ala, which is the CK2 phosphorylation site, partially inhibits cell cycle progression in G1 to G2 phase following 6-TG treatment. Conclusion: CK2 is essential for apoptosis inhibition following DNA damage induced by 6-TG, controlling caspase activity.
Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine
Authors: S. F. Noujaim, J. A. Stuckey, D. Ponce-Balbuena, T. Ferrer-Villada, A. Lopez-Izquierdo, S. V. Pandit, J. A. Sanchez-Chapula, J. Jalife
Journal: Cardiovascular Research (2011)

Chloroquine, an anti-malarial quinoline, is structurally similar to quinidine. Both drugs have been shown to block ion channels. We tested the hypothesis that chloroquine's mode of interaction with the vestibule of the cytoplasmic domain of the inward rectifier potassium channel Kir2.1 makes it a more effective IK1 blocker and anti-fibrillatory agent than quinidine. We used comparative molecular modelling and ligand docking of the three-dimensional structures of quinidine and chloroquine in the intracellular domain of Kir2.1. Simulations predicted that chloroquine effectively blocks potassium flow by binding at the centre of the ion permeation vestibule of Kir2.1. In contrast, quinidine binds the vestibular side, only partially blocking ion movement. We tested the modelling predictions in Kir2.1-expressing human embryonic kidney (HEK)-293 cells. The half-maximal inhibitory concentration for chloroquine block of IK1 was 1.2 µM, while that of quinidine was 57 µM. Finally, we used optical mapping of Langendorff-perfused mouse hearts with cardiac-specific Kir2.1 up-regulation to compare the anti-fibrillatory effects of the drugs. In five of six hearts, 10 μM quinidine slowed the frequency but did not terminate the tachyarrhythmia. In five of five hearts, 10 μM chloroquine terminated the arrhythmia, restoring sinus rhythm. Quinidine only partially blocks IK1. Chloroquine binds at the centre of the ion permeation vestibule of Kir2.1, which makes it a more effective IK1 blocker and anti-fibrillatory agent than quinidine. Integrating the structural biology of drug-ion channel interactions with cellular electrophysiology and optical mapping is an excellent approach to understand the molecular mechanisms of anti-arrhythmic drug action and for drug discovery.
Simulation Study of the Reliability and Robustness of the Statistical Methods for Detecting Positive Selection at Single Amino Acid Sites
Authors: Yoshiyuki Suzuki, Masatoshi Nei
Journal: Molecular Biology and Evolution (2002)

Inferring positive selection at single amino acid sites is of biological and medical importance. Parsimony-based and likelihood-based methods have been developed for this purpose, but the reliabilities of these methods are not well understood. Because the evolutionary models assumed in these methods are only rough approximations to reality, it is desirable that the methods are not very sensitive to violation of the assumptions made. In this study we show by computer simulation that the likelihood-based method is sensitive to violation of the assumptions and produces many false-positive results under certain conditions, whereas the parsimony-based method tends to be conservative. These observations, together with those from previous studies, suggest that the positively selected sites inferred by the parsimony-based method are more reliable than those inferred by the likelihood-based method.
Preclinical Development of an Anti-NaPi2b (<i>SLC34A2</i>) Antibody–Drug Conjugate as a Therapeutic for Non–Small Cell Lung and Ovarian Cancers
Authors: Kedan Lin, Bonnee Rubinfeld, Crystal Zhang, Ron Firestein, Eric Harstad, Leslie Roth, Siao Ping Tsai, Melissa Schutten, Keyang Xu, Maria Hristopoulos, Paul Polakis
Journal: Clinical Cancer Research (2015)

Antibody-drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium-phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non-small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments.
Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
Authors: Ian Judson, Jaap Verweij, Hans Gelderblom, Jörg T Hartmann, Patrick Schöffski, Jean-Yves Blay, J Martijn Kerst, Josef Sufliarsky, Jeremy Whelan, Peter Hohenberger, Anders Krarup-Hansen, Thierry Alcindor, Sandrine Marreaud, Saskia Litière, Catherine Hermans, Cyril Fisher, Pancras C W Hogendoorn, A Paolo dei Tos, Winette T A van der Graaf
Journal: The Lancet Oncology (2014)
The Evolution of an α-Esterase Pseudogene Inactivated in the Drosophila melanogaster Lineage
Authors: G. Charles de Q. Robin, R. J. Russell, D. J. Cutler, J. G. Oakeshott
Journal: Molecular Biology and Evolution (2000)

Previous analyses of the α-esterase cluster of Drosophila melanogaster revealed 10 active genes and the DmαE4a-Ψ pseudogene. Here, we reconstruct the evolution of the pseudogene from the sequences of 12 alleles from widely scattered D. melanogaster populations and single alleles from Drosophila simulans and Drosophila yakuba. All of the DmαE4a-Ψ alleles contain numerous inactivating mutations, suggesting that pseudogene alleles are fixed in natural populations. Several lines of evidence also suggest that DmαE4a is now evolving without selective constraint in the D. melanogaster lineage. There are three polymorphic indels which result in frameshifts; a key nucleotide of the intron splice acceptor is polymorphic; the neutral mutation parameter θ̂ is the same for replacement and silent sites; one of the nonsilent polymorphisms results in a stop codon; only 1 of the 13 replacement polymorphisms is biochemically conservative; residues that are conserved among active esterases have different states in DmαE4a-Ψ; and there are about half as many transitional polymorphisms as transversional ones. In contrast, the D. simulans and D. yakuba orthologs DsαE4a and DyαE4a do not have the inactivating mutations of DmαE4a-Ψ and appear to be evolving under the purifying selection typical of protein- encoding genes. For instance, there have been more substitutions in the introns than in the exons, and more in silent sites than in replacement sites. Furthermore, most of the amino acid substitutions that have occurred between DyαE4a and DsαE4a are located in sites that typically vary among active α-esterases rather than those that are usually conserved. We argue that the original αE4a gene had a function which it has lost since the divergence of the D. melanogaster and D. simulans lineages.
Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction
Authors: Simon R Dixon, Thanh T Nguyen, William W O’Neill, Robert J Whitbourn, Michael W Dae, Eberhard Grube, Warren Sherman, Gary L Schaer, J.Stephen Jenkins, Donald S Baim, Raymond J Gibbons, Richard E Kuntz, Jeffrey J Popma
Journal: Journal of the American College of Cardiology (2002)
Drug resistance and tuberculosis elimination in low-incidence countries
Authors: Dennis Falzon, Jean-Pierre Zellweger, Giovanni Battista Migliori, Ernesto Jaramillo
Journal: European Respiratory Journal (2014)

Countries on track to eliminate TB in the 21st century should be vigilant about the threat of drugresistant strains http://ow.ly/AWJ36Countries that have already reduced their tuberculosis (TB) caseloads to low levels are now embarking on the road to reduce them even further and faster [1,2].In these countries, TB cases now predominate in subgroups of the population that are at greater risk of infection, progression to disease or unfavourable outcome, risks that oftentimes overlap within the same individual [3].As low TB incidence countries approach the pre-elimination threshold, i.e. moving from ,100 TB cases per million population per year today to ,10 TB cases per million, it is expected that the concentration of disease in these subgroups will persist and possibly intensify as a result of the continued, natural attrition of the older population that accounts for many of the native TB cases today [4].If the declining trend in TB incidence in these countries continues, TB will become rarer.The prospect of having fewer cases in the future does not automatically imply that the task of controlling TB becomes any lighter for national authorities.In fact, cases may become more difficult to find and to treat as a result of patient mobility, absent or incomplete healthcare coverage, lack of entitlements for those with irregular legal status, and other vulnerabilities linked to poverty, substance use, and co-existence of diseases such as HIV and diabetes, in a context of diminishing resources and expertise for TB case management.The development of resistance to anti-TB medication, which may be potentiated by some of these factors, compounds the picture even further.These epidemiological developments may put the progress towards TB elimination at risk.The large majority of the TB cases occurring in most of the world and in low TB incidence settings remains drug susceptible and potentially curable with standard, first-line regimens, which have become widely available in recent decades.One of the threats to TB elimination has been the propagation of resistance, much of it fuelled by the improper use of the drugs making up these regimens.The emergence of combined resistance to rifampicin and isoniazid, the two most effective anti-TB medicines today (multidrug-resistant (MDR)-TB), has now become a matter of global concern [5].While the bulk of the global MDR-TB burden occurs in large, populous, middle-income countries, richer countries with low TB incidence rates are not spared.International clusters of drug-resistant TB cases have involved, among others, western European countries and the USA [6,7].In many low TB incidence countries, TB patients of foreign origin are at higher risk of MDR-TB than native patients; in 18 European countries in 2012, for instance, the pooled
Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: A preliminary study
Authors: Raquel Abecasis, David Kravetz, Eduardo Fassio, Beatriz Ameigeiras, Daniel Garcia, Rogelio Isla, Graciela Landeira, Nora Dominguez, Gustavo Romero, Julio Argonz, Ruben Terg
Journal: Hepatology (2003)

Treatment with β-blockers fails to decrease portal pressure in nearly 40% of cirrhotic patients. Recent studies have suggested that treatment with spironolactone reduces pressure and flow in the portal and variceal systems. This trial was designed to assess if nadolol plus spironolactone is more effective than nadolol alone to prevent the first variceal bleeding. One hundred patients with medium and large varices who had never bled and were without ascites were included in a prospective, randomized, multicenter, double-blind, placebo-controlled trial. The patients were randomized into 2 groups: 51 received nadolol plus placebo (N + P) and 49 received nadolol plus spironolactone 100 mg/d (N + S). Hepatic venous pressure gradient (HVPG) and activity of the renin-aldosterone system (plasma renin activity/plasma aldosterone levels) were measured in 24 patients. There were no significant differences in the appearance of variceal bleeding and ascites between groups at a mean follow-up of 22 ± 16 months. However, analyzing both complications together, the incidence was significantly higher in the N + P group than in the N + S group (39% vs. 20%; P &lt; .04). Clinical ascites was also higher in patients in the N + P group than in the N + S group (21% vs. 6%; P &lt; .04). Significant increases in plasma renin activity and plasma aldosterone levels were only observed in patients in the N + S group ( P &lt; .01). The cumulative probabilities of remaining free of bleeding and ascites were similar in both groups after 70 months of follow-up. In conclusion, these results suggest that nadolol plus spironolactone does not increase the efficacy of nadolol alone in the prophylaxis of the first variceal bleeding. However, when bleeding and ascites were considered together, the combined therapy effectively reduced the incidence of both portal-hypertensive complications.
Etiologic, Phenomenologic, and Endophenotypic Overlap of Schizophrenia and Bipolar Disorder
Authors: Godfrey D. Pearlson
Journal: Annual Review of Clinical Psychology (2015)

This review examines the history of psychiatric nosology, with particular reference to the nineteenth-century origins of the concepts of manic-depressive illness and schizophrenia as distinct clinical syndromes and their evolution and diagnostic refinement over time. I document how the terminology applied to these entities has generated controversy, and discuss the ways in which the resulting diagnostic entities as defined by pure phenomenological symptom descriptors fail to capture discrete diagnostic distinctions, leading some researchers to posit an illness continuum rather than separate disorders. Furthermore, the two syndromes overlap substantially on multiple biologic measures, and clarity is lacking as to the underlying etiology and pathology necessary to move from descriptions of clinical syndromes to diseases. I next examine how biologically based classifications agnostic to conventional diagnostic schemes may be useful and how these are being implemented in practice, and conclude by summarizing where such approaches are likely to lead.
Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma
Authors: Sylvain Ferrandon, Céline Malleval, Badia El Hamdani, Priscillia Battiston-Montagne, Radu Bolbos, Jean-Baptiste Langlois, Patrick Manas, Sergei M Gryaznov, Gersende Alphonse, Jérôme Honnorat, Claire Rodriguez-Lafrasse, Delphine Poncet
Journal: Molecular Cancer (2015)

Glioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Most GBMs express telomerase; a high level of intra-tumoral telomerase activity (TA) is predictive of poor prognosis. Thus, telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. Since typical treatments for GBM include RT, our objective was to evaluate the efficiency of Imetelstat (TA inhibitor) combined with RT.We used a murine orthotopic model of human GBM (N = 8 to11 mice per group) and μMRI imaging to evaluate the efficacy of Imetelstat (delivered by intra-peritoneal injection) alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase.Imetelstat is currently evaluated in refractory brain tumors in young patients (without RT). Our results support its clinical evaluation combined with RT to treat GBM.
Use of somatic cell genetics to study chromosomes contributing to antigen plus I recognition by T cell hybridomas.
Authors: P Marrack, J Kappler
Journal: The Journal of Experimental Medicine (1983)

Keyhole limpet hemocyanin (KLH)/I region-specific T cell hybridomas have been prepared by fusing KLH/I-specific T cell blasts from mice with single pairs of metacentric chromosomes to the inducible, interleukin 2 (IL-2)-secreting T cell hybridoma FS6-14.13.AG2.1. T cell hybridomas with KLH/I receptors were identified by their ability to secrete IL-2 in response to KLH and the appropriate antigen-presenting cells. After cloning and subcloning, KLH/I reactivity was correlated with the presence or absence of metacentric chromosomes derived from the KLH/I-specific T cell blast parent. Hybridomas were identified that had lost all chromosomes 4 and 6 or 16 and 17 derived from their normal T cell parent, but retained the ability to respond to KLH/I. This suggested that products of genes on these chromosomes did not contribute to the specific portions of T cell Ag/I receptors. These gene products would include, of course, kappa and lambda chains and H-2. We did not obtain any T cell hybridomas that had lost both metacentric (8.12) chromosomes derived from T cells of the Robertsonian mouse strain Rb(8.12)5, so we could not draw any conclusions about the contributions of products of genes on these chromosomes. T cell hybridomas with KLH/I reactivity were found that contained only one metacentric (8.12) chromosome derived from this strain. Moreover, a T cell hybridoma was found that retained both metacentric (8.12) chromosomes from its normal T cell parent, but had lost KLH/I reactivity. These results suggested that neither two chromosomes 8 nor two chromosomes 12 were required for antigen/I reactivity in normal T cells and that antigen/I reactivity was controlled, at least in part, by genes mapping on chromosomes other than 8 or 12.