bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion
Authors: Golding Sarah E. , Rosenberg Elizabeth , Valerie Nicholas , Hussaini Isa , Frigerio Mark , Cockcroft Xiaoling F. , Chong Wei Yee , Hummersone Marc , Rigoreau Laurent , Menear Keith A. , O'Connor Mark J. , Povirk Lawrence F. , van Meter Timothy , Valerie Kristoffer 
Published: October 2009

Abstract
Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with Ki and IC50 values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was countered by low levels of okadaic acid, a phosphatase inhibitor, and A-T cells were impaired in S473 AKT phosphorylation in response to radiation and insulin and unresponsive to KU-60019. We also show that KU-60019 inhibits glioma cell migration and invasion in vitro, suggesting that glioma growth and motility might be controlled by ATM via AKT. Inhibitors of MEK and AKT did not further radiosensitize cells treated with KU-60019, supporting the idea that KU-60019 interferes with prosurvival signaling separate from its radiosensitizing properties. Altogether, KU-60019 inhibits the DNA damage response, reduces AKT phosphorylation and prosurvival signaling, inhibits migration and invasion, and effectively radiosensitizes human glioma cells. [Mol Cancer Ther 2009;8(10):2894–902]
Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators
Authors: Wilson William R. , Stribbling Stephen M. , Pruijn Frederik B. , Syddall Sophie P. , Patterson Adam V. , Liyanage H.D. Sarath , Smith Eileen , Botting K. Jane , Tercel Moana 
Published: October 2009

Abstract
Hypoxia represents an important therapeutic target in tumors because of the resistance of hypoxic cells to radiotherapy and chemotherapy and because it is more severe in many tumors than in normal tissues. Here, we describe a class of prodrugs, nitro-chloromethylindolines, which undergo hypoxia-selective activation by endogenous nitroreductases in tumor cells to form the corresponding amino compounds. The latter are chemically related to the cyclopropylindoline antitumor antibiotics and they share the same properties of sequence-selective DNA minor groove alkylation and high cytotoxic potency. Of three alkylating subunits investigated, the chloromethylbenzindoline (CBI) structure provided the most favorable prodrug properties: aerobic cytotoxic potency of the amines was approximately 90- to 3,000-fold higher than the corresponding nitro compounds, and the nitro compounds showed air/anoxia potency differentials of up to 300-fold. Selective alkylation of adenine N3 in calf thymus DNA by an amino-CBI was shown by characterization of the thermal depurination product; the same adduct was shown in hypoxic RIF-1 cells exposed to the corresponding nitro-CBI prodrug under hypoxic (but not oxic) conditions. The amino metabolite generated from a nitro-CBI by cells expressing Escherichia coli nfsB nitroreductase in multicellular layer cultures was shown to elicit bystander killing of surrounding cells. Nitro-CBI prodrugs were &gt;500-fold less toxic to mice than amino-CBIs by i.p. administration and provided selective killing of hypoxic cells in RIF-1 tumors (although only at maximally tolerated doses). Nitro-CBIs are novel lead hypoxia-activated prodrugs that represent the first examples of hypoxia-selective generation of potent DNA minor groove alkylating agents. [Mol Cancer Ther 2009;8(10):2903–13]
A cross-sectional study comparing variation in body surface area and chemotherapy dosing in pediatric oncology using two different methods
Authors: Jastaniah Wasil , Aseeri Mohammed 
Published: October 2009

Purpose. Standardizing body surface area (BSA) determination is essential for avoiding variation in chemotherapy dosage calculations. In this study, we compared variation in BSA calculation using weight and height by the Mosteller formula with weight alone using recently adapted table at a local oncology center. Methods. Cross-sectional study of pediatric oncology patients presenting to a pediatric oncology clinic over a week period of time. Results. One-hundred consecutive pediatric oncology patients presented to the clinic. The mean BSA calculated by the Mosteller formula was 0.83 m2 (SD 0.24) and the mean BSA determined by the table (based on weight alone) was 0.82 m2 (SD 0.25). The mean variation in dosing between the two methods was 1.64% (SD 3.4). Only 13 out of 100 patients (13%) had equal dosing using both methods and 21 out of 100 patients (21%) had dosing variation greater than 5%. When comparing both methods, using paired t-test, the difference was statistically significant (t(99) = 3.99 and p < 0.001). Conclusion. Significant differences in BSAbased chemotherapy dosing exist in our center. The Mosteller method should remain the standard until prospective studies are performed to determine the significance of this dosing variability on toxicity and survival outcome.
Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation
Authors: Guerrero Jose A. , Kyei Mark , Russell Susan , Liu Junling , Gartner T. Kent , Storrie Brian , Ware Jerry 
Published: October 2009

AbstractPlatelet-type von Willebrand disease (PT-VWD) is a bleeding disorder of the platelet glycoprotein Ib-IX/von Willebrand factor (VWF) axis caused by mutations in the glycoprotein Ib-IX receptor that lead to an increased affinity with VWF. In this report, platelets from a mouse expressing a mutation associated with PT-VWD have been visualized using state-of-the art image collection and processing. Confocal analysis revealed that VWF bound to the surface of single platelets and bridging micro-aggregates of platelets. Surface-bound VWF appears as a large, linear structure on the surface of 50% of the PT-VWD platelets. In vivo thrombus formation after chemical injury to the carotid artery revealed a severe impairment to occlusion as a consequence of the PT-VWD mutation. In vitro stimulation of PT-VWD platelets with adenosine diphosphate or thrombin demonstrates a significant block in their ability to bind fibrinogen. The impairment of in vivo thrombus formation and in vitro fibrinogen binding are more significant than might be expected from the observed platelet binding to VWF polymers over a small portion of the plasma membrane. Visualization of the receptor/ligand interaction and characterization of a severe antithrombotic phenotype provide a new understanding on the molecular basis of bleeding associated with the PT-VWD phenotype.
Testing mitochondrial sequences and anonymous nuclear markers for phylogeny reconstruction in a rapidly radiating group: molecular systematics of the Delphininae (Cetacea: Odontoceti: Delphinidae)
Authors: Kingston Sarah E , Adams Lara D , Rosel Patricia E 
Published: October 2009

Abstract

Background
Many molecular phylogenetic analyses rely on DNA sequence data obtained from single or multiple loci, particularly mitochondrial DNA loci. However, phylogenies for taxa that have undergone recent, rapid radiation events often remain unresolved. Alternative methodologies for discerning evolutionary relationships under these conditions are desirable. The dolphin subfamily Delphininae is a group that has likely resulted from a recent and rapid radiation. Despite several efforts, the evolutionary relationships among the species in the subfamily remain unclear.

Results
Here, we compare a phylogeny estimated using mitochondrial DNA (mtDNA) control region sequences to a multi-locus phylogeny inferred from 418 polymorphic genomic markers obtained from amplified fragment length polymorphism (AFLP) analysis. The two sets of phylogenies are largely incongruent, primarily because the mtDNA tree provides very poor resolving power; very few species' nodes in the tree are supported by bootstrap resampling. The AFLP phylogeny is considerably better resolved and more congruent with relationships inferred from morphological data. Both phylogenies support paraphyly for the genera Stenella and Tursiops. The AFLP data indicate a close relationship between the two spotted dolphin species and recent ancestry between Stenella clymene and S. longirostris. The placement of the Lagenodelphis hosei lineage is ambiguous: phenetic analysis of the AFLP data is consistent with morphological expectations but the phylogenetic analysis is not.

Conclusion
For closely related, recently diverged taxa, a multi-locus genome-wide survey is likely the most comprehensive approach currently available for phylogenetic inference.
Voice disorders and mental health in teachers: a cross-sectional nationwide study
Authors: Nerrière Eléna , Vercambre Marie-Noël , Gilbert Fabien , Kovess-Masféty Viviane 
Published: October 2009

Abstract

Background
Teachers, as professional voice users, are at particular risk of voice disorders. Among contributing factors, stress and psychological tension could play a role but epidemiological data on this problem are scarce. The aim of this study was to evaluate prevalence and cofactors of voice disorders among teachers in the French National Education system, with particular attention paid to the association between voice complaint and psychological status.

Methods
The source data come from an epidemiological postal survey on physical and mental health conducted in a sample of 20,099 adults (in activity or retired) selected at random from the health plan records of the national education system. Overall response rate was 53%. Of the 10,288 respondents, 3,940 were teachers in activity currently giving classes to students. In the sample of those with complete data (n = 3,646), variables associated with voice disorders were investigated using logistic regression models. Studied variables referred to demographic characteristics, socio-professional environment, psychological distress, mental health disorders (DSM-IV), and sick leave.

Results
One in two female teachers reported voice disorders (50.0%) compared to one in four males (26.0%). Those who reported voice disorders presented higher level of psychological distress. Sex- and age-adjusted odds ratios [95% confidence interval] were respectively 1.8 [1.5-2.2] for major depressive episode, 1.7 [1.3-2.2] for general anxiety disorder, and 1.6 [1.2-2.2] for phobia. A significant association between voice disorders and sick leave was also demonstrated (1.5 [1.3-1.7]).

Conclusion
Voice disorders were frequent among French teachers. Associations with psychiatric disorders suggest that a situation may exist which is more complex than simple mechanical failure. Further longitudinal research is needed to clarify the comorbidity between voice and psychological disorders.
Reduction of liver macrophage transduction by pseudotyping lentiviral vectors with a fusion envelope from Autographa californicaGP64 and Sendai virus F2 domain
Authors: Markusic David M , van Til Niek P , Hiralall Johan K , Elferink Ronald PJ Oude , Seppen Jurgen 
Published: October 2009

Abstract

Background
Lentiviral vectors are well suited for gene therapy because they can mediate long-term expression in both dividing and nondividing cells. However, lentiviral vectors seem less suitable for liver gene therapy because systemically administered lentiviral vectors are preferentially sequestered by liver macrophages. This results in a reduction of available virus and might also increase the immune response to the vector and vector products.
Reduction of macrophage sequestration is therefore essential for efficient lentiviral liver gene therapy.

Results
Fusions were made of Autographa californica GP64 and the hepatocyte specific Sendai Virus envelope proteins. Lentiviral vectors were produced with either wild type GP64, Sendai-GP64, or both wild type GP64 and Sendai-GP64 and tested in vitro and in vivo for hepatocyte and macrophage gene transfer.
Sendai-GP64 pseudotyped vectors showed specific gene transfer to HepG2 hepatoma cells, with no detectable transduction of HeLa cervical carcinoma cells, and a decreased affinity for RAW mouse macrophages. Co-expression of wild type GP64 and Sendai-GP64 resulted in improved viral titers while retaining increased affinity for HepG2 cells.
In vivo, the Sendai-GP64 vectors also showed decreased transduction of murine liver macrophages.

Conclusion
We demonstrate reduced macrophage transduction in vitro and in vivo with GP64/Sendai chimeric envelope proteins.
Placental malaria and low birth weight in pregnant women living in a rural area of Burkina Faso following the use of three preventive treatment regimens
Authors: Tiono Alfred B , Ouedraogo Alphonse , Bougouma Edith C , Diarra Amidou , Konaté Amadou T , Nébié Issa , Sirima Sodiomon B 
Published: October 2009

Abstract

Background
The weekly chemoprophylaxis of malaria during pregnancy with chloroquine (CQ) has become problematic with the increasing resistance of Plasmodium falciparum to this drug. There was a need to test the benefits of new strategies over the classical chemoprophylaxis. This study was conducted to provide data to the National Malarial Control Programme for an evidence-based policy change decision making process. It compares the efficacy of two IPT regimens, using chloroquine (CQ) or sulphadoxine/pyrimethamine (SP), with the classical chemoprophylaxis regimen using CQ in reducing the adverse outcomes of malaria infection, for the mother and the foetus.

Methods
Pregnant women attending the first antenatal care visit were randomly assigned to one of the three treatment regimens. They were subsequently followed up till delivery. Maternal, placental and cord blood samples were obtained upon delivery to check for P. falciparum infection.

Results
A total of 648 pregnant women were enrolled in the study. Delivery outcome were available for 423 of them. Peripheral maternal P. falciparum infection at delivery was found in 25.8% of the women. The proportion of women with maternal infection was significantly lower in the IPTp/SP group than in the CQ group (P << 0.000). The prevalence of placental malaria was 18.8% in the CWC/CQ group; 15.9% in the IPTp/CQ group and 10.6% in the IPTp/SP group. The incidence of LBW (weigth < 2,500 g) was significantly higher among infants of mothers in the CWC/CQ group (23.9%) as compared with those of mothers in the IPTp/CQ (15.6%) and IPTp/SP (11.6%) groups (p = 0.02)

Conclusion
Intermittent preventive treatment with SP has shown clear superiority in reducing adverse outcomes at delivery, as compared with intermittent preventive treatment with CQ and classical chemoprophylaxis with CQ.
Detection of NP, N3 and N7 antibodies to avian influenza virus by indirect ELISA using yeast-expressed antigens
Authors: Upadhyay Chitra , Ammayappan Arun , Vakharia Vikram N 
Published: October 2009

Abstract

Background
Avian influenza viruses, belonging to the family Orthomyxoviridae, possess distinct combinations of hemagglutinin (H) and the neuraminidase (N) surface glycoproteins. Typing of both H and N antigens is essential for the epidemiological and surveillance studies. Therefore, it is important to find a rapid, sensitive, and specific method for their assay, and ELISA can be useful for this purpose, by using recombinant proteins.

Results
The nucleoprotein (NP) and truncated neuraminidase subtype 3 and 7 of avian influenza virus (AIV) were expressed in Saccharomyces cerevisiae and used to develop an indirect enzyme-linked immunosorbent assay for antibody detection. The developed assays were evaluated with a panel of 64 chicken serum samples. The performance of NP-ELISA was compared with the commercially available ProFlok® AIV ELISA kit. The results showed comparable agreement and sensitivity between the two tests, indicating that NP-ELISA assay can be used for screening the influenza type A antibody in AIV infected birds. The N3 and N7- ELISAs also reacted specifically to their type specific sera and did not exhibit any cross-reaction with heterologous neuraminidase subtype specific sera.

Conclusion
The study demonstrates the expression of the NP, N3, and N7 proteins of AIV in yeast (S. cerevisiae) and their application in developing an indirect ELISA for detecting NP, N3 and N7 antibodies from AIV-infected chicken sera. The described indirect ELISAs are rapid, sensitive, specific and can be used as promising tests during serological surveillance.
An occasional diagnosis of myasthenia gravis - a focus on thymus during cardiac surgery: a case report
Authors: Agrifoglio Marco , Barili Fabio , Dainese Luca , Cappai Antioco , Cheema Faisal H , Biglioli Paolo 
Published: October 2009

Abstract

Background
Myasthenia gravis, an uncommon autoimmune syndrome, is commonly associated with thymus abnormalities. Thymomatous myasthenia gravis is considered to have worst prognosis and thymectomy can reverse symptoms if precociously performed.

Case report
We describe a case of a patient who underwent mitral valve repair and was found to have an occasional thymomatous mass during the surgery. A total thymectomy was performed concomitantly to the mitral valve repair.

Conclusion
The diagnosis of thymomatous myasthenia gravis was confirmed postoperatively. Following the surgery this patient was strictly monitored and at 1-year follow-up a complete stable remission had been successfully achieved.
Multidendritic sensory neurons in the adult Drosophila abdomen: origins, dendritic morphology, and segment- and age-dependent programmed cell death
Authors: Shimono Kohei , Fujimoto Azusa , Tsuyama Taiichi , Yamamoto-Kochi Misato , Sato Motohiko , Hattori Yukako , Sugimura Kaoru , Usui Tadao , Kimura Ken-ichi , Uemura Tadashi 
Published: October 2009

Abstract
Background
For the establishment of functional neural circuits that support a wide range of animal behaviors, initial circuits formed in early development have to be reorganized. One way to achieve this is local remodeling of the circuitry hardwiring. To genetically investigate the underlying mechanisms of this remodeling, one model system employs a major group of Drosophila multidendritic sensory neurons - the dendritic arborization (da) neurons - which exhibit dramatic dendritic pruning and subsequent growth during metamorphosis. The 15 da neurons are identified in each larval abdominal hemisegment and are classified into four categories - classes I to IV - in order of increasing size of their receptive fields and/or arbor complexity at the mature larval stage. Our knowledge regarding the anatomy and developmental basis of adult da neurons is still fragmentary.

Results
We identified multidendritic neurons in the adult Drosophila abdomen, visualized the dendritic arbors of the individual neurons, and traced the origins of those cells back to the larval stage. There were six da neurons in abdominal hemisegment 3 or 4 (A3/4) of the pharate adult and the adult just after eclosion, five of which were persistent larval da neurons. We quantitatively analyzed dendritic arbors of three of the six adult neurons and examined expression in the pharate adult of key transcription factors that result in the larval class-selective dendritic morphologies. The 'baseline design' of A3/4 in the adult was further modified in a segment-dependent and age-dependent manner. One of our notable findings is that a larval class I neuron, ddaE, completed dendritic remodeling in A2 to A4 and then underwent caspase-dependent cell death within 1 week after eclosion, while homologous neurons in A5 and in more posterior segments degenerated at pupal stages. Another finding is that the dendritic arbor of a class IV neuron, v'ada, was immediately reshaped during post-eclosion growth. It exhibited prominent radial-to-lattice transformation in 1-day-old adults, and the resultant lattice-shaped arbor persisted throughout adult life.

Conclusion
Our study provides the basis on which we can investigate the genetic programs controlling dendritic remodeling and programmed cell death of adult neurons, and the life-long maintenance of dendritic arbors.
ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage
Authors: Yeap Leng-Siew , Hayashi Katsuhiko , Surani M Azim 
Published: October 2009

Abstract

Background
Pluripotency, the capacity for indefinite self-renewal and differentiation into diverse cell types is a unique state exhibited by embryonic stem (ES) cells. Transcriptional regulators, such as Oct4, are critical for pluripotency, but the role of epigenetic modifiers remains to be fully elucidated.

Results
Here, we show that ERG-associated protein with SET domain (ESET), a histone methyltransferase enzyme, maintains pluripotency through repression of Cdx2, a key trophectoderm determinant, by histone H3 lysine 9 trimethylation (H3K9me3) of the promoter region. Notably, this repression is mediated through the synergistic function of small ubiquitin-related modifier (SUMO)ylated ESET and Oct4. ESET localises to the promyelocytic leukaemia (PML) nuclear bodies and is SUMOylated in ES cells. Interaction of ESET with Oct4 depends on a SUMO-interacting motif (SIM) in Oct4, which is critical for the repression of Cdx2.

Conclusion
Loss of ESET or Oct4 results in strikingly similar phenotypes both in ES cells with their differentiation into trophectoderm cells, and in early embryos where there is a failure of development of the pluripotent inner cell mass (ICM) of blastocysts. We propose that SUMOylated ESET-Oct4 complex is critical for both the initiation and maintenance of pluripotency through repression of differentiation, particularly of the trophectoderm lineage by epigenetic silencing of Cdx2.