bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mx Is Dispensable for Interferon-Mediated Resistance of Chicken Cells against Influenza A Virus
Authors: Schusser Benjamin , Reuter Antje , von der Malsburg Alexander , Penski Nicola , Weigend Steffen , Kaspers Bernd , Staeheli Peter , Härtle Sonja 
Published: June 2011

ABSTRACT

The type I interferon (IFN) system plays an important role in antiviral defense against influenza A viruses (FLUAV), which are natural chicken pathogens. Studies of mice identified the Mx1 protein as a key effector molecule of the IFN-induced antiviral state against FLUAV. Chicken
Mx
genes are highly polymorphic, and recent studies suggested that an Asn/Ser polymorphism at amino acid position 631 determines the antiviral activity of the chicken Mx protein. By employing chicken embryo fibroblasts with defined Mx-631 polymorphisms and retroviral vectors for the expression of Mx isoforms in chicken cells and embryonated eggs, we show here that neither the 631Asn nor the 631Ser variant of chicken Mx was able to confer antiviral protection against several lowly and highly pathogenic FLUAV strains. Using a short interfering RNA (siRNA)-mediated knockdown approach, we noted that the antiviral effect of type I IFN in chicken cells was not dependent on Mx, suggesting that some other IFN-induced factors must contribute to the inhibition of FLUAV in chicken cells. Finally, we found that both isoforms of chicken Mx protein appear to lack GTPase activity, which might explain the observed lack of antiviral activity.
Protection against Rectal Transmission of an Emtricitabine-Resistant Simian/Human Immunodeficiency Virus SHIV162p3M184VMutant by Intermittent Prophylaxis with Truvada
Authors: Cong Mian-er , Youngpairoj Ae S. , Zheng Qi , Aung Wutyi , Mitchell James , Sweeney Elizabeth , Hanson Debra L. , Hendry R. Michael , Dobard Charles , Heneine Walid , García-Lerma J. Gerardo 
Published: June 2011

ABSTRACTDaily preexposure prophylaxis (PrEP) with Truvada (emtricitabine [FTC] and tenofovir disoproxil fumarate [TDF]) is a novel HIV prevention strategy recently found to reduce HIV incidence among men who have sex with men. We used a macaque model of HIV transmission to investigate if Truvada maintains prophylactic efficacy against an FTC-resistant isolate containing the M184V mutation. Five macaques received a dose of Truvada 3 days before exposing them rectally to the simian/human immunodeficiency virus mutant SHIV162p3M184V, followed by a second dose 2 h after exposure. Five untreated animals were used as controls. Virus exposures were done weekly for up to 14 weeks. Despite the high (>100-fold) level of FTC resistance conferred by M184V, all five treated animals were protected from infection, while the five untreated macaques were infected (P= 0.0008). Our results show that Truvada maintains high prophylactic efficacy against an FTC-resistant isolate. Increased susceptibility to tenofovir due to M184V and other factors, including residual antiviral activity by FTC and/or reduced virus fitness due to M184V, may all have contributed to the observed protection.
Host Response to Polyomavirus Infection Is Modulated by RNA Adenosine Deaminase ADAR1 but Not by ADAR2
Authors: George Cyril X. , Samuel Charles E. 
Published: June 2011

ABSTRACT

Adenosine deaminases acting on RNA (ADARs) catalyze the C-6 deamination of adenosine (A) to produce inosine (I), which behaves as guanine (G), thereby altering base pairing in RNAs with double-stranded character. Two genes,
adar1
and
adar2
, are known to encode enzymatically active ADARs in mammalian cells. Furthermore, two size forms of ADAR1 are expressed by alternative promoter usage, a short (p110) nuclear form that is constitutively made and a long (p150) form that is interferon inducible and present in both the cytoplasm and nucleus. ADAR2 is also a constitutively expressed nuclear protein. Extensive A-to-G substitution has been described in mouse polyomavirus (PyV) RNA isolated late times after infection, suggesting modification by ADAR. To test the role of ADAR in PyV infection, we used genetically null mouse embryo fibroblast cells deficient in either ADAR1 or ADAR2. The single-cycle yields and growth kinetics of PyV were comparable between
adar1
−/−
and
adar2
−/−
genetic null fibroblast cells. While large T antigen was expressed to higher levels in
adar1
−/−
cells than
adar2
−/−
cells, less difference was seen in VP1 protein expression levels between the two knockout MEFs. However, virus-induced cell killing was greatly enhanced in PyV-infected
adar1
−/−
cells compared to that of
adar2
−/−
cells. Complementation with p110 protected cells from PyV-induced cytotoxicity. UV-irradiated PyV did not display any enhanced cytopathic effect in
adar1
−/−
cells. Reovirus and vesicular stomatitis virus single-cycle yields were comparable between
adar1
−/−
and
adar2
−/−
cells, and neither reovirus nor VSV showed enhanced cytotoxicity in
adar1
−/−
-infected cells. These results suggest that ADAR1 plays a virus-selective role in the host response to infection.
The impact of genital warts: loss of quality of life and cost of treatment in eight sexual health clinics in the UK
Authors: Woodhall S C , Jit M , Soldan K , Kinghorn G , Gilson R , Nathan M , Ross J D , Lacey C J N 
Published: June 2011

ObjectivesTo estimate the loss of quality of life and cost of treatment associated with genital warts seen in sexual health clinics.MethodsA cross-sectional questionnaire study and case note review of individuals with genital warts, carried out in eight sexual health clinics in England and Northern Ireland. Individuals with genital warts attending the participating clinics were invited to take part in the questionnaire study. 895 participants were recruited. A separate sample of 370 participants who had attended a participating clinic with a first visit for a first or recurrent episode of genital warts between April and June 2007 was included in the case note review. Quality of life was measured using the EQ-5D questionnaire and the cost of an episode of care was derived from the case note review.ResultsThe weighted mean EQ-5D index score was 0.87 (95% CI 0.85 to 0.89). The weighted mean disutility was 0.056 (95% CI 0.038 to 0.074). The estimated mean loss of quality-adjusted life-years associated with an episode of genital warts was 0.018 (95% CI 0.0079 to 0.031), equivalent to 6.6 days of healthy life lost per episode. The weighted mean cost per episode of care was £94 (95% CI £84 to £104), not including the cost of a sexually transmitted infection screen.ConclusionsGenital warts have a substantial impact on the health service and the individual. This information can be utilised for economic evaluation of human papillomavirus vaccination.
Selection and characterization ofSpiroplasma citrimutants by random transposome mutagenesis
Authors: Mutaqin Kikin , Comer Jana L. , Wayadande Astri C. , Melcher Ulrich , Fletcher Jacqueline 
Published: June 2011

Phytopathogenic spiroplasmas can multiply in vascular plants and insects. A deeper understanding of this dual-host life could be furthered through the identification by random mutagenesis of spiroplasma genes required. The ability of the EZ::TN™ <DHFR-1> Tnp transposome™ system to create random insertional mutations in the genome of Spiroplasma citri was evaluated. The efficiency of electroporation-mediated transformation of S. citri BR3-3X averaged 28.8 CFUs/ng transposome for 109spiroplasma cells. Many transformants appearing on the selection plates were growth impaired when transferred to broth. Altering broth composition in various ways did not improve their growth. However, placing colonies into a small broth volume resulted in robust growth and successful subsequent passages of a subset of transformants. PCR using primers for the dihydrofolate reductase gene confirmed the transposon’s presence in the genomes of selected transformants. Southern blot hybridization and nucleotide sequencing suggested that insertion was random within the chromosome and usually at single sites. The insertions were stable. Growth rates of all transformants were lower than that of the wild-type S. citri, but none lost the ability to adhere to a Circulifer tenellus (CT-1) cell line. The EZ::TN™ <DHFR-1> Tnp transposome™ system represents an additional tool for genetic manipulation of the fastidious spiroplasmas.
Involvement of BMPR2 in the protective effect of fluoxetine against monocrotaline-induced endothelial apoptosis in rats
Authors: Wang Yun , Zhang Xin-Hua , Wang Huai-Liang 
Published: June 2011

Mutations in bone morphogenetic protein (BMP) receptor II (BMPR2) are associated with the apoptosis of the pulmonary artery endothelial cells and the loss of the pulmonary small vessels. The present study was designed to investigate the involvement of BMPR2 in the protective effect of fluoxetine against monocrotaline (MCT)-induced endothelial apoptosis in rats. Models of pulmonary arterial hypertension in rats were established by a single intraperitoneal injection of MCT (60 mg/kg). Fluoxetine (2 and 10 mg/kg) was intragastrically administered once a day. After 21 days, MCT caused pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling and significantly reduced the BMPR2 expression in lungs and pulmonary arteries. Fluoxetine dose-dependently inhibited MCT-induced pulmonary arterial hypertension and effectively protected the lungs against MCT-induced endothelial apoptosis, reduction in the number of alveolar sacs, and loss of the pulmonary small vessels. Fluoxetine reversed the expression of cyclic guanosine 3′,5′-monophosphate-dependent kinase І, BMPR2, phospho-Smad1, β-catenin, and reduced the expression of caspase 3 in rat lungs. These findings suggest that BMPR2 is probably involved in the protective effect of fluoxetine against MCT-induced endothelial apoptosis in rats.
Protective effect ofl-citrulline against acute gastric mucosal lesions induced by ischemia–reperfusion in rats
Authors: Gou Lingshan , Zhang Ling , Yin Cui , Jia Genguang , Yin Xiaoxing , Zhuang Xuemei , Xu Xiaodong , Liu Yi 
Published: June 2011

The present study investigated the protective effect of l-citrulline on gastric mucosal injury induced by ischemia–reperfusion (IR) in rats. Under anesthesia, the celiac artery was clamped for 30 min, and then the clamp was removed for 60 min reperfusion. Sixty minutes before ischemia, l-citrulline was administered intragastrically at doses of 300, 600, and 900 mg/kg. After the experiment, the stomachs were removed for biochemical and histological examinations. Pretreatment with l-citrulline (300, 600, and 900 mg/kg) significantly ameliorated the gastric damage caused by IR. Moreover, l-citrulline prevented the production of lipid peroxidation and inhibited the increase of myeloperoxidase activity. The elevation in total nitric oxide synthase (NOS) activity, inducible NOS activity, and inducible NOS protein expression as well as the decrease in constitutive NOS activity and gastric mucus level in the gastric mucosa induced by IR were significantly prevented. However, the protective effect mediated by l-citrulline was significantly antagonized by coadministration of l-nitroarginine methyl ester (10 mg/kg, s.c.). These results suggest that part of the mechanism of gastric protection by l-citrulline might be through inhibiting neutrophil infiltration and preserving gastric mucus synthesis and secretion in rats, functions that are closely related to the maintenance of constitutive NOS activity.
RELAXATION TWO-PHASE FLOW MODELS AND THE SUBCHARACTERISTIC CONDITION
Authors: FLÅTTEN TORE , LUND HALVOR 
Published: June 2011

The subcharacteristic condition for hyperbolic relaxation systems states that wave velocities of an equilibrium system cannot exceed the corresponding wave velocities of its relaxation system. This condition is central to the stability of hyperbolic relaxation systems, and is expected to hold for most such models describing natural phenomena. In this paper, we study a hierarchy of two-phase flow models. We consider relaxation with respect to volume transfer, heat transfer and mass transfer. We formally verify that our relaxation processes are consistent with the first and second laws of thermodynamics, and present analytical expressions for the wave velocities for each model in the hierarchy. Through an appropriate choice of variables, we prove directly by sums-of-squares that for all relaxation processes considered, the subcharacteristic condition holds for any thermodynamically stable equation of state.
Killing of Chronic Lymphocytic Leukemia by the Combination of Fludarabine and Oxaliplatin Is Dependent on the Activity of XPF Endonuclease
Authors: Zecevic Alma , Sampath Deepa , Ewald Brett , Chen Rong , Wierda William , Plunkett William 
Published: June 2011

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) resistant to fludarabine-containing treatments responds to oxaliplatin-based therapy that contains fludarabine. We postulated that a mechanism for this activity is the incorporation of fludarabine into DNA during nucleotide excision repair (NER) stimulated by oxaliplatin adducts.
Experimental Design: We analyzed CLL cell viability, DNA damage, and signaling pathways in response to treatment by fludarabine, oxaliplatin, or the combination. The dependency of the combination on oxaliplatin-induced DNA repair was investigated using siRNA in CLL cells or cell line models of NER deficiency.
Results: Synergistic apoptotic killing was observed in CLL cells after exposure to the combination in vitro. Oxaliplatin induced DNA synthesis in CLL cells, which was inhibited by fludarabine and was eliminated by knockdown of XPF, the NER 5′-endonuclease. Wild-type Chinese hamster ovarian cells showed synergistic killing after combination treatment, whereas only additive killing was observed in cells lacking XPF. Inhibition of repair by fludarabine in CLL cells was accompanied by DNA single-strand break formation. CLL cells initiated both intrinsic and extrinsic apoptotic pathways as evidenced by the loss of mitochondrial outer membrane potential and partial inhibition of cell death upon incubation with FasL antibody.
Conclusions: The synergistic cell killing is caused by a mechanistic interaction that requires the initiation of XPF-dependent excision repair in response to oxaliplatin adducts, and the inhibition of that process by fludarabine incorporation into the repair patch. This combination strategy may be useful against other malignancies. Clin Cancer Res; 17(14); 4731–41. ©2011 AACR.
Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept
Authors: de Groot John F. , Piao Yuji , Tran Hai , Gilbert Mark , Wu Hua-Kang , Liu Jun , Bekele B. Nebiyou , Cloughesy Tim , Mehta Minesh , Robins H. Ian , Lassman Andrew , DeAngelis Lisa , Camphausen Kevin , Chen Alice , Yung WKA , Prados Michael , Wen Patrick Y. , Heymach John V. 
Published: June 2011

Abstract
Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.
Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.
Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1+ monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9.
Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872–81. ©2011 AACR.
Phase I Study Utilizing a Novel Antigen-Presenting Cell–Targeted Vaccine with Toll-like Receptor Stimulation to Induce Immunity to Self-antigens in Cancer Patients
Authors: Morse Michael A. , Chapman Robert , Powderly John , Blackwell Kimberly , Keler Tibor , Green Jennifer , Riggs Renee , He Li-Zhen , Ramakrishna Venky , Vitale Laura , Zhao Biwei , Butler Stephen A. , Hobeika Amy , Osada Takuya , Davis Thomas , Clay Timothy , Lyerly H. Kim 
Published: June 2011

Abstract
Purpose: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity.
Experimental Design: Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-β) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC.
Results: CDX-1307 induced consistent humoral and T-cell responses to hCG-β when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions.
Conclusions: APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy. Clin Cancer Res; 17(14); 4844–53. ©2011 AACR.
Molecular and Cellular Pharmacology of the Novel Noncamptothecin Topoisomerase I Inhibitor Genz-644282
Authors: Sooryakumar Dhriti , Dexheimer Thomas S. , Teicher Beverly A. , Pommier Yves 
Published: June 2011

Abstract
Camptothecin derivatives are powerful anticancer drugs because of their ability to trap topoisomerase I (Top1)–DNA cleavage complexes. However, they exhibit clinical limitations due to the instability of their α-hydroxylactone six-membered E-ring structure. In addition, they exhibit bone marrow and intestinal toxicity, especially in adults, and are drug efflux substrates. Here, we report a novel Top1 inhibitor, Genz-644282. We show that Genz-644282 and its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with camptothecin. The compound also induces protein-linked DNA breaks and Top1–DNA cleavage complexes that persist longer after compound removal than camptothecin. Concentration-dependent and persistent γH2AX formation was readily observed in cells treated with Genz-644282, and was present in greater than 50% of the cell population following 24 hours compound exposure. The compound shows partial cross-resistance in cell lines resistant to camptothecin. These cell lines include the human prostate DU145RC0.1 and the leukemic CEM/C2 cells. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR. Together, our results provide the first molecular and cellular characterization of Genz-644282 and its clinically relevant metabolites. Mol Cancer Ther; 10(8); 1490–9. ©2011 AACR.
Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling
Authors: Barkan Batya , Kloog Yoel , Ehrlich Marcelo 
Published: June 2011

Abstract
Neurofibromin-deficient (Nf1−/−) malignant peripheral nerve sheath tumors (MPNST) are highly invasive, refractory to chemotherapy, and characterized by overactivated Ras. Ras activates mitogenic pathways and regulates morphogenic programs—such as those induced by bone morphogenetic proteins (BMP) and TGF-β. The role of such a cross-talk in determining the phenotype and transformation potential of MPNSTs is unknown. Here, we used MPNST cell lines and selective Ras inhibition with S-trans,trans-farnesylthiosalicylic-acid (FTS; salirasib) in conjunction with specific inhibitors of TGF-β and BMP signaling. FTS perturbed signaling of BMP4 and TGF-β1 to Smad-dependent and Erk-dependent pathways. Furthermore, FTS inhibited motility and spreading, reduced the gelatinase secretion, eliminated the expression and activation of regulators of cell–matrix interaction, and altered gene expression. These phenomena are indicative of a phenotypic reversion of NF1-defficient cells by FTS. Inhibition of BMP4 and TGF-β by noggin and SB-431542, respectively, mimicked the FTS-mediated effects on adhesion, spreading, and cell morphology. This strongly suggests that a cross-talk among TGF-β superfamily ligands and Ras plays a significant role in the transformation of NF1−/− MPNSTs. Our results support the therapeutic potential of FTS, in conjuncture with BMP and TGF-β pathway inhibitors, toward the inhibition of mitogenic and morphogenic signaling pathways and the alleviation of NF1 symptoms. Mol Cancer Ther; 10(8); 1317–26. ©2011 AACR.