bluuebunny/crossref_metadata_2025_split huggingface dataset:
G
2
/M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex
Authors: Berger Gregory , Lawrence Madeleine , Hué Stephane , Neil Stuart J. D. 
Published: October 2014

ABSTRACT

The accessory gene
vpr
, common to all primate lentiviruses, induces potent G
2
/M arrest in cycling cells. A recent study showed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway. To confirm these observations, we have examined the G
2
/M arrest phenotypes of a panel of simian immunodeficiency virus (SIV) Vpr proteins. We show that SIV Vpr proteins differ in their ability to promote cell cycle arrest in human cells. While this is dependent on the DCAF1/DDB1/CUL4 ubiquitin ligase complex, interaction with human DCAF1 does not predict G
2
/M arrest activity of SIV Vpr in human cells. In all cases, SIV Vpr-mediated cell cycle arrest in human cells correlated with interaction with human SLX4 (huSLX4) and could be abolished by small interfering RNA (siRNA) depletion of any member of the SLX4 complex. In contrast, all but one of the HIV/SIV Vpr proteins tested, including those that lacked activity in human cells, were competent for G
2
/M arrest in grivet cells. Correspondingly, here cell cycle arrest correlated with interaction with the grivet orthologues of the SLX4 complex, suggesting a level of host adaptation in these interactions. Phylogenetic analyses strongly suggest that G
2
/M arrest/SLX4 interactions are ancestral activities of primate lentiviral Vpr proteins and that the ability to dysregulate the Fanconi anemia DNA repair pathway is an essential function of Vpr
in vivo
.

IMPORTANCE
The Vpr protein of HIV-1 and related viruses is essential for the virus
in vivo
. The ability of Vpr to block the cell cycle at mitotic entry is well known, but the importance of this function for viral replication is unclear. Recent data have shown that HIV-1 Vpr targets the Fanconi anemia DNA repair pathway by interacting with and activating an endonuclease complex, SLX4/MUS81/EME1, that processes interstrand DNA cross-links. Here we show that the ability of a panel of SIV Vpr proteins to mediate cell cycle arrest correlates with species-specific interactions with the SLX4 complex in human and primate cells. The results of these studies suggest that the SLX4 complex is a conserved target of primate lentiviral Vpr proteins and that the ability to dysregulate members of the Fanconi anemia DNA repair pathway is essential for HIV/SIV replication
in vivo
.
Malawi Polyomavirus Is a Prevalent Human Virus That Interacts with Known Tumor Suppressors
Authors: Berrios Christian , Jung Joonil , Primi Blake , Wang Michael , Pedamallu Chandrasekhar , Duke Fujiko , Marcelus Christina , Cheng Jingwei , Garcea Robert L. , Meyerson Matthew , DeCaprio James A. 
Published: October 2014

ABSTRACT
Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential.
Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0
Authors: Conwell Sara E. , White Anne E. , Harper J. Wade , Knipe David M. 
Published: October 2014

ABSTRACT

The herpes simplex virus 1 (HSV-1) immediate early protein ICP0 performs many functions during infection, including transactivation of viral gene expression, suppression of innate immune responses, and modification and eviction of histones from viral chromatin. Although these functions of ICP0 have been characterized, the detailed mechanisms underlying ICP0's complex role during infection warrant further investigation. We thus undertook an unbiased proteomic approach to identifying viral and cellular proteins that interact with ICP0 in the infected cell. Cellular candidates resulting from our analysis included the ubiquitin-specific protease USP7, the transcriptional repressor TRIM27, DNA repair proteins NBN and MRE11A, regulators of apoptosis, including BIRC6, and the proteasome. We also identified two HSV-1 early proteins involved in nucleotide metabolism, U
L
39 and U
L
50, as novel candidate interactors of ICP0. Because TRIM27 was the most statistically significant cellular candidate, we investigated the relationship between TRIM27 and ICP0. We observed rapid, ICP0-dependent loss of TRIM27 during HSV-1 infection. TRIM27 protein levels were restored by disrupting the RING domain of ICP0 or by inhibiting the proteasome, arguing that TRIM27 is a novel degradation target of ICP0. A mutant ICP0 lacking E3 ligase activity interacted with endogenous TRIM27 during infection as demonstrated by reciprocal coimmunoprecipitation and supported by immunofluorescence data. Surprisingly, ICP0-null mutant virus yields decreased upon TRIM27 depletion, arguing that TRIM27 has a positive effect on infection despite being targeted for degradation. These results illustrate a complex interaction between TRIM27 and viral infection with potential positive or negative effects of TRIM27 on HSV under different infection conditions.

IMPORTANCE
During productive infection, a virus must simultaneously redirect multiple cellular pathways to replicate itself while evading detection by the host's defenses. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein regulates various cellular pathways concurrently by targeting a diverse set of cellular factors for degradation. While some of these targets have been previously identified and characterized, we undertook a proteomic screen to identify additional targets of this activity to further characterize ICP0's role during infection. We describe a set of candidate interacting proteins of ICP0 identified through this approach and our characterization of the most statistically significant result, the cellular transcriptional repressor TRIM27. We present TRIM27 as a novel degradation target of ICP0 and describe the relationship of these two proteins during infection.
Cross-cultural adaptation, evaluation and validation of the Spouse Response Inventory: a study protocol
Authors: Kaiser Ulrike , Steinmetz Dorit , Scharnagel Rüdiger , Jensen Mark P , Balck Friedrich , Sabatowski Rainer 
Published: October 2014

IntroductionSince the response of spouses has been proven to be an important reinforcement of pain behaviour and disability it has been addressed in research and therapy. Fordyce suggestedpain behaviourandwell behaviourbe considered in explaining suffering in chronic pain patients. Among existing instruments concerning spouse's responses the aspect of well behaviour has not been examined so far. The SRI (Spouse Response Inventory) tries to consider pain behaviour and well behaviour and appears to be acceptable because of its brevity and close proximity to daily language. Theaim of the studyis the translation into German, followed by evaluation and validation, of the SRI on a German sample of patients with chronic pain.Methods and analysesThe study is comprehensively designed: initially, the focus will lie on thetranslationof the instrument following the guidelines for cross-cultural translation and adaptation andevaluationof the German version according to the source study. Subsequently, avalidationreferring to predictive, incremental and construct validation will be conducted using instruments based on similar or close but different constructs. Evaluation of the resulting SRI-G (SRI-German) will be conducted on a sample of at least 30 patients with chronic pain attending a comprehensive pain centre. For validation at least 120 patients with chronic headache, back pain, cancer related pain and somatoform pain disorder shall be included, for a total of 480 patients. Separate analyses according to specific pain diagnoses will be performed to ensure psychometric property, interpretability and control of diagnosis of specific limitations. Analyses will include comprehensive investigation of psychometric property of the scale by hierarchical regression analyses, correlation analyses, multivariate analysis of variance and exploratory factor analyses (SPSS).EthicsThe study protocol was approved by the Ethics Committee of the University of Dresden (EK 335 122008) based on the Helsinki declaration.
Job demand and control in mid-life and physical and mental functioning in early old age: do childhood factors explain these associations in a British birth cohort?
Authors: von Bonsdorff Mikaela B , Cooper Rachel , Kuh Diana 
Published: October 2014

ObjectivesAdverse work-related exposures have been linked with decreased physical and mental functioning in later life, however, whether childhood factors explain the associations between work exposures and functioning is unknown. Our aim was to investigate if job demand and control in mid-life were related to self-reported physical and mental functioning in early old age and whether childhood factors explained these associations.DesignProspective cohort study.SettingEngland, Scotland and Wales.Participants and outcome measuresData come from the UK Medical Research Council National Survey of Health and Development, a cohort with follow-up since birth in 1946. 1485 occupationally active study members had data available on job demand and control in mid-life and on physical and mental functioning assessed using the Short Form-36 questionnaire at 60–64 years.ResultsThose with higher job control in mid-life had better physical functioning than those who reported lower job control (β 0.51, 95% CI 0.02 to 1.01, p=0.04 adjusted for adult confounders). Those with higher job demand in mid-life had poorer mental functioning (β −0.82, 95% CI −1.14 to −0.51, p<0.001). Associations between job control and mental functioning were similar but less pronounced. Adjustment for childhood factors (father's and mother's educational attainment, parents’ interest in school at age 7 and cognitive ability at age 8) partially explained the association between job control and physical functioning, but did not explain the association between job demand and mental functioning.ConclusionsJob demand and control in mid-life are differentially associated with mental and physical functioning in early old age and some of these associations may be partially explained by childhood factors.
The use of parental occupation in adolescent health surveys. An application of ISCO-based measures of occupational status
Authors: Pförtner Timo-Kolja , Günther Sebastian , Levin Kate A , Torsheim Torbjørn , Richter Matthias 
Published: October 2014

BackgroundRecent research has emphasised that the challenge in researching socioeconomic differences in adolescent health cross-nationally lies in providing valid and comparable measures of socioeconomic position (SEP) across regions. This study aims to examine measures of occupational status derived from the International Standard Classiﬁcation of Occupations (ISCO), alongside commonly used affluence measures in association with adolescent self-rated health (SRH).MethodsData were from the 2005/2006 ‘Health Behaviour in School-aged Children study’ (HBSC); 27 649 individuals aged 11, 13 and 15 years from Germany, Macedonia, Norway, Turkey, Wales and Scotland. Three occupational scales were compared: the International Socioeconomic Index of Occupational Status (ISEI), the Standard International Occupational Prestige Scale (SIOPS) and the Erikson–Goldthorpe–Portocarero class categories (EGP). Correlation analyses compared these occupational scales with the family affluence scale (FAS) and a family well-off measure, while logistic regression assessed the association between occupational scales and poor SRH. Multiple imputation techniques investigated possible bias arising from parental occupation missingness.ResultsModerate correlations existed between occupational scales and FAS and family well-off. Socioeconomic inequalities in poor SRH were found for ISEI, SIOPS and EGP in all regions, independent of FAS and family well-off. Models of imputed data sets did not alter the results. The relationship between SEP and SRH was therefore not biased by high levels of missing values for ISCO.ConclusionsISCO-based indicators of occupational status in cross-national self-administered adolescent health surveys were found to be robust measures of SEP in adolescence. These measure different aspects of SEP independent of FAS and family well-off.
Omentalisation in the treatment of sublumbar abscessation: long‐term outcome in 10 dogs
Authors: Woodbridge N. , Martinoli S. , Cherubini G. B. , Caine A. , Nelissen P. , White R. 
Published: October 2014

The objectives of this study were to report the technique of omentalisation for the management of sublumbar abscessation associated with suspected migrating plant material, the intraoperative and postoperative complications that occurred and the long‐term outcome of the cases. A retrospective case series of dogs (n=10) with sublumbar abscessation managed by exploration and drainage combined with omentalisation of the abscess cavity is reported in this study. The sublumbar area was approached through a ventral midline coeliotomy, the abscess was explored, drained, debrided and subsequently packed with omentum. One dog sustained an aortic rupture during exploration of the abscess, the aorta was repaired; there were no postoperative complications. There was long‐term (>12 months) resolution of clinical signs in all dogs. Drainage and omentalisation of sublumbar abscesses resulted in complete resolution of signs in all dogs and was associated with a low incidence of complications. Omentalisation is an effective treatment for dogs presenting with sublumbar abscesses associated with suspected migrating plant material.
Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects
Authors: Chan C.T. , Qi J. , Smith W. , Paranol R. , Mazitschek R. , West N. , Reeves R. , Chiosis G. , Schreiber S.L. , Bradner J.E. , Paulmurugan R. , Gambhir S.S. 
Published: October 2014

Abstract
Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(α/β)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21waf1 upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control–treated mice as determined by BLI. Small animal 18F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor. Cancer Res; 74(24); 7475–86. ©2014 AACR.
Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy
Authors: Kemper Kristel , de Goeje Pauline L. , Peeper Daniel S. , van Amerongen Renée 
Published: October 2014

Abstract
Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called “phenotype switching” has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal–like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention. Cancer Res; 74(21); 5937–41. ©2014 AACR.
SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer
Authors: Ming Mei , Han Weinong , Zhao Baozhong , Sundaresan Nagalingam R. , Deng Chu-Xia , Gupta Mahesh P. , He Yu-Ying 
Published: October 2014

Abstract
SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. Cancer Res; 74(20); 5925–33. ©2014 AACR.
Emerging Role of Infectious Etiologies in the Pathogenesis of Marginal Zone B-cell Lymphomas
Authors: Zucca Emanuele , Bertoni Francesco , Vannata Barbara , Cavalli Franco 
Published: October 2014

Abstract
Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sjögren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-κB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice.
See all articles in this CCR Focus section, “Paradigm Shifts in Lymphoma.”
Clin Cancer Res; 20(20); 5207–16. ©2014 AACR.
Phosphoinositide 3-Kinase Inhibitors Combined with Imatinib in Patient-Derived Xenograft Models of Gastrointestinal Stromal Tumors: Rationale and Efficacy
Authors: Van Looy Thomas , Wozniak Agnieszka , Floris Giuseppe , Sciot Raf , Li Haifu , Wellens Jasmien , Vanleeuw Ulla , Fletcher Jonathan A. , Manley Paul W. , Debiec-Rychter Maria , Schöffski Patrick 
Published: October 2014

AbstractIntroduction: The PI3K signaling pathway drives tumor cell proliferation and survival in gastrointestinal stromal tumor (GIST). We tested the in vivo efficacy of three PI3K inhibitors (PI3Ki) in patient-derived GIST xenograft models.Experimental Design: One hundred and sixty-eight nude mice were grafted with human GIST carrying diverse KIT genotypes and PTEN genomic status. Animals were dosed orally for two weeks as follows: control group (untreated); imatinib (IMA); PI3Ki (BKM120—buparlisib, BEZ235, or BYL719) or combinations of imatinib with a PI3Ki. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. Furthermore, tumor regrowth was evaluated for three weeks after treatment cessation.Results: PI3Ki monotherapy showed a significant antitumor effect, reflected in tumor volume reduction or stabilization, inhibitory effects on mitotic activity, and PI3K signaling inhibition. The IMA+PI3Ki combination remarkably improved the efficacy of either single-agent treatment with more pronounced tumor volume reduction and enhanced proapoptotic effects over either single agent. Response to IMA+PI3Ki was found to depend on the KIT genotype and specific model-related molecular characteristics.Conclusion: IMA+PI3Ki has significant antitumor efficacy in GIST xenografts as compared with single-agent treatment, resulting in more prominent tumor volume reduction and enhanced induction of apoptosis. Categorization of GIST based on KIT genotype and PI3K/PTEN genomic status combined with dose optimization is suggested for patient selection for clinical trials exploring such combinations. Clin Cancer Res; 20(23); 6071–82. ©2014 AACR.