bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccinia Virus Mutations in the L4R Gene Encoding a Virion Structural Protein Produce Abnormal Mature Particles Lacking a Nucleocapsid
Authors: Jesus Desyree Murta , Moussatche Nissin , Condit Richard C. 
Published: September 2014

ABSTRACT
Electron micrographs from the 1960s revealed the presence of an S-shaped tubular structure in the center of the vaccinia virion core. Recently, we showed that packaging of virus transcription enzymes is necessary for the formation of the tubular structure, suggesting that the structure is equivalent to a nucleocapsid. Based on this study and on what is known about nucleocapsids of other viruses, we hypothesized that in addition to transcription enzymes, the tubular structure also contains the viral DNA and a structural protein as a scaffold. The vaccinia virion structural protein L4 stands out as the best candidate for the role of a nucleocapsid structural protein because it is abundant, it is localized in the center of the virion core, and it binds DNA. In order to gain more insight into the structure and relevance of the nucleocapsid, we analyzed thermosensitive and inducible mutants in the L4R gene. Using a cryo-fixation method for electron microscopy (high-pressure freezing followed by freeze-substitution) to preserve labile structures like the nucleocapsid, we were able to demonstrate that in the absence of functional L4, mature particles with defective internal structures are produced under nonpermissive conditions. These particles do not contain a nucleocapsid. In addition, the core wall of these virions is abnormal. This suggests that the nucleocapsid interacts with the core wall and that the nucleocapsid structure might be more complex than originally assumed.

IMPORTANCE
The vaccinia virus nucleocapsid has been neglected since the 1960s due to a lack of electron microscopy techniques to preserve this labile structure. With the advent of cryo-fixation techniques, like high-pressure freezing/freeze-substitution, we are now able to consistently preserve and visualize the nucleocapsid. Because vaccinia virus early transcription is coupled to the viral core structure, detailing the structure of the nucleocapsid is indispensable for determining the mechanisms of vaccinia virus core-directed transcription. The present study represents our second attempt to understand the structure and biological significance of the nucleocapsid. We demonstrate the importance of the protein L4 for the formation of the nucleocapsid and reveal in addition that the nucleocapsid and the core wall may be associated, suggesting a higher level of complexity of the nucleocapsid than predicted. In addition, we prove the utility of high-pressure freezing in preserving the vaccinia virus nucleocapsid.
Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction
Authors: Chtarbanova Stanislava , Lamiable Olivier , Lee Kwang-Zin , Galiana Delphine , Troxler Laurent , Meignin Carine , Hetru Charles , Hoffmann Jules A. , Daeffler Laurent , Imler Jean-Luc 
Published: September 2014

ABSTRACT

Drosophila
C virus (DCV) is a positive-sense RNA virus belonging to the
Dicistroviridae
family. This natural pathogen of the model organism
Drosophila melanogaster
is commonly used to investigate antiviral host defense in flies, which involves both RNA interference and inducible responses. Although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. Here, we characterize the pathogenesis associated with systemic DCV infection. Comparison of the transcriptome of flies infected with DCV or two other positive-sense RNA viruses, Flock House virus and Sindbis virus, reveals that DCV infection, unlike those of the other two viruses, represses the expression of a large number of genes. Several of these genes are expressed specifically in the midgut and also are repressed by starvation. We show that systemic DCV infection triggers a nutritional stress in
Drosophila
which results from intestinal obstruction with the accumulation of peritrophic matrix at the entry of the midgut and the accumulation of the food ingested in the crop, a blind muscular food storage organ. The related virus cricket paralysis virus (CrPV), which efficiently grows in
Drosophila
, does not trigger this pathology. We show that DCV, but not CrPV, infects the smooth muscles surrounding the crop, causing extensive cytopathology and strongly reducing the rate of contractions. We conclude that the pathogenesis associated with systemic DCV infection results from the tropism of the virus for an important organ within the foregut of dipteran insects, the crop.

IMPORTANCE
DCV is one of the few identified natural viral pathogens affecting the model organism
Drosophila melanogaster
. As such, it is an important virus for the deciphering of host-virus interactions in insects. We characterize here the pathogenesis associated with DCV infection in flies and show that it results from the tropism of the virus for an essential but poorly characterized organ in the digestive tract, the crop. Our results may have relevance for other members of the
Dicistroviridae
, some of which are pathogenic to beneficial or pest insect species.
Association of skirt size and postmenopausal breast cancer risk in older women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
Authors: Fourkala Evangelia-Ourania , Burnell Matthew , Cox Catherine , Ryan Andy , Salter Laura Currin , Gentry-Maharaj Aleksandra , Parmar Mahesh , Jacobs Ian , Menon Usha 
Published: September 2014

ObjectivesSeveral studies suggest that overall and central-obesity are associated with increased breast cancer (BC) risk in postmenopausal-women. However, there are no studies investigating changes of central obesity and BC. We report on the association of BC risk with self-reported skirt size (SS; waist-circumference proxy) changes between 20s and postmenopausal-age.DesignProspective cohort-study.SettingUK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) involving the nine trial centres in England.ParticipantsPostmenopausal-women aged >50 with no known history of BC prior to or on the day of completion of the study-entry questionnaire.InterventionsAt recruitment and at study entry, women were asked to complete a questionnaire. Women were followed-up via ‘flagging’ at the NHS Information Centre in England and the Hospital Episode Statistics.Main outcome-measureTime to initial BC diagnosis.ResultsBetween 2 January 2005 and 1 July 2010, 92 834 UKCTOCS participants (median age 64.0) completed the study-entry questionnaire. During median follow-up of 3.19 years (25th–75th centile: 2.46–3.78), 1090 women developed BC. Model adjusted analysis for potential confounders showed body mass index (BMI) at recruitment to UKCTOCS (HR for a 5 unit change=1.076, 95% CI 1.012 to 1.136), current SS at study entry (HR=1.051; 95% CI 1.014 to 1.089) and change in SS per 10 years (CSS) (HR=1.330; 95% CI 1.121 to 1.579) were associated with increased BC risk but not SS at 25 (HR=1.006; 95% CI 0.958 to 1.056). CSS was the most predictive singe adiposity measure and further analysis including both CSS and BMI in the model revealed CSS remained significant (HR=1.266; 95% CI 1.041 to 1.538) but not BMI (HR=1.037; 95% CI 0.970 to 1.109).ConclusionsCSS is associated with BC risk independent of BMI. A unit increase in UK SS (eg, 12–14) every 10-years between 25 and postmenopausal-age is associated with postmenopausal BC risk by 33%. Validation of these results could provide women with a simple and easy to understand message.Trial registration numberISRCTN22488978.
Haematologists’ perceptions of palliative care and specialist palliative care referral: a qualitative study
Authors: Wright Bethany , Forbes Karen 
Published: September 2014

ObjectivesThis study explored the views and perceptions of haematologists towards palliative care, based on their own clinical experiences, focusing on those factors that helped or hindered referral to specialist palliative care (SPC) services.MethodWe conducted in-depth face-to-face interviews with a purposive sample of eight trainee and consultant haematologists working in tertiary referral centres in the West Midlands. All interviews were recorded, transcribed and subsequently analysed using the principles of the grounded theory approach.ResultsData analysis revealed a core category around boundaries alongside four emerging categories: perceptions of palliative care; philosophy of approach; determining roles; and responsibility and control. Positive attitudes towards SPC involvement were expressed by most participants. The role of SPC services was sometimes difficult for participants to define, with timing of referral often determined by their level of confidence in providing end-of-life care. Almost all highlighted a lack of inpatient palliative care unit provision; this was viewed negatively and impacted on referral.ConclusionsWhile positive attitudes towards palliative care were expressed, barriers to collaboration between haematology and SPC services were identified and provided opportunities for improved interdisciplinary working. Suggestions for improvement are focused around: improved training; enhanced mutual respect and understanding; clearer definition of the role of SPC services; and consistency and flexibility in service provision.
Making patient and public involvement in cancer and palliative research a reality: academic support is vital for success
Authors: Collins Karen , Boote Jonathan , Ardron David , Gath Jacqui , Green Tracy , Ahmedzai Sam H 
Published: September 2014

ObjectivePatient and public involvement (PPI) has become an established theme within the UK health research policy and is recognised as an essential force in the drive to improve the quality of services and research. These developments have been particularly rapid in the cancer field.MethodsThis paper outlines a model of PPI in research (known as the North Trent Cancer Research Network Consumer Research Panel, NTCRN CRP; comprising 38 cancer and palliative care patients/carers) and the key benefits and challenges to effective PPI in cancer research.ResultsThe PPI model has become a sustainable, inclusive and effective way of implementing PPI within the cancer context. Challenges include (1) a lack of time and funding available to support the PPI model; (2) tensions between different stakeholder groups when developing and conducting health research; (3) panel members finding it difficult to effectively integrate into research meetings when their role and contribution is not made clear at the outset or when unfamiliar language and jargon are used and not explained; (4) some professionals remain unclear about the role and practical implications of PPI in research. However, notwithstanding its financial and organisational challenges, the way that the NTCRN CRP is supported has provided a solid base for it to flourish.ConclusionsPPI provides considerable opportunities for patients and the public to work collaboratively with professionals to influence the cancer research agenda, with the contribution of PPI to the research process being integral to the entire process from the outset, rather than appended to it.
Pretargeted Dual-Modality Immuno-SPECT and Near-Infrared Fluorescence Imaging for Image-Guided Surgery of Prostate Cancer
Authors: Lütje Susanne , Rijpkema Mark , Goldenberg David M. , van Rij Catharina M. , Sharkey Robert M. , McBride William J. , Franssen Gerben M. , Frielink Cathelijne , Helfrich Wijnand , Oyen Wim J.G. , Boerman Otto C. 
Published: September 2014

Abstract
Radical removal of malignant lesions may be improved using tumor-targeted dual-modality probes that contain both a radiotracer and a fluorescent label to allow for enhanced intraoperative delineation of tumor resection margins. Because pretargeting strategies yield high signal-to-background ratios, we evaluated the feasibility of a pretargeting strategy for intraoperative imaging in prostate cancer using an anti–TROP-2 x anti-HSG bispecific antibody (TF12) in conjunction with the dual-labeled diHSG peptide (RDC018) equipped with both a DOTA chelate for radiolabeling purposes and a fluorophore (IRdye800CW) to allow near-infrared optical imaging. Nude mice implanted s.c. with TROP-2–expressing PC3 human prostate tumor cells or with PC3 metastases in the scapular and suprarenal region were injected i.v. with 1 mg of TF12 and, after 16 hours of tumor accumulation and blood clearance, were subsequently injected with 10 MBq, 0.2 nmol/mouse of either 111In-RDC018 or 111In-IMP288 as a control. Two hours after injection, both microSPECT/CT and fluorescence images were acquired, both before and after resection of the tumor nodules. After image acquisition, the biodistribution of 111In-RDC018 and 111In-IMP288 was determined and tumors were analyzed immunohistochemically. The biodistribution of the dual-label RDC018 showed specific accumulation in the TROP-2–expressing PC3 tumors (12.4 ± 3.7% ID/g at 2 hours postinjection), comparable with 111In-IMP288 (9.1 ± 2.8% ID/g at 2 hours postinjection). MicroSPECT/CT and near-infrared fluorescence (NIRF) imaging confirmed this TROP-2–specific uptake of the dual-label 111In-RDC018 in both the s.c. and metastatic growing tumor model. In addition, PC3 metastases could be visualized preoperatively with SPECT/CT and could subsequently be resected by image-guided surgery using intraoperative NIRF imaging, showing the preclinical feasibility of pretargeted dual-modality imaging approach in prostate cancer. Cancer Res; 74(21); 6216–23. ©2014 AACR.
In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer
Authors: Santos Mirentxu , Martínez-Fernández Mónica , Dueñas Marta , García-Escudero Ramón , Alfaya Begoña , Villacampa Felipe , Saiz-Ladera Cristina , Costa Clotilde , Oteo Marta , Duarte José , Martínez Victor , Gómez-Rodriguez Ma José , Martín Ma Luisa , Fernández Manoli , Viatour Patrick , Morcillo Miguel A. , Sage Julien , Castellano Daniel , Rodriguez-Peralto Jose L. , de la Rosa Federico , Paramio Jesús M 
Published: September 2014

Abstract
Bladder cancer is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here, we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate bladder cancer development. The characterization of the mouse tumors revealed multiple molecular features of human bladder cancer, including the activation of E2F transcription factor and subsequent Ezh2 expression and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial bladder cancer. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirmed the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human patients with superficial bladder cancer is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial bladder cancer and demonstrate the existence of an Rb–E2F–Ezh2 axis in bladder whose disruption can promote tumor development. Cancer Res; 74(22); 6565–77. ©2014 AACR.
Vitamin D Suppresses Leptin Stimulation of Cancer Growth through microRNA
Authors: Kasiappan Ravi , Sun Yuefeng , Lungchukiet Panida , Quarni Waise , Zhang Xiaohong , Bai Wenlong 
Published: September 2014

AbstractObesity is a pandemic and major risk factor for cancers. The reduction of obesity would have been an effective strategy for cancer prevention, but the reality is that worldwide obesity has kept increasing for decades, remaining a major avoidable cancer risk secondary only to smoke. The present studies suggest that vitamin D may be an effective agent to reduce obesity-associated cancer risks in women. Molecular analyses showed that leptin increased human telomerase reverse transcriptase (hTERT) mRNA expression and cell growth through estrogen receptor-α (ERα) activation in ovarian cancer cells, which was suppressed by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with microRNA (miRNA) sponges. In mice, high-fat diet (HFD) stimulation of ovarian tumor growth was remarkably suppressed by 1,25(OH)2D3 analogue EB1089, which was also compromised by miR-498 sponges. EB1089 did not alter HFD-induced increase in serum leptin levels but increased miR-498 and decreased the diet-induced hTERT expression in tumors. Quantitative RT-PCR analyses revealed an inverse correlation between hTERT mRNA and miR-498 in response to 1,25(OH)2D3 in estrogen-sensitive ovarian, endometrial, and breast cancers. The studies suggest that miR-498-mediated hTERT downregulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women. Cancer Res; 74(21); 6194–204. ©2014 AACR.
A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation
Authors: Ott Heidi M. , Graves Alan P. , Pappalardi Melissa B. , Huddleston Michael , Halsey Wendy S. , Hughes Ashley M. , Groy Arthur , Dul Edward , Jiang Yong , Bai Yuchen , Annan Roland , Verma Sharad K. , Knight Steven D. , Kruger Ryan G. , Dhanak Dashyant , Schwartz Benjamin , Tummino Peter J. , Creasy Caretha L. , McCabe Michael T. 
Published: September 2014

Abstract
The EZH2 methyltransferase silences gene expression through methylation of histone H3 on lysine 27 (H3K27). Recently, EZH2 mutations have been reported at Y641, A677, and A687 in non-Hodgkin lymphoma. Although the Y641F/N/S/H/C and A677G mutations exhibit clearly increased activity with substrates dimethylated at lysine 27 (H3K27me2), the A687V mutant has been shown to prefer a monomethylated lysine 27 (H3K27me1) with little gain of activity toward H3K27me2. Herein, we demonstrate that despite this unique substrate preference, A687V EZH2 still drives increased H3K27me3 when transiently expressed in cells. However, unlike the previously described mutants that dramatically deplete global H3K27me2 levels, A687V EZH2 retains normal levels of H3K27me2. Sequencing of B-cell–derived cancer cell lines identified an acute lymphoblastic leukemia cell line harboring this mutation. Similar to exogenous expression of A687V EZH2, this cell line exhibited elevated H3K27me3 while possessing H3K27me2 levels higher than Y641- or A677-mutant lines. Treatment of A687V EZH2-mutant cells with GSK126, a selective EZH2 inhibitor, was associated with a global decrease in H3K27me3, robust gene activation, caspase activation, and decreased proliferation. Structural modeling of the A687V EZH2 active site suggests that the increased catalytic activity with H3K27me1 may be due to a weakened interaction with an active site water molecule that must be displaced for dimethylation to occur. These findings suggest that A687V EZH2 likely increases global H3K27me3 indirectly through increased catalytic activity with H3K27me1 and cells harboring this mutation are highly dependent on EZH2 activity for their survival. Mol Cancer Ther; 13(12); 3062–73. ©2014 AACR.
A Study on the Scale Dependence of the Predictability of Precipitation Patterns
Authors: Surcel Madalina , Zawadzki Isztar , Yau M. K. 
Published: September 2014

Abstract
A methodology is proposed to investigate the scale dependence of the predictability of precipitation patterns at the mesoscale. By applying it to two or more precipitation fields, either modeled or observed, a decorrelation scale can be defined such that all scales smaller than are fully decorrelated. For precipitation forecasts from a radar data–assimilating storm-scale ensemble forecasting (SSEF) system, is found to increase with lead time, reaching 300 km after 30 h. That is, for , the ensemble members are fully decorrelated. Hence, there is no predictability of the model state for these scales. For , the ensemble members are correlated, indicating some predictability by the ensemble. When applied to characterize the ability to predict precipitation as compared to radar observations by numerical weather prediction (NWP) as well as by Lagrangian persistence and Eulerian persistence, increases with lead time for most forecasting methods, while it is constant (300 km) for non–radar data–assimilating NWP.
Comparing the different forecasting models, it is found that they are similar in the 0–6-h range and that none of them exhibit any predictive ability at meso-γ and meso-β scales after the first 2 h. On the other hand, the radar data–assimilating ensemble exhibits predictability of the model state at these scales, thus causing a systematic difference between corresponding to the ensemble and corresponding to model and radar. This suggests that either the ensemble does not have sufficient spread at these scales or that the forecasts suffer from biases.
Evaluation of Long-Term SSM/I-Based Precipitation Records over Land
Authors: Alemohammad Seyed Hamed , Entekhabi Dara , McLaughlin Dennis B. 
Published: September 2014

AbstractThe record of global precipitation mapping using Special Sensor Microwave Imager (SSM/I) measurements now extends over two decades. Similar measurements, albeit with different retrieval algorithms, are to be used in the Global Precipitation Measurement (GPM) mission as part of a constellation to map global precipitation with a more frequent data refresh rate. Remotely sensed precipitation retrievals are prone to both magnitude (precipitation intensity) and phase (position) errors. In this study, the ground-based radar precipitation product from the Next Generation Weather Radar stage-IV (NEXRAD-IV) product is used to evaluate a new metric of error in the long-term SSM/I-based precipitation records. The new metric quantifies the proximity of two multidimensional datasets. Evaluation of the metric across the years shows marked seasonality and precipitation intensity dependence. Drifts and changes in the instrument suite are also evident. Additionally, the precipitation retrieval errors conditional on an estimate of background surface soil moisture are estimated. The dynamic soil moisture can produce temporal variability in surface emissivity, which is a source of error in retrievals. Proper filtering has been applied in the analysis to differentiate between the detection error and the retrieval error. The identification of the different types of errors and their dependence on season, intensity, instrument, and surface conditions provide guidance to the development of improved retrieval algorithms for use in GPM constellation-based precipitation data products.