bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China
Authors: Kang Le-Ni , Jeronimo Jose , Qiao You-Lin , Zhao Fang-Hui , Chen Wen , Valdez Melissa , Zhang Xun , Bansil Pooja , Paul Proma , Bai Ping , Peck Roger , Li Jing , Chen Feng , Stoler Mark H. , Castle Philip E. 
Published: March 2014

ABSTRACT

careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (
n
= 127), and secondary endpoint was CIN2+ (
n
= 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948,
P
= 0.166), and better than careHPV-S (0.878;
P
< 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.
Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model
Authors: Cox Reagan G. , Erickson John J. , Hastings Andrew K. , Becker Jennifer C. , Johnson Monika , Craven Ryan E. , Tollefson Sharon J. , Boyd Kelli L. , Williams John V. 
Published: March 2014

ABSTRACTHuman metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. G. Cox, S. B. Livesay, M. Johnson, M. D. Ohi, and J. V. Williams, J. Virol. 86:12148–12160, 2012), which we hypothesized would elicit F-specific antibody and T cell responses. In this study, we tested whether VLP immunization could induce protective immunity to HMPV by using a mouse model. C57BL/6 mice were injected twice intraperitoneally with VLPs alone or with adjuvant and subsequently challenged with HMPV. Mice were euthanized 5 days postinfection, and virus titers, levels of neutralizing antibodies, and numbers of CD3+T cells were quantified. Mice immunized with VLPs mounted an F-specific antibody response and generated CD8+T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant, though adjuvant reduced cellular immune responses. Two doses of VLPs conferred complete protection from HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of acute respiratory infection in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach. We generated HMPV VLPs by expressing the viral matrix (M) and fusion (F) proteins in mammalian cells. We found that mice immunized with VLPs mounted an F-specific antibody response and generated CD8+T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant. Two doses of VLPs conferred complete protection against HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.
Animal Model of Respiratory Syncytial Virus: CD8
+
T Cells Cause a Cytokine Storm That Is Chemically Tractable by Sphingosine-1-Phosphate 1 Receptor Agonist Therapy
Authors: Walsh Kevin B. , Teijaro John R. , Brock Linda G. , Fremgen Daniel M. , Collins Peter L. , Rosen Hugh , Oldstone Michael B. A. 
Published: March 2014

ABSTRACT

The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8
+
T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8
+
T cell response, resulting in diminished pulmonary disease and enhanced survival.

IMPORTANCE
A dysregulated overly exuberant immune response, termed a “cytokine storm,” accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3
Authors: Xiang Zichun , Li Linlin , Lei Xiaobo , Zhou Hongli , Zhou Zhuo , He Bin , Wang Jianwei 
Published: March 2014

ABSTRACT

Human enterovirus 68 (EV68) is a member of the EV-D species, which belongs to the EV genus of the
Picornaviridae
family. Over the past several years, there have been increasingly documented outbreaks of respiratory disease associated with EV68. As a globally emerging pathogen, EV68 infects both adults and children. However, the molecular basis of EV68 pathogenesis is unknown. Here we report that EV68 inhibits Toll-like receptor 3 (TLR3)-mediated innate immune responses by targeting the TIR domain-containing adaptor inducing beta interferon (TRIF). In infected HeLa cells, EV68 inhibits poly(I·C)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression. Further investigations revealed that TRIF, a critical adaptor downstream of TLR3, is targeted by EV68. When expressed alone, 3C
pro
, an EV68-encoded protease, cleaves TRIF. 3C
pro
mediates TRIF cleavage at Q312 and Q653, which are sites in the amino- and carboxyl-terminal domains, respectively. This cleavage relies on 3C
pro
's cysteine protease activity. Cleavage of TRIF abolishes the capacity of TRIF to activate NF-κB and IFN-β signaling. These results suggest that control of TRIF by 3C
pro
may be a mechanism by which EV68 subverts host innate immune responses.

IMPORTANCE
EV68 is a globally emerging pathogen, but the molecular basis of EV68 pathogenesis is unclear. Here we report that EV68 inhibits TLR3-mediated innate immune responses by targeting TRIF. Further investigations revealed that TRIF is cleaved by 3C
pro
. These results suggest that control of TRIF by 3C
pro
may be a mechanism by which EV68 impairs type I IFN production in response to TLR3 activation.
Investments in respiratory infectious disease research 1997–2010: a systematic analysis of UK funding
Authors: Head Michael G , Fitchett Joseph R , Cooke Mary K , Wurie Fatima B , Hayward Andrew C , Lipman Marc C , Atun Rifat 
Published: March 2014

ObjectivesRespiratory infections are responsible for a large global burden of disease. We assessed the public and philanthropic investments awarded to UK institutions for respiratory infectious disease research to identify areas of underinvestment. We aimed to identify projects and categorise them by pathogen, disease and position along the research and development value chain.SettingThe UK.ParticipantsInstitutions that host and carry out infectious disease research.Primary and secondary outcome measuresThe total amount spent and number of studies with a focus on several different respiratory pathogens or diseases, and to correlate these against the global burden of disease; also the total amount spent and number of studies relating to the type of science, the predominant funder in each category and the mean and median award size.ResultsWe identified 6165 infectious disease studies with a total investment of £2·6 billion. Respiratory research received £419 million (16.1%) across 1192 (19.3%) studies. The Wellcome Trust provided greatest investment (£135.2 million; 32.3%). Tuberculosis received £155 million (37.1%), influenza £80 million (19.1%) and pneumonia £27.8 million (6.6%). Despite high burden, there was relatively little investment in vaccine-preventable diseases including diphtheria (£0.1 million, 0.03%), measles (£5.0 million, 1.2%) and drug-resistant tuberculosis. There were 802 preclinical studies (67.3%) receiving £273 million (65.2%), while implementation research received £81 million (19.3%) across 274 studies (23%). There were comparatively few phase I–IV trials or product development studies. Global health research received £68.3 million (16.3%). Relative investment was strongly correlated with 2010 disease burden.ConclusionsThe UK predominantly funds preclinical science. Tuberculosis is the most studied respiratory disease. The high global burden of pneumonia-related disease warrants greater investment than it has historically received. Other priority areas include antimicrobial resistance (particularly within tuberculosis), economics and proactive investments for emerging infectious threats.
Cancer Cell Dormancy in Novel Mouse Models for Reversible Pancreatic Cancer: A Lingering Challenge in the Development of Targeted Therapies
Authors: Lin Wan-Chi , Rajbhandari Nirakar , Wagner Kay-Uwe 
Published: March 2014

Abstract
Significant advances have been made in the identification of key molecular pathways that play pivotal roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Among the common genetic and epigenetic changes, oncogenic mutations in Kras and upregulation of the c-Myc oncogene are frequent events in PDAC. Using genetically defined in vivo models, several studies have recently demonstrated that expression of mutant Kras and c-Myc is equally important for the initiation and maintenance of pancreatic cancer. The targeted downregulation of a single oncogene resulted in cancer cell death at primary and metastatic sites. These findings are very encouraging and provide a strong rationale for the development of targeted therapies against these oncogenic drivers. Despite what seemed to be a complete response to the ablation of the oncogene, a few dormant cancer cells remained present, and it was demonstrated that they are a cellular reservoir for a swift relapse of pancreatic cancer following oncogene reactivation. This review summarizes the basic principles of cancer dormancy and the applicability of the novel genetic models for reversible metastatic PDAC to elucidate the role of cancer stem cells as well as biologic and molecular mechanisms that mediate the survival of dormant tumor cells. Cancer Res; 74(8); 2138–43. ©2014 AACR.
In VivoFluorescence Lifetime Imaging for Monitoring the Efficacy of the Cancer Treatment
Authors: Ardeshirpour Yasaman , Chernomordik Victor , Hassan Moinuddin , Zielinski Rafal , Capala Jacek , Gandjbakhche Amir 
Published: March 2014

AbstractPurpose: Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors.Experimental Design: HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size.Results: Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (∼0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns.Conclusions: The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. Clin Cancer Res; 20(13); 3531–9. ©2014 AACR.
p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis
Authors: Alspach Elise , Flanagan Kevin C. , Luo Xianmin , Ruhland Megan K. , Huang Hui , Pazolli Ermira , Donlin Maureen J. , Marsh Timothy , Piwnica-Worms David , Monahan Joseph , Novack Deborah V. , McAllister Sandra S. , Stewart Sheila A. 
Published: March 2014

Abstract
Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromal-specific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME.
Significance: The TME plays a key role in tumorigenesis. We demonstrate that p38MAPK governs a posttranscriptional mechanism that sustains the protumorigenic SASP. Inhibition of p38MAPK abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Thus, p38MAPK is a TME-specific Achilles' heel that may be exploited as a new therapeutic target. Cancer Discov; 4(6); 716–29. ©2014 AACR.
See related commentary by Isacke and Barcellos-Hoff, p. 637
This article is highlighted in the In This Issue feature, p. 621
Fibrin clot properties and their modulation in thrombotic disorders
Authors: Undas Anetta 
Published: March 2014

SummaryAccumulating evidence indicates that accelerated formation of fibrin clots composed of compact, highly-branched networks with thin fibres which are relatively resistant to plasmin-mediated lysis can be commonly observed in patients with venous or arterial thrombosis. This review discusses characteristics of fibrin clot structure and function in patients with various thromboembolic manifestations, in particular myocardial infarction, ischaemic stroke and venous thromboembolism, based on the publications till December 2013. Moreover, factors will be presented that in vivo unfavourably determine altered fibrin clot properties in thrombotic disorders and modalities that can improve clot phenotype.
Effects of Diabatic Heating and Cooling in the Rapid Filamentation Zone on Structure and Intensity of a Simulated Tropical Cyclone
Authors: Li Qingqing , Wang Yuqing , Duan Yihong 
Published: March 2014

Abstract
The effects of diabatic heating and cooling in the rapid filamentation zone (RFZ), within which inner rainbands are often active, on tropical cyclone (TC) structure and intensity are investigated based on idealized numerical experiments using a cloud-resolving TC model (TCM4). The results show that removal of heating (cooling) in the RFZ would reduce (increase) the TC intensity. Diabatic heating in the RFZ plays an important role in increasing the inner-core size whereas diabatic cooling tends to limit the inner-core size increase or even reduce the inner-core size of a TC. Removal of both diabatic heating and cooling in the RFZ greatly suppresses the activity of inner rainbands but leads to the quasi-periodic development of a convective ring immediately outside of the inner core. A similar convective ring also develops in an experiment with the removal of diabatic heating only in the RFZ. With diabatic cooling removed only in the RFZ, an annular-hurricane-like structure arises with the outer rainbands largely suppressed.
The Convective Boundary Layer in the Terra Incognita
Authors: Zhou Bowen , Simon Jason S. , Chow Fotini K. 
Published: March 2014

Abstract
Numerical simulations of a convective boundary layer (CBL) are performed to investigate model behavior in the terra incognita, also known as the gray zone. The terra incognita of the CBL refers to a range of model grid spacing that is comparable to the size of the most energetic convective eddies, which are on the order of the boundary layer depth. Using the Rayleigh–Bénard thermal instability as reference, a set of idealized simulations is used to show that gray zone modeling is not only a numerical challenge, but also poses dynamical difficulties. When the grid spacing falls within the CBL gray zone, grid-dependent convection can occur. The size of the initial instability structures is set by the grid spacing rather than the natural state of the flow. This changes higher-order flow statistics and poses fundamental difficulties for gray zone modeling applications.
Quality of the Target Area for Metrics with Different Nonlinearities in a Mesoscale Convective System
Authors: Huang Ling , Meng Zhiyong 
Published: March 2014

Abstract
A direct piece-by-piece data assimilation targeting strategy through observing system simulation experiments was used to examine the quality of the target area for forecast metrics with different nonlinearities in a mesoscale convective vortex–associated rainfall event from both a deterministic and probabilistic perspective.
The target area was determined based on the impact of assimilating synthetic wind-profiler observations, piece by piece, on the forecast error of strongly nonlinear rainfall and weakly nonlinear total energy around the initial vortex center. The quality of the target area in terms of its effectiveness and variability was examined for members of a reasonable ensemble. Apparently different target areas were found for different members, even for those with very small differences for both forecast metrics, with a larger variability observed for rainfall than for total energy. This result indicated that target areas estimated in deterministic scenarios are likely unreliable.
Probabilistic target areas were created by averaging data-impact index values over the ensemble. Significant differences were also observed in the ensemble-based target areas for rainfall and total energy. For total energy, assimilating data in an inaccurate target area could decrease the forecast error at a similar magnitude as that in the target area. For rainfall, however, much less error reduction was obtained, the magnitude of which was almost comparable to the no-data-assimilation experiment. Overall, the results of this study suggest that designing a particular observation plan based on an estimated target area could be unnecessary for total energy and useless for rainfall, given the difficulty involved in accurately determining a target area in an operational setting.
Comparison of Hearing Results of Malleovestibulopexy and Total Ossicular Replacement Prosthesis for Chronic Otitis Media Patients With a Mobile Stapes Footplate
Authors: Chen Zhengnong , Sun Xiaoqiang , Zhou Huiqun , Shi Haibo , Wu Yaqin , Yin Shankai 
Published: March 2014

Objective: This study aimed to assess differences in hearing outcomes using the malleostapedotomy or malleovestibulopexy (MVP) and total ossicular replacement prosthesis (TORP) techniques in chronic otitis media patients with a mobile stapes footplate. Study Design: Case series with planned data collection. Setting: A university medical center. Subjects and Methods: In total, 27 patients with chronic otitis media at the Sixth Hospital affiliated with Shanghai Jiao Tong University, between January and October 2010, were included. All patients had destruction of incus and stapes superstructures and a mobile stapes footplate. In all patients, surgery was performed under general anesthesia by a retroauricular approach. After the lesions were removed completely, ossicular reconstruction was performed using 1 of the techniques. In all patients, pure-tone audiograms were assessed before and 12 months after surgery. Results: Thirteen patients underwent MVP surgery, whereas the other 14 cases received traditional TORP surgery. All patients showed improvements in functional hearing after surgery. Although the numbers of ears that had closure of the air–bone gap within 20 dB in the MVP group were not statistically significantly higher than those in the TORP group (Fisher’s exact test, P > .05), the average postoperative gain of the MVP group was significantly higher than that of the TORP group ( t test, P < .05). Conclusion: Functional hearing in chronic otitis media patients with a mobile stapes footplate was better in those who underwent MVP surgery than in those who underwent TORP surgery.