bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonglycosylated G-Protein Vaccine Protects against Homologous and Heterologous Respiratory Syncytial Virus (RSV) Challenge, while Glycosylated G Enhances RSV Lung Pathology and Cytokine Levels
Authors: Fuentes Sandra , Coyle Elizabeth M. , Golding Hana , Khurana Surender 
Published: May 2015

ABSTRACTNew efforts are under way to develop a vaccine against respiratory syncytial virus (RSV) that will provide protective immunity without the potential for vaccine-associated disease enhancement such as that observed in infants following vaccination with formalin-inactivated RSV vaccine. In addition to the F fusion protein, the G attachment surface protein is a target for neutralizing antibodies and thus represents an important vaccine candidate. However, glycosylated G protein expressed in mammalian cells has been shown to induce pulmonary eosinophilia upon RSV infection in a mouse model. In the current study, we evaluated in parallel the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain (amino acids 67 to 298) expressed inEscherichia coli(REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model. Vaccination with REG generated neutralizing antibodies against RSV A2 in 7/11 BALB/c mice, while RMG did not elicit neutralizing antibodies. Total serum binding antibodies against the recombinant proteins (both REG and RMG) were measured by surface plasmon resonance (SPR) and were found to be >10-fold higher for REG- than for RMG-vaccinated animals. Reduction of lung viral loads to undetectable levels after homologous (RSV-A2) and heterologous (RSV-B1) viral challenge was observed in 7/8 animals vaccinated with REG but not in RMG-vaccinated animals. Furthermore, enhanced lung pathology and elevated Th2 cytokines/chemokines were observed exclusively in animals vaccinated with RMG (but not in those vaccinated with REG or phosphate-buffered saline [PBS]) after homologous or heterologous RSV challenge. This study suggests that bacterially produced unglycosylated G protein could be developed alone or as a component of a protective vaccine against RSV disease.IMPORTANCENew efforts are under way to develop vaccines against RSV that will provide protective immunity without the potential for disease enhancement. The G attachment protein represents an important candidate for inclusion in an effective RSV vaccine. In the current study, we evaluated the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain produced inE. coli(REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model (strains A2 and B1). The unglycosylated G generated high protective immunity and no lung pathology, even in animals that lacked anti-RSV neutralizing antibodies prior to RSV challenge. Control of viral loads correlated with antibody binding to the G protein. In contrast, the glycosylated G protein provided poor protection and enhanced lung pathology after RSV challenge. Therefore, bacterially produced unglycosylated G protein holds promise as an economical approach to a protective vaccine against RSV.
Promotion of Endoplasmic Reticulum-Associated Degradation of Procathepsin D by Human Herpesvirus 8-Encoded Viral Interleukin-6
Authors: Chen Daming , Nicholas John 
Published: May 2015

ABSTRACT
The interleukin-6 homologue (viral interleukin-6 [vIL-6]) of human herpesvirus 8 is implicated in viral pathogenesis due to its proproliferative, inflammatory, and angiogenic properties, effected through gp130 receptor signaling. In primary effusion lymphoma (PEL) cells, vIL-6 is expressed latently and is essential for normal cell growth and viability. This is mediated partly via suppression of proapoptotic cathepsin D (CatD) via cocomplexing of the endoplasmic reticulum (ER)-localized CatD precursor, pro-CatD (pCatD), and vIL-6 with the previously uncharacterized ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). vIL-6 suppression of CatD occurs also during reactivated productive replication in PEL cells and is likely to contribute to proreplication functions of vIL-6. Here, we report that vIL-6 suppresses CatD through vIL-6, VKORC1v2, and pCatD association with components of the ER-associated degradation (ERAD) machinery. In transfected cells, expression of vIL-6 along with CatD led to proteasome-dependent (inhibitor-sensitive) decreases in CatD levels and the promotion of pCatD polyubiquitination. Depletion of particular ERAD-associated isomerases, lectins, and translocon components, including ERAD E3 ubiquitin ligase HRD1, diminished suppression of CatD by vIL-6. Coprecipitation assays identified direct or indirect interactions of VKORC1v2, vIL-6, and pCatD with translocon proteins (SEL1L and/or HRD1) and ERAD-associated lectins OS9 and XTP3-B. Endogenous CatD expression in PEL cells was increased by depletion of ERAD components, and suppression of CatD by vIL-6 overexpression in PEL cells was dependent on HRD1. Our data reveal a new mechanism of ER-localized vIL-6 activity and further characterize VKORC1v2 function.

IMPORTANCE
Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6), unlike cellular IL-6 proteins, is secreted inefficiently and sequestered mainly in the endoplasmic reticulum (ER), from where it can signal through the gp130 receptor. We have recently reported that vIL-6 also associates with a novel membrane protein termed vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2) and mediates suppression of VKORC1v2-cointeracting cathepsin D, a stress-released proapoptotic protein negatively impacting HHV-8 latently infected primary effusion lymphoma (PEL) cell viability and reactivated virus productive replication. Here, we have examined the mechanistic basis of the VKORC1v2–vIL-6 interaction-dependent suppression of cathepsin D and have found that this novel activity of vIL-6 is mediated through coassociation of VKORC1v2, procathepsin D, and vIL-6 with components of the ER-associated degradation (ERAD) machinery. Our findings provide information of significance for potential antiviral and therapeutic targeting of VKORC1v2-mediated vIL-6 activities and also indicate the nature of VKORC1v2 function in normal cell biology.
The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response
Authors: Mehrabadi Mohammad , Hussain Mazhar , Matindoost Leila , Asgari Sassan 
Published: May 2015

ABSTRACT

RNA interference (RNAi) is considered an ancient antiviral defense in diverse organisms, including insects. Virus infections generate double-strand RNAs (dsRNAs) that trigger the RNAi machinery to process dsRNAs into virus-derived short interfering RNAs (vsiRNAs), which target virus genomes, mRNAs, or replication intermediates. Viruses, in turn, have evolved viral suppressors of RNAi (VSRs) to counter host antiviral RNAi. Following recent discoveries that insects mount an RNAi response against DNA viruses, in this study, we found that
Autographa californica
multiple nucleopolyhedrovirus (AcMNPV) infection similarly induces an RNAi response in
Spodoptera frugiperda
cells by generating a large number of vsiRNAs postinfection. Interestingly, we found that AcMNPV expresses a potent VSR to counter RNAi. The viral
p35
gene, which is well known as an inhibitor of apoptosis, was found to be responsible for the suppression of RNAi in diverse insect and mammalian cells. The VSR activity of p35 was further confirmed by a
p35
-null AcMNPV that did not suppress the response. In addition, our results showed that the VSR activity is not due to inhibition of dsRNA cleavage by Dicer-2 but acts downstream in the RNAi pathway. Furthermore, we found that the VSR activity is not linked to the antiapoptotic activity of the protein. Overall, our results provide evidence for the existence of VSR activity in a double-stranded DNA virus and identify the responsible gene, which is involved in the inhibition of RNAi as well as apoptosis.

IMPORTANCE
Our findings demonstrate the occurrence of an insect RNAi response against a baculovirus (AcMNPV) that is highly utilized in microbial control, biological and biomedical research, and protein expression. Moreover, our investigations led to the identification of a viral suppressor of RNAi activity and the gene responsible for the activity. Notably, this gene is also a potent inhibitor of apoptosis. The outcomes signify the dual role of a virus-encoded protein in nullifying two key antiviral responses, apoptosis and RNAi.
MED12is frequently mutated in breast phyllodes tumours: a study of 112 cases
Authors: Ng Cedric Chuan Young , Tan Jing , Ong Choon Kiat , Lim Weng Khong , Rajasegaran Vikneswari , Nasir Nur Diyana Md , Lim Jeffrey Chun Tatt , Thike Aye Aye , Salahuddin Syed Ahmed , Iqbal Jabed , Busmanis Inny , Chong Angela Phek Yoon , Teh Bin Tean , Tan Puay Hoon 
Published: May 2015

AimTo determine the frequency ofMED12mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes.MethodsPhyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of theMED12gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out.ResultsThere were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosingMED12mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harbouredMED12mutations experienced improved disease-free survivals, with higher recurrence likelihood in those withoutMED12mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015).ConclusionsSimilar to fibroadenomas, phyllodes tumours show a high frequency ofMED12mutations, affirming the close biological relationship between these fibroepithelial neoplasms.
Timescales of mingling in shallow magmatic reservoirs
Authors: Montagna C. P. , Papale P. , Longo A. 
Published: May 2015

Abstract
Arrival of magma from depth into shallow reservoirs has been documented as one of the possible processes leading to eruption. Magma intruding and rising to the surface interacts with the already emplaced, degassed magmas residing at shallower depths, leaving chemical signatures in the erupted products.
We performed two-dimensional numerical simulations of the arrival of gas-rich magmas into shallow reservoirs. We solve the fluid dynamics for the two interacting magmas, evaluating the space–time evolution of the physical properties of the mixture.
Convection and mingling develop quickly into the chamber and feeding conduit/dyke, leading on longer timescales to a density stratification with the lighter, gas-richer magma, mixed with different proportions of the resident magma, rising to the top of the chamber due to buoyancy. Over timescales of hours, the magmas in the reservoir appear to have mingled throughout, and convective patterns become harder to identify.
Our simulations have been performed changing the geometry of the shallow reservoir and the gas content of the initial end-member magmas. Horizontally elongated magma chambers, as well as higher density contrasts between the two magmas, cause faster ascent velocities and also increase the mixing efficiency.

Supplementary material:

Videos showing the evolution of magma composition with time in the shallow chamber for simulations 1–4 are available at
www.geolsoc.org.uk/SUP18819
Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth
Authors: Ma Xiaojun , Aoki Tomohiro , Tsuruyama Tatsuaki , Narumiya Shuh 
Published: May 2015

Abstract
Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer. Cancer Res; 75(14); 2822–32. ©2015 AACR.
Cancer Immunotherapy: More Is (Much) Better
Authors: Yarden Yosef , Sela Michael 
Published: May 2015

Abstract
Although antibodies against EGFR and HER2 are used to treat cancer, only some patients respond and resistance often emerges. Jacobsen and colleagues present in this issue experimental evidence favoring replacement of the currently applied monoclonal antibodies with oligoclonal mixtures of six synergistic antibodies, simultaneously engaging EGFR, HER2, and also HER3. Clin Cancer Res; 21(18); 4030–2. ©2015 AACR.
See related article by Jacobsen et al., p. 4110
Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery
Authors: Musumeci Giuseppe , Lettieri Corrado , Limbruno Ugo , Senni Michele , Guagliumi Giulio , Valsecchi Orazio , Angiolillo Dominick , Rossini Roberta , Capodanno Davide 
Published: May 2015

SummaryWhen patients with coronary stents undergo non-cardiac surgery, bridging therapy with low-molecular-weight heparin (LMWH) is not infrequent in clinical practice. However, the efficacy and safety of this approach is poorly understood. This was a retrospective analysis of patients with coronary stent(s) on any antiplatelet therapy undergoing non-cardiac surgery between March 2003 and February 2012. The primary efficacy endpoint was the 30-day incidence of major adverse cardiac or cerebrovascular events (MACCE), defined as the composite of cardiac death, myocardial infarction, acute coronary syndrome leading to hospitalisation, or stroke. The primary safety endpoint was the 30-day composite of Bleeding Academic Research Consortium (BARC) bleedings ≥ 2. Among 515 patients qualifying for the analysis, LMWH bridging was used in 251 (49 %). At 30 days, MACCE occurred more frequently in patients who received LMWH (7.2 % vs 1.1 %, p=0.001), driven by a higher rate of myocardial infarction (4.8 % vs 0 %, p< 0.001). This finding was consistent across several instances of statistical adjustment and after the propensity matching of 179 pairs. Patients bridged with LMWH also experienced a significantly higher risk of BARC bleedings ≥ 2 (21.9 % vs 11.7 %, p=0.002) compared to those who were not, which remained significant across different methods of statistical adjustment and propensity matching. In conclusion, LMWH bridging in patients with coronary stents undergoing surgery is a common and possibly harmful practice, resulting in worse ischaemic outcomes at 30 days, and a significant risk of bleeding.
Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding
Authors: Chai-Adisaksopha Chatree , Hillis Christopher , Monreal Manuel , Witt Daniel , Crowther Mark 
Published: May 2015

SummaryGastrointestinal (GI) bleeding commonly complicates anticoagulant therapy. We aimed to systematically review the published literature to determine the risk of thromboembolism, recurrent GI bleeding and mortality for patients on long-term anticoagulation who experience GI bleeding based on whether anticoagulation therapy was resumed. We performed a systematic review of phase III randomised controlled trials and cohort studies in patients with atrial fibrillation or venous thromboembolism who received oral anticoagulant. We searched MEDLINE, EMBASE and CENTRAL (from 1996-July 2014), conferences abstracts (from January 2006-July 2014) and www.clinicaltrials.gov (up to the last week of July 2014) with no language restriction. Two reviewers independently performed study selection, data extraction and study quality assessment. A total of three studies were included in the meta-analysis. The resumption of warfarin was associated with a significant reduction in thromboembolic events (hazard ratio [HR] 0.68, 95 % confidence interval [CI] 0.52 to 0.88, p < 0.004, I2=82 %). There was an increase in recurrent GI bleeding but not statistically significant for patients who restarted warfarin compared to those who did not (HR 1.20, 95 % CI 0.97 to 1.48, p = 0.10, I2 = 0 %). Resumption of warfarin was associated with significant reduction in mortality (HR 0.76, 95 % CI 0.66 to 0.88, p < 0.001, I2 = 87 %). This meta-analysis demonstrates that resumption of warfarin following interruption due to GI bleeding is associated with a reduction in thromboembolic events and mortality without a statistically significant increase in recurrent GI bleeding.Institution where the work was performed: McMaster University, Hamilton, Ontario, Canada.
Discharge Hospice Referral and Lower 30-Day All-Cause Readmission in Medicare Beneficiaries Hospitalized for Heart Failure
Authors: Kheirbek Raya E. , Fletcher Ross D. , Bakitas Marie A. , Fonarow Gregg C. , Parvataneni Sridivya , Bearden Donna , Bailey Frank A. , Morgan Charity J. , Singh Steven , Blackman Marc R. , Zile Michael R. , Patel Kanan , Ahmed Momanna B. , Tucker Rodney O. , Brown Cynthia J. , Love Thomas E. , Aronow Wilbert S. , Roseman Jeffrey M. , Rich Michael W. , Allman Richard M. , Ahmed Ali 
Published: May 2015

Background—
Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown.

Methods and Results—
Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998–2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06–0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04–0.21) and 0.17 (0.08–0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients).

Conclusions—
A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral.
TRMM LIS Climatology of Thunderstorm Occurrence and Conditional Lightning Flash Rates*
Authors: Cecil Daniel J. , Buechler Dennis E. , Blakeslee Richard J. 
Published: May 2015

Abstract
The Lightning Imaging Sensor (LIS) on the Tropical Rainfall Measuring Mission (TRMM) satellite has previously been used to build climatologies of mean lightning flash rate across the global tropics and subtropics. This new work explores climatologies of thunderstorm occurrence as seen by LIS and the conditional mean flash rates when thunderstorms do occur. The region where thunderstorms are seen most often by LIS extends slightly farther east in central Africa than the corresponding region with the highest total mean annual flash rates. Presumably this reflects a difference between more frequent thunderstorm initiation in the east and upscale growth as storms move westward. There are some differences between locations with the greatest total lightning flash counts and those where thunderstorms occur most often. The greatest conditional mean flash rates—considering only those TRMM orbits that do have lightning in a given grid box—are found in subtropical regions. The highest values are in Argentina, with the central United States, Pakistan, eastern China, and the east coast of Australia also having particularly high values.
Simulation Activity in Otolaryngology Residencies
Authors: Deutsch Ellen S. , Wiet Gregory J. , Seidman Michael , Hussey Heather M. , Malekzadeh Sonya , Fried Marvin P. 
Published: May 2015

ObjectivesSimulation has become a valuable tool in medical education, and several specialties accept or require simulation as a resource for resident training or assessment as well as for board certification or maintenance of certification. This study investigates current simulation resources and activities in US otolaryngology residency programs and examines interest in advancing simulation training and assessment within the specialty.Study DesignWeb‐based survey.SettingUS otolaryngology residency training programs.Subjects and MethodsAn electronic web‐based survey was disseminated to all US otolaryngology program directors to determine their respective institutional and departmental simulation resources, existing simulation activities, and interest in further simulation initiatives. Descriptive results are reported.ResultsResponses were received from 43 of 104 (43%) residency programs. Simulation capabilities and resources are available in most respondents’ institutions (78.6% report onsite resources; 73.8% report availability of models, manikins, and devices). Most respondents (61%) report limited simulation activity within otolaryngology. Areas of simulation are broad, addressing technical and nontechnical skills related to clinical training (94%). Simulation is infrequently used for research, credentialing, or systems improvement. The majority of respondents (83.8%) expressed interest in participating in multicenter trials of simulation initiatives.ConclusionMost respondents from otolaryngology residency programs have incorporated some simulation into their curriculum. Interest among program directors to participate in future multicenter trials appears high. Future research efforts in this area should aim to determine optimal simulators and simulation activities for training and assessment as well as how to best incorporate simulation into otolaryngology residency training programs.