bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells
Authors: Lawrence Tessa M. , Hudacek Andrew W. , de Zoete Marcel R. , Flavell Richard A. , Schnell Matthias J. 
Published: March 2013

ABSTRACT
Inflammasome activation is important for the development of an effective host defense against many pathogens, including RNA viruses. However, the mechanism by which the inflammasome recognizes RNA viruses and its role in rabies virus (RABV) pathogenicity and immunogenicity remain poorly defined. To determine the function of the inflammasome in response to RABV infection, we infected murine bone marrow-derived dendritic cells (BMDCs) with RABV. Our results indicate that the infection of BMDCs with RABV induces both the production of pro-interleukin-1β (pro-IL-1β) and its processing, resulting in the secretion of active IL-1β through activation of the NLRP3-, ASC-, and caspase-1-dependent inflammasome. As previously shown for the induction of type I interferon by RABV, the induction of pro-IL-1β also depends upon IPS-1. We demonstrate that both the production of pro-IL-1β and activation of the inflammasome require viral replication. We also demonstrate that increased viral replication in BMDCs derived from IFNAR-deficient mice resulted in significantly more IL-1β release. Additionally, IL-1 receptor-deficient mice show an increase in RABV pathogenicity. Taken together, these results indicate an important role of the inflammasome in innate immune recognition of RABV.
Identification of Dominant Antibody-Dependent Cell-Mediated Cytotoxicity Epitopes on the Hemagglutinin Antigen of Pandemic H1N1 Influenza Virus
Authors: Srivastava Vikram , Yang Zheng , Hung Ivan Fan Ngai , Xu Jianqing , Zheng Bojian , Zhang Mei-Yun 
Published: March 2013

ABSTRACTAntibody-dependent cell-mediated cytotoxicity (ADCC) bridges innate and adaptive immunity, and it involves both humoral and cellular immune responses. ADCC has been found to be a main route of immune protection against viral infectionsin vivo. Hemagglutinin (HA) of influenza virus is highly immunogenic and considered the most important target for immune protection. Several potent cross-reactive HA-specific neutralizing monoclonal antibodies (MAbs) have been reported, and their conserved neutralizing epitopes have been revealed, but there has been no report so far about ADCC epitopes on HA. Here we identified two dominant ADCC epitopes, designated E1 (amino acids [aa] 92 to 117) and E2 (aa 124 to 159), on HA of pandemic H1N1 influenza virus by epitope mapping of convalescent-phase plasma IgG antibodies from six H1N1-infected human subjects in China that exhibited different levels of ADCC activity. The E1 and E2 ADCC epitopes overlapped with immunodominant epitopes of HA. Depletion of purified patient plasma IgG antibodies with EBY100 yeast cells expressing E1 or E2 decreased the ADCC activity of the IgG antibodies. E1 and E2 sequences were found to be highly conserved in H1N1 strains but less so in other subtypes of influenza A viruses. Our study may aid in designing immunogens that can elicit antibodies with high ADCC activity. Vaccine immunogens designed to include the structural determinants of potent broadly neutralizing antibodies and ADCC epitopes may confer comprehensive immune protection against influenza virus infection.
Rational Design of a Flavivirus Vaccine by Abolishing Viral RNA 2′-
O
Methylation
Authors: Li Shi-Hua , Dong Hongping , Li Xiao-Feng , Xie Xuping , Zhao Hui , Deng Yong-Qiang , Wang Xiao-Yu , Ye Qing , Zhu Shun-Ya , Wang Hong-Jiang , Zhang Bo , Leng Qi-Bin , Zuest Roland , Qin E-De , Qin Cheng-Feng , Shi Pei-Yong 
Published: March 2013

ABSTRACT

Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2′-
O
cap of their RNA; alternatively, they “snatch” host mRNA cap to form the 5′ end of viral RNA. The function of 2′-
O
methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2′-
O
methylation is replicative, but its viral RNA lacks 2′-
O
methylation and is recognized and eliminated by the host immune response. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N-7 and 2′-
O
cap methylations as well as evasion of host innate immune response. Recombinant virus completely defective in 2′-
O
methylation was stable in cell culture after being passaged for >30 days. The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation
in vivo
. A single dose of immunization induced full protection against lethal challenge with JEV strains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the results demonstrate the feasibility of using 2′-
O
methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2′-
O
methyltransferases.
Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials
Authors: Laporte Silvy , Squifflet Pierre , Baroux Noémie , Fossella Frank , Georgoulias Vassilis , Pujol Jean-Louis , Douillard Jean-Yves , Kudoh Shinzohy , Pignon Jean-Pierre , Quinaux Emmanuel , Buyse Marc 
Published: March 2013

ObjectivesTo investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC).DesignMeta-analysis of individual patient data from randomised trials.SettingFive randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC.Participants2331 patients with advanced NSCLC.Primary and secondary outcome measuresSurrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS.ResultsThe median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata.ConclusionsThese analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation.
Direct measurement of recoil effects on
40
Ar/
39
Ar standards
Authors: Hall Chris M. 
Published: March 2013

Abstract

Advances in the
40
Ar/
39
Ar method using new techniques have led to considerable efforts to improve the accuracy of the calibration of interlaboratory standards. However, the accuracy of the method ultimately relies on the measurement of
40
Ar*/
39
Ar
K
ratios on standards that have been calibrated with the K–Ar method. Usually a
40
Ar/
39
Ar total gas age is assumed to equate to a K–Ar age, but this assumes that there is zero loss of
39
Ar due to recoil. Traditional
40
Ar/
39
Ar total gas ages are Ar retention ages and are not strictly comparable to K–Ar ages. Efforts to estimate the importance of this effect on standards have relied on indirect evidence for
39
Ar recoil. We report direct measurements of
39
Ar recoil for primary and secondary standards using the vacuum-encapsulation technique and show that adjustments to some standard ages may be needed. Revised ages corrected for recoil are given for hornblendes MMhb-1 and Hb3gr, biotites GA1550 and FCT-3 and sanidines FCT-2 and TCR-2. The results show that, in most cases, recoil loss exceeds that which would be expected from grain size and geometry. Internal defects within mineral grains are likely the dominant control on the fraction of recoiled
39
Ar lost from these standards.

Supplementary material:

Detailed data tables are available at
http://www.geolsoc.org.uk/SUP18587
.
CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer
Authors: Burkhardt Lia , Fuchs Sarah , Krohn Antje , Masser Sawinee , Mader Malte , Kluth Martina , Bachmann Frederik , Huland Hartwig , Steuber Thomas , Graefen Markus , Schlomm Thorsten , Minner Sarah , Sauter Guido , Sirma Hüseyin , Simon Ronald 
Published: March 2013

Abstract
Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostate cancer. Using single-nucleotide polymorphism (SNP) arrays, we mapped a 1.3 megabase minimally deleted region including only the repulsive guidance molecule B (RGMB) and chromodomain helicase DNA-binding protein 1 (CHD1) genes. Functional analyses showed that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, prostate-specific antigen (PSA) biochemical failure (P = 0.0038), and absence of ERG fusion (P &lt; 0.0001). We found that inactivation of CHD1 in vitro prevents formation of ERG rearrangements due to impairment of androgen receptor (AR)-dependent transcription, a prerequisite for ERG translocation. CHD1 is required for efficient recruitment of AR to responsive promoters and regulates expression of known AR-responsive tumor suppressor genes, including NKX3-1, FOXO1, and PPARγ. Our study establishes CHD1 as the 5q21 tumor suppressor gene in prostate cancer and shows a key role of this chromatin remodeling factor in prostate cancer biology. Cancer Res; 73(9); 2795–805. ©2013 AACR.
Center of Cancer Systems Biology Second Annual Workshop—Tumor Metronomics: Timing and Dose Level Dynamics
Authors: Hahnfeldt Philip , Hlatky Lynn , Klement Giannoula Lakka 
Published: March 2013

Abstract
Metronomic chemotherapy, the delivery of doses in a low, regular manner so as to avoid toxic side effects, was introduced over 12 years ago in the face of substantial clinical and preclinical evidence supporting its tumor-suppressive capability. It constituted a marked departure from the classic maximum-tolerated dose (MTD) strategy, which, given its goal of rapid eradication, uses dosing sufficiently intense to require rest periods between cycles to limit toxicity. Even so, upfront tumor eradication is frequently not achieved with MTD, whereupon a de facto goal of longer-term tumor control is often pursued. As metronomic dosing has shown tumor control capability, even for cancers that have become resistant to the same drug delivered under MTD, the question arises whether it may be a preferable alternative dosing approach from the outset. To date, however, our knowledge of the coupled dynamics underlying metronomic dosing is neither sufficiently well developed nor widely enough disseminated to establish its actual potential. Meeting organizers thus felt the time was right, armed with new quantitative approaches, to call a workshop on “Tumor Metronomics: Timing and Dose Level Dynamics” to explore prospects for gaining a deeper, systems-level appreciation of the metronomics concept. The workshop proved to be a forum in which experts from the clinical, biologic, mathematical, and computational realms could work together to clarify the principles and underpinnings of metronomics. Among other things, the need for significant shifts in thinking regarding endpoints to be used as clinical standards of therapeutic progress was recognized. Cancer Res; 73(10); 2949–54. ©2013 AACR.
Molecular Profiling of Aromatase Inhibitor–Treated Postmenopausal Breast Tumors Identifies Immune-Related Correlates of Resistance
Authors: Dunbier Anita K. , Ghazoui Zara , Anderson Helen , Salter Janine , Nerurkar Ashutosh , Osin Peter , A'hern Roger , Miller William R. , Smith Ian E. , Dowsett Mitch 
Published: March 2013

AbstractPurpose: Estrogen withdrawal by treatment with aromatase inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor–positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of aromatase inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of AI treatment.Experimental Design: Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response.Results: A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate &lt; 0.01). Proliferation-associated genes and classical estrogen-dependent genes were strongly downregulated whereas collagens and chemokines were upregulated. Pretreatment expression of an inflammatory signature correlated with antiproliferative response to anastrozole and this observation was validated in an independent study. Higher expression of immune-related genes such as SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response (P &lt; 0.001) and validated in an independent cohort.Conclusions: The molecular response to aromatase inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from aromatase inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for aromatase inhibitor-treated patients. Clin Cancer Res; 19(10); 2775–86. ©2013 AACR.
FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547
Authors: Xie Liang , Su Xinying , Zhang Lin , Yin Xiaolu , Tang Lili , Zhang Xiuhua , Xu Yanping , Gao Zeren , Liu Kunji , Zhou Minhua , Gao Beirong , Shen Danping , Zhang Lianhai , Ji Jiafu , Gavine Paul R. , Zhang Jingchuan , Kilgour Elaine , Zhang Xiaolin , Ji Qunsheng 
Published: March 2013

Abstract
Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATP-competitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1–3, in patients with FGFR2-amplified gastric cancer.
Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.
Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.
Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572–83. ©2013 AACR.
The HSP90 Inhibitor NVP-AUY922 Potently Inhibits Non–Small Cell Lung Cancer Growth
Authors: Garon Edward B. , Finn Richard S. , Hamidi Habib , Dering Judy , Pitts Sharon , Kamranpour Naeimeh , Desai Amrita J. , Hosmer Wylie , Ide Susan , Avsar Emin , Jensen Michael Rugaard , Quadt Cornelia , Liu Manway , Dubinett Steven M. , Slamon Dennis J. 
Published: March 2013

AbstractHeat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non–small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 &lt; 100 nmol/L. IC100 (complete inhibition of proliferation) &lt; 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene. These data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLCs. Mol Cancer Ther; 12(6); 890–900. ©2013 AACR.
Rapamycin Inhibits Smooth Muscle Cell Proliferation and Obstructive Arteriopathy Attributable to Elastin Deficiency
Authors: Li Wei , Li Qingle , Qin Lingfeng , Ali Rahmat , Qyang Yibing , Tassabehji May , Pober Barbara R. , Sessa William C. , Giordano Frank J. , Tellides George 
Published: March 2013

Objective—
Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency.

Approach and Results—

As previously reported,
Eln
−/−
mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas
Eln
+/−
mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in
Eln
−/−
pups and prevented medial hyperlamellation in
Eln
+/−
weanlings without compromising aortic size. However, rapamycin did not prolong the survival of
Eln
−/−
pups, and it retarded the somatic growth of juvenile
Eln
+/−
and
Eln
+/+
mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome.

Conclusions—
mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.
Long-Chain Monounsaturated Fatty Acids and Incidence of Congestive Heart Failure in 2 Prospective Cohorts
Authors: Imamura Fumiaki , Lemaitre Rozenn N. , King Irena B. , Song Xiaoling , Steffen Lyn M. , Folsom Aaron R. , Siscovick David S. , Mozaffarian Dariush 
Published: March 2013

Background—
Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown.

Methods and Results—

We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2±5.2 years) in the Cardiovascular Health Study (CHS; 1992–2006) and 3577 middle-aged adults (mean age, 54.1±5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987–2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003–2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95% confidence interval, 1.02–1.76) and 1.57 (95% confidence interval, 1.11–2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95% confidence interval, 1.23–2.50) and 1.92 (95% confidence interval, 1.22–3.03) for 24:1, respectively (
P
for trend ≤0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard.

Conclusions—
Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.