bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in MMP-9 and TIMP-1 Concentrations in Cerebrospinal Fluid after 1 Week of Treatment of Childhood Bacterial Meningitis
Authors: Roine Irmeli , Pelkonen Tuula , Lauhio Anneli , Lappalainen Maija , Cruzeiro Manuel Leite , Bernardino Luis , Tervahartiala Taina , Sorsa Timo , Peltola Heikki 
Published: April 2015

ABSTRACT
We explored the changes of the initially highly upgraded cerebrospinal fluid matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP 1 (TIMP-1) response during recovery of childhood bacterial meningitis and their association with outcome. The sizes of these changes varied substantially, but a steeper decrease in the MMP-9 and an increase of the TIMP-1 concentrations augured a better outcome.
Equine and Canine Influenza H3N8 Viruses Show Minimal Biological Differences Despite Phylogenetic Divergence
Authors: Feng Kurtis H. , Gonzalez Gaelle , Deng Lingquan , Yu Hai , Tse Victor L. , Huang Lu , Huang Kai , Wasik Brian R. , Zhou Bin , Wentworth David E. , Holmes Edward C. , Chen Xi , Varki Ajit , Murcia Pablo R. , Parrish Colin R. 
Published: April 2015

ABSTRACT
The A/H3N8 canine influenza virus (CIV) emerged from A/H3N8 equine influenza virus (EIV) around the year 2000 through the transfer of a single virus from horses to dogs. We defined and compared the biological properties of EIV and CIV by examining their genetic variation, infection, and growth in different cell cultures, receptor specificity, hemagglutinin (HA) cleavage, and infection and growth in horse and dog tracheal explant cultures. Comparison of sequences of viruses from horses and dogs revealed mutations that may be linked to host adaptation and tropism. We prepared infectious clones of representative EIV and CIV strains that were similar to the consensus sequences of viruses from each host. The rescued viruses, including HA and neuraminidase (NA) double reassortants, exhibited similar degrees of long-term growth in MDCK cells. Different host cells showed various levels of susceptibility to infection, but no differences in infectivity were seen when comparing viruses. All viruses preferred α2-3- over α2-6-linked sialic acids for infections, and glycan microarray analysis showed that EIV and CIV HA-Fc fusion proteins bound only to α2-3-linked sialic acids. Cleavage assays showed that EIV and CIV HA proteins required trypsin for efficient cleavage, and no differences in cleavage efficiency were seen. Inoculation of the viruses into tracheal explants revealed similar levels of infection and replication by each virus in dog trachea, although EIV was more infectious in horse trachea than CIV.

IMPORTANCE
Influenza A viruses can cross species barriers and cause severe disease in their new hosts. Infections with highly pathogenic avian H5N1 virus and, more recently, avian H7N9 virus have resulted in high rates of lethality in humans. Unfortunately, our current understanding of how influenza viruses jump species barriers is limited. Our aim was to provide an overview and biological characterization of H3N8 equine and canine influenza viruses using various experimental approaches, since the canine virus emerged from horses approximately 15 years ago. We showed that although there were numerous genetic differences between the equine and canine viruses, this variation did not result in dramatic biological differences between the viruses from the two hosts, and the viruses appeared phenotypically equivalent in most assays we conducted. These findings suggest that the cross-species transmission and adaptation of influenza viruses may be mediated by subtle changes in virus biology.
Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus
Authors: von Recum-Knepper Jessica , Sadewasser Anne , Weinheimer Viola K. , Wolff Thorsten 
Published: April 2015

ABSTRACT
Influenza A virus (IAV) infection provokes an antiviral response involving the expression of type I and III interferons (IFN) and IFN-stimulated genes (ISGs) in infected cell cultures. However, the spatiotemporal dynamics of the IFN reaction are incompletely understood, as previous studies investigated mainly the population responses of virus-infected cultures, although substantial cell-to-cell variability has been documented. We devised a fluorescence-activated cell sorting-based assay to simultaneously quantify expression of viral antigens and ISGs, such as ISG15, MxA, and IFIT1, in IAV-infected cell cultures at the single-cell level. This approach revealed that seasonal IAV triggers an unexpected asymmetric response, as the major cell populations expressed either viral antigen or ISG, but rarely both. Further investigations identified a role of the viral NS1 protein in blocking ISG expression in infected cells, which surprisingly did not reduce paracrine IFN signaling to noninfected cells. Interestingly, viral ISG control was impaired in cultures infected with avian-origin IAV, including the H7N9 virus from eastern China. This phenotype was traced back to polymorphic NS1 amino acids known to be important for stable binding of the polyadenylation factor CPSF30 and concomitant suppression of host cell gene expression. Most significantly, mutation of two amino acids within the CPSF30 attachment site of NS1 from seasonal IAV diminished the strict control of ISG expression in infected cells and substantially attenuated virus replication. In conclusion, our approach revealed an asymmetric, NS1-dependent ISG induction in cultures infected with seasonal IAV, which appears to be essential for efficient virus propagation.

IMPORTANCE
Interferons are expressed by infected cells in response to IAV infection and play important roles in the antiviral immune response by inducing hundreds of interferon-stimulated genes (ISGs). Unlike many previous studies, we investigated the ISG response at the single-cell level, enabling novel insights into this virus-host interaction. Hence, cell cultures infected with seasonal IAV displayed an asymmetric ISG induction that was confined almost exclusively to noninfected cells. In comparison, ISG expression was observed in larger cell populations infected with avian-origin IAV, suggesting a more resolute antiviral response to these strains. Strict control of ISG expression by seasonal IAV was explained by the binding of the viral NS1 protein to the polyadenylation factor CPSF30, which reduces host cell gene expression. Mutational disruption of CPSF30 binding within NS1 concomitantly attenuated ISG control and replication of seasonal IAV, illustrating the importance of maintaining an asymmetric ISG response for efficient virus propagation.
Clinical outcomes of patients with acute minor stroke receiving rescue IA therapy following early neurological deterioration
Authors: Kim Joon-Tae , Heo Suk-Hee , Yoon Woong , Choi Kang-Ho , Park Man-Seok , Saver Jeffrey L , Cho Ki-Hyun 
Published: April 2015

BackgroundPatients presenting with minor ischemic stroke frequently have early neurological deterioration (END) and poor final outcome. The optimal management of patients with END has not been determined.ObjectiveTo investigate rescue IA therapy (IAT) when patients with acute minor ischemic stroke develop END.MethodsThis was a retrospective study of consecutively registered patients with acute minor stroke and END. ‘END’ was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) scores by 1 or more points (or development of new neurological symptoms) and ‘ΔEND−NIHSS’ was defined as numerical difference between NIHSS scores at the time of END and before END. Rescue IAT following END was adjusted for the covariates to evaluate the association between IAT and favorable outcome at 3 months.ResultsAmong 982 patients with acute minor ischemic stroke, END occurred in 232 (23.6%). Of the 209 patients with END with full data available, 87 (41.6%) had favorable outcomes at 3 months. Rescue IAT following END was performed in 28 (13.4%). Favorable 3-month outcomes were seen in 50% of patients undergoing rescue IAT, including 8/19 (42.1%) undergoing rescue IAT beyond 8 h. By multivariate logistic regression analysis, rescue IAT following END was independently associated with favorable outcome at 3 months (OR=10.9; 95% CI 3.06 to 38.84; p<0.001).ConclusionsThe results suggest that rescue IAT may be safe and effective when END occurs in selected patients with acute minor ischemic stroke. Further prospective and randomized studies are needed to confirm our results.
The 7-year teesside experience of primary prevention ICD indications following primary PCI (PPCI) and the potential impact of a change in NICE guidance
Authors: Phan Thanh Trung , Khan Saima , Mahmood Muhammad Muzaffar , Mani Sudha , Wadehra Vineet , de Belder Mark , Thornley Andrew , James Simon , Linker Nicholas J , Turley Andrew J 
Published: April 2015

IntroductionThe recovery of LV function in patients with severe LV impairment in the acute phase following primary percutaneous coronary intervention (PPCI) is not well established. The indication for a primary prevention ICD post-STEMI is dependent on which screening guidance, NICE or ESC, is followed. The potential impact of the new NICE guidance is estimated.MethodsWe performed a retrospective analysis of all patients presenting with a STEMI over a 7-year period (2005–2012) treated with PPCI to determine in-hospital mortality, LV function at index presentation, at 3 months and the predicted primary prevention ICD implantation rate using NICE (TA095) and ESC 2006 guidelines. Predicted implant rates using the new NICE guidance (TA314) and actual implantation rates were also assessed.Results3902 patients with a mean age of 65±13 years underwent PPCI. Of those patients surviving until discharge, 332 (10%) had LVEF ≤35%. 254 of 332 patients (76%) with a severely impaired ventricle were followed up at participating centres. 210 of 254 (83%) patients had a repeat echocardiogram within 3 months post-MI; among these patients, 89 (42%) remained to have LVEF ≤35%. The number of patients fulfilling NICE and ESC criteria for primary prevention ICD implantation was 14 (16%) and 84 (94%), respectively. The actual number of patients receiving an ICD was 17 (19%). The number of patients fulfilling the new NICE (TA314) guidance was 84 (94%).ConclusionsA small proportion of patients with STEMIs undergoing PPCI have a severely impaired LV systolic function. A large proportion of these patients will have improved LV systolic function at 3 months. There is a five-fold difference in the predicted ICD implantation rates depending on which guidance is followed—NICE versus ESC. The potential impact of the new NICE (TA314) guidance on ICD implantation will be a significant increase in ICD implantation rates.
Pre-salt microbialites from the Campos Basin (offshore Brazil): image log facies, facies model and cyclicity in lacustrine carbonates
Authors: Muniz M. C. , Bosence D. W. J. 
Published: April 2015

Abstract

This study uses a borehole image log, supported by limited sidewall-core samples, and conventional wireline logs to erect facies and stratigraphic models for the Aptian pre-salt microbial carbonates (Macabu Formation (Fm)) of the southern Campos Basin, Brazil. This supports the widely held view that these reservoirs are very significant, unusual, partly microbial, and lacustrine in origin. This single-well study penetrates 220 m of microbialite facies from the pre-salt Lagoa Feia Group non-marine carbonates. Continuous borehole images, available sidewall-core data, and gamma-ray and sonic wireline logs are used to identify and characterize borehole image facies. These facies are interpreted to have formed in four lacustrine depositional environments: deep subaqueous, intermediate subaqueous, shallow subaqueous and subaerial. The borehole image facies commonly show shallowing-upward facies trends topped by emergent surfaces. Such trends are interpreted as metre-scale, high-frequency cycles that are grouped into lower order depositional sequences interpreted from the gamma-ray log. A Fischer plot of the high-frequency cycle suggests that the entire Macabu Fm is represented by a decrease in the accommodation space followed by increase in the accommodation space; consistent with this suggestion are trends in δ
18
O values from an adjacent well that indicate an initial trend of increased evaporation followed by increased freshwater inflow (lighter δ
18
O and thicker cycles).
A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients
Authors: Lee Eudocia Q. , Kaley Thomas J. , Duda Dan G. , Schiff David , Lassman Andrew B. , Wong Eric T. , Mikkelsen Tom , Purow Benjamin W. , Muzikansky Alona , Ancukiewicz Marek , Huse Jason T. , Ramkissoon Shakti , Drappatz Jan , Norden Andrew D. , Beroukhim Rameen , Weiss Stephanie E. , Alexander Brian M. , McCluskey Christine S. , Gerard Mary , Smith Katrina H. , Jain Rakesh K. , Batchelor Tracy T. , Ligon Keith L. , Wen Patrick Y. 
Published: April 2015

Abstract
Purpose: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM).
Experimental Design: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis.
Results: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0–22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9–20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75).
Conclusions: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study. Clin Cancer Res; 21(16); 3610–8. ©2015 AACR.
Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer
Authors: Bruun Jarle , Kolberg Matthias , Ahlquist Terje C. , Røyrvik Ellen C. , Nome Torfinn , Leithe Edward , Lind Guro E. , Merok Marianne A. , Rognum Torleiv O. , Bjørkøy Geir , Johansen Terje , Lindblom Annika , Sun Xiao-Feng , Svindland Aud , Liestøl Knut , Nesbakken Arild , Skotheim Rolf I. , Lothe Ragnhild A. 
Published: April 2015

Abstract
Purpose: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis.
Experimental Design: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903).
Results: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5′ UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (&gt;75 years), stage II patients, and those with rectal cancer.
Conclusions: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. Clin Cancer Res; 21(16); 3759–70. ©2015 AACR.
Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer
Authors: Takahashi Hidekazu , Nishimura Junichi , Kagawa Yoshinori , Kano Yoshihiro , Takahashi Yusuke , Wu Xin , Hiraki Masayuki , Hamabe Atsushi , Konno Masamitsu , Haraguchi Naotsugu , Takemasa Ichiro , Mizushima Tsunekazu , Ishii Masaru , Mimori Koshi , Ishii Hideshi , Doki Yuichiro , Mori Masaki , Yamamoto Hirofumi 
Published: April 2015

Abstract
Polypyrimidine tract–binding protein (PTBP1) is an RNA-binding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2:PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expression levels were positively correlated to poor prognosis and lymph node metastasis. In analyses of colorectal cancer cells using siRNA for PTBP1, we observed that PTBP1 affects cell invasion, which was partially correlated to CD44 splicing, and this correlation was also confirmed in clinical samples. PTBP1 expression also affected anchorage-independent growth in colorectal cancer cell lines. PTBP1 expression also affected cell proliferation. Using time-lapse imaging analysis, PTBP1 was implicated in prolonged G2–M phase in HCT116 cells. As for the mechanism of prolonged G2–M phase in HCT116 siPTBP1 cells, Western blotting revealed that PTBP1 expression level was correlated to CDK11p58 expression level, which was reported to play an important role on progression to complete mitosis. These findings indicated that PTBP1 is a potential therapeutic target for colorectal cancer. Mol Cancer Ther; 14(7); 1705–16. ©2015 AACR.
Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis
Authors: Dowsett Laura , Piper Sophie , Slaviero Anna , Dufton Neil , Wang Zhen , Boruc Olga , Delahaye Matthew , Colman Lucy , Kalk Eliza , Tomlinson James , Birdsey Graeme , Randi Anna M. , Leiper James 
Published: April 2015

Background—

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1
En−/−
) to investigate the significance of endothelial ADMA in cardiovascular homeostasis.

Methods and Results—

DDAH1 deletion in the DDAH1
En−/−
mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1
En−/−
mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1
En−/−
mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo.

Conclusions—
We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.
hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine
Authors: Melgari Dario , Brack Kieran E. , Zhang Chuan , Zhang Yihong , El Harchi Aziza , Mitcheson John S. , Dempsey Christopher E. , Ng G. André , Hancox Jules C. 
Published: April 2015

Background

Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal
HCN
‐channels. This study investigated the propensity of ivabradine to interact with

KCNH
2

‐encoded human Ether‐à‐go‐go–Related Gene (
hERG
) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia.

Methods and Results

Patch clamp recordings of
hERG
current (I
h

ERG

) were made from
hERG
expressing cells at 37°C. I
h

ERG

was inhibited with an
IC
50
of 2.07 μmol/L for the
hERG
1a isoform and 3.31 μmol/L for coexpressed
hERG
1a/1b. The voltage and time‐dependent characteristics of I
h

ERG

block were consistent with preferential gated‐state‐dependent channel block. Inhibition was partially attenuated by the N588K inactivation‐mutant and the S624A pore‐helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK‐based homology model of
hERG
, the 2 aromatic rings of the drug could form multiple π‐π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (
MAP
) recordings from guinea‐pig Langendorff‐perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the
MAPD
90
restitution curve.

Conclusions

Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between
hERG
and
HCN
channels: it inhibits I
h

ERG

with similar potency to that reported for native I
f
and
HCN
channels, with S6 binding determinants resembling those observed for
HCN
4. These findings may have important implications both clinically and for future bradycardic drug design.