bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of 24-Hour Posaconazole and Voriconazole MIC Readings versus the CLSI 48-Hour Broth Microdilution Reference Method: Application of Epidemiological Cutoff Values to Results from a Global Candida Antifungal Surveillance Program
Authors: Pfaller M. A. , Boyken L. B. , Hollis R. J. , Kroeger J. , Messer S. A. , Tendolkar S. , Diekema D. J. 
Published: February 2011

ABSTRACT

We performed 24- and 48-h MIC determinations of posaconazole and voriconazole against more than 16,000 clinical isolates of
Candida
species. By using the 24- and 48-h epidemiological cutoff values (ECVs), the categorical agreement between the 24-h and reference 48-h broth microdilution results ranged from 97.1% (
C. parapsilosis
and voriconazole) to 99.8% (
C. krusei
and voriconazole), with 0.0 to 2.9% very major discrepancies (VMD). The essential agreement (within 2 log
2
dilutions) between the 24- and 48-h results was 99.6% for both posaconazole and voriconazole. The MIC results obtained for both posaconazole and voriconazole after only 24 h of incubation may be used to determine the susceptibilities of
Candida
spp. to these important antifungal agents. The applications of ECVs to this large collection of
Candida
isolates suggests the potential to develop 24-h species-specific clinical breakpoints for both posaconazole and voriconazole.
Loss of Asparagine-Linked Glycosylation Sites in Variable Region 5 of Human Immunodeficiency Virus Type 1 Envelope Is Associated with Resistance to CD4 Antibody Ibalizumab
Authors: Toma Jonathan , Weinheimer Steven P. , Stawiski Eric , Whitcomb Jeannette M. , Lewis Stanley T. , Petropoulos Christos J. , Huang Wei 
Published: February 2011

ABSTRACTIbalizumab (formerly TNX-355) is a first-in-class, monoclonal antibody inhibitor of CD4-mediated human immunodeficiency type 1 (HIV-1) entry. Multiple clinical trials with HIV-infected patients have demonstrated the antiviral activity, safety, and tolerability of ibalizumab treatment. A 9-week phase Ib study adding ibalizumab monotherapy to failing drug regimens led to transient reductions in HIV viral loads and the evolution of HIV-1 variants with reduced susceptibility to ibalizumab. This report characterizes these variants by comparing the phenotypic susceptibilities and envelope (env) sequences of (i) paired baseline and on-treatment virus populations, (ii) individualenvclones from selected paired samples, and (iii)envclones containing site-directed mutations. Viruses with reduced susceptibility to ibalizumab were found to exhibit reduced susceptibility to the anti-CD4 antibody RPA-T4. Conversely, susceptibility to soluble CD4, which targets the HIV-1 gp120 envelope protein, was enhanced. No changes in susceptibility to the fusion inhibitor enfuvirtide or the CCR5 antagonist maraviroc were observed. Functionally, viruses with reduced ibalizumab susceptibility also displayed high levels of infectivity relative to those of paired baseline viruses. Individualenvclones exhibiting reduced ibalizumab susceptibility contained multiple amino acid changes in different regions relative to the paired baseline clones. In particular, clones with reduced susceptibility to ibalizumab contained fewer potential asparagine-linked glycosylation sites (PNGSs) in variable region 5 (V5) than did paired ibalizumab-susceptible clones. The reduction in ibalizumab susceptibility due to the loss of V5 PNGSs was confirmed by site-directed mutagenesis. Taken together, these findings provide important insights into resistance to this new class of antiretroviral drug.
Key Genomic Changes Necessary for an
In Vivo
Lethal Mouse Marburgvirus Variant Selection Process
Authors: Lofts Loreen L. , Wells Jay B. , Bavari Sina , Warfield Kelly L. 
Published: February 2011

ABSTRACT

Marburgvirus (MARV) infections are generally lethal in humans and nonhuman primates but require
in vivo
lethal mouse variant selection by the serial transfer (passage) of the nonlethal virus into naïve mice to propagate a lethal infection. The passage of progenitor (wild-type) MARV or Ravn virus (RAVV) from infected
scid
BALB/c mouse liver homogenates into immunocompetent BALB/c mice results in the selection of lethal mouse viruses from within the quasispecies sufficient to establish lethality in immunocompetent mice. Genomic analysis in conjunction with the passage history of each mutation detailed the altered primary and secondary structures of the viral genomic RNA throughout the process. Key findings included the following: (i) a VP40:D184N mutation previously identified in the lethal guinea pig MARV genome was the first mutation to occur during the passage of both the MARV and RAVV variants; (ii) there was biased hypermutagenesis in the RAVV variant genome; (iii) there were two identical mutations in lethal mouse MARV and RAVV variants, VP40:Y19H in the PPPY motif and VP40:D184N in a loop structure between the two VP40 domains; (iv) the passage of wild-type MARV and RAVV in mice resulted in the selection of viral variants from among the quasispecies with different genotypes than those of the wild-type viruses; and (v) a lethal mouse RAVV variant had different tissue tropisms distinct from those of its wild-type virus. These studies provide insights into how marburgviruses manipulate the host for enzymes, metabolites, translation regulators, and effectors of the innate immune response to serve as potential viral countermeasures.
Gag Localization and Virus-Like Particle Release Mediated by the Matrix Domain of Human T-Lymphotropic Virus Type 1 Gag Are Less Dependent on Phosphatidylinositol-(4,5)-Bisphosphate than Those Mediated by the Matrix Domain of HIV-1 Gag
Authors: Inlora Jingga , Chukkapalli Vineela , Derse David , Ono Akira 
Published: February 2011

ABSTRACT

The human immunodeficiency virus type 1 (HIV-1) Gag matrix (MA) domain facilitates Gag targeting and binding to the plasma membrane (PM) during virus assembly. Interaction with a PM phospholipid, phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P
2
], plays a key role in these MA functions. Previous studies showed that overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV), which depletes cellular PI(4,5)P
2
, mislocalizes HIV-1 Gag to the cytosol and greatly reduces HIV-1 release efficiency. In this study, we sought to determine the role of the MA-PI(4,5)P
2
interaction in Gag localization and membrane binding of a deltaretrovirus, human T-lymphotropic virus type 1 (HTLV-1). We compared the chimeric HIV-1 Gag (HTMA), in which MA was replaced with HTLV-1 MA, with wild-type HIV-1 and HTLV-1 Gag for PI(4,5)P
2
dependence. Our results demonstrate that, unlike HIV-1 Gag, subcellular localization of and VLP release by HTLV-1 and HTMA Gag were minimally sensitive to 5ptaseIV overexpression. These results suggest that the interaction of HTLV-1 MA with PI(4,5)P
2
is not essential for HTLV-1 particle assembly. Furthermore, liposome-binding analyses showed that both HTLV-1 and HTMA Gag can bind membrane efficiently even in the absence of PI(4,5)P
2
. Efficient HTLV-1 Gag binding to liposomes was largely driven by electrostatic interaction, unlike that of HIV-1 Gag, which required specific interaction with PI(4,5)P
2
. Furthermore, membrane binding of HTLV-1 Gag
in vitro
was not suppressed by RNA, in contrast to HIV-1 Gag. Altogether, our data suggest that Gag targeting and membrane binding mediated by HTLV-1 MA does not require PI(4,5)P
2
and that distinct mechanisms regulate HIV-1 and HTLV-1 Gag membrane binding.
Interferon Signaling Remains Functional during Henipavirus Infection of Human Cell Lines
Authors: Virtue Elena R. , Marsh Glenn A. , Wang Lin-Fa 
Published: February 2011

ABSTRACT
Henipaviruses encode several proteins from the P gene, of which V and W have been demonstrated by gene-based transfection studies to antagonize the innate immune response, blocking both type I interferon production and signaling. This study examines the effects of henipavirus infection on the innate immune response in human cell lines. We report that henipavirus infection does not result in interferon production, with the virus antagonizing this response. In contrast to published transfection studies, our study found that the interferon signaling pathways are only partially blocked by henipavirus infection of human cell lines.
Vif Substitution Enables Persistent Infection of Pig-Tailed Macaques by Human Immunodeficiency Virus Type 1
Authors: Thippeshappa Rajesh , Polacino Patricia , Yu Kimata Monica T. , Siwak Edward B. , Anderson David , Wang Weiming , Sherwood Laura , Arora Reetakshi , Wen Michael , Zhou Paul , Hu Shiu-Lok , Kimata Jason T. 
Published: February 2011

ABSTRACT

Among Old World monkeys, pig-tailed macaques (Pt) are uniquely susceptible to human immunodeficiency virus type 1 (HIV-1), although the infection does not persist. We demonstrate that the susceptibility of Pt T cells to HIV-1 infection is due to the absence of postentry inhibition by a TRIM5 isoform. Notably, substitution of the viral infectivity factor protein, Vif, with that from pathogenic SIVmne enabled replication of HIV-1 in Pt T cells
in vitro
. When inoculated into juvenile pig-tailed macaques, the Pt-tropic HIV-1 persistently replicated for more than 1.5 to 2 years, producing low but measurable plasma viral loads and persistent proviral DNA in peripheral blood mononuclear cells. It also elicited strong antibody responses. However, there was no decline in CD4
+
T cells or evidence of disease. Surprisingly, the Pt-tropic HIV-1 was rapidly controlled when inoculated into newborn Pt macaques, although it transiently rebounded after 6 months. We identified two notable differences between the Pt-tropic HIV-1 and SIVmne. First, SIV Vif does not associate with Pt-tropic HIV-1 viral particles. Second, while Pt-tropic HIV-1 degrades both Pt APOBEC3G and APOBEC3F, it prevents their inclusion in virions to a lesser extent than pathogenic SIVmne. Thus, while SIV Vif is necessary for persistent infection by Pt-tropic HIV-1, improved expression and inhibition of APOBEC3 proteins may be required for robust viral replication
in vivo
. Additional adaptation of the virus may also be necessary to enhance viral replication. Nevertheless, our data suggest the potential for the pig-tailed macaque to be developed as an animal model of HIV-1 infection and disease.
Influence of Gag-Protease-Mediated Replication Capacity on Disease Progression in Individuals Recently Infected with HIV-1 Subtype C
Authors: Wright Jaclyn K. , Novitsky Vladimir , Brockman Mark A. , Brumme Zabrina L. , Brumme Chanson J. , Carlson Jonathan M. , Heckerman David , Wang Bingxia , Losina Elena , Leshwedi Mopo , van der Stok Mary , Maphumulo Lungile , Mkhwanazi Nompumelelo , Chonco Fundisiwe , Goulder Philip J. R. , Essex Max , Walker Bruce D. , Ndung'u Thumbi 
Published: February 2011

ABSTRACT

HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (
P
= 0.37) but were significantly lower in individuals with below-median viral load set points (
P
= 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (
P
= 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (
P
= 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (
P
= 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (
P
= 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.
Identification of Human Parainfluenza Virus Type 2 (HPIV-2) V Protein Amino Acid Residues That Reduce Binding of V to MDA5 and Attenuate HPIV-2 Replication in Nonhuman Primates
Authors: Schaap-Nutt Anne , Higgins Caraline , Amaro-Carambot Emerito , Nolan Sheila M. , D'Angelo Christopher , Murphy Brian R. , Collins Peter L. , Schmidt Alexander C. 
Published: February 2011

ABSTRACT

Human parainfluenza virus type 2 (HPIV-2), an important pediatric respiratory pathogen, encodes a V protein that inhibits type I interferon (IFN) induction and signaling. Using reverse genetics, we attempted the recovery of a panel of V mutant viruses that individually contained one of six cysteine-to-serine (residues 193, 197, 209, 211, 214, and 218) substitutions, one of two paired charge-to-alanine (R175A/R176A and R205A/K206A) substitutions, or a histidine-to-phenylalanine (H174F) substitution. This mutagenesis was performed using a cDNA-derived HPIV-2 virus that expressed the V and P coding sequences from separate mRNAs. Of the cysteine substitutions, only C193S, C214S, and C218S yielded viable virus, and only the C214S mutant replicated well enough for further analysis. The H174F, R175A/R176A, and R205A/K206A mutants were viable and replicated well. The H174F and R205A/K206A mutants did not differ from the wild-type (WT) V in their ability to physically interact with MDA5, a cytoplasmic sensor of nonself RNA that induces type I IFN. Like WT HPIV-2, these mutants inhibited IFN-β induction and replicated efficiently in African green monkeys (AGMs). In contrast, the C214S and R175A/R176A mutants did not bind MDA5 efficiently, did not inhibit interferon regulatory factor 3 (IRF3) dimerization or IFN-β induction, and were attenuated in AGMs. These findings indicate that V binding to MDA5 is important for HPIV-2 virulence in nonhuman primates and that some V protein residues involved in MDA5 binding are not essential for efficient HPIV-2 growth
in vitro
. Using a transient expression system, 20 additional mutant V proteins were screened for MDA5 binding, and the region spanning residues 175 to 180 was found to be essential for this activity.
Promoting calls to a quitline: quantifying the influence of message theme, strong negative emotions and graphic images in television advertisements
Authors: Farrelly Matthew C , Davis Kevin C , Nonnemaker James M , Kamyab Kian , Jackson Christine 
Published: February 2011

ObjectiveTo understand the relative effectiveness of television advertisements that differ in their thematic focus and portrayals of negative emotions and/or graphic images in promoting calls to a smokers' quitline.MethodsRegression analysis is used to explain variation in quarterly media market-level per smoker calls to the New York State Smokers' Quitline from 2001 to 2009. The primary independent variable is quarterly market-level delivery of television advertisements measured by target audience rating points (TARPs). Advertisements were characterised by their overall objective—promoting cessation, highlighting the dangers of secondhand smoke (SHS) or other—and by their portrayals of strong negative emotions and graphic images.ResultsPer smoker call volume is positively correlated with total TARPs (p<0.001), and cessation advertisements are more effective than SHS advertisements in promoting quitline call volume. Advertisements with graphic images only or neither strong negative emotions nor graphic images are associated with higher call volume with similar effect sizes. Call volume was not significantly associated with the number of TARPs for advertisements with strong negative emotions only (p=0.71) or with both graphic images and strong emotions (p=0.09).ConclusionsExposure to television advertisements is strongly associated with quitline call volume, and both cessation and SHS advertisements can be effective. The use of strong negative emotions in advertisements may be effective in promoting smoking cessation in the population but does not appear to influence quitline call volume. Further research is needed to understand the role of negative emotions in promoting calls to quitlines and cessation more broadly among the majority of smokers who do not call quitlines.
Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy
Authors: Pan Yaozhu , Gao Ying , Chen Liang , Gao Guangxun , Dong Hongjuan , Yang Yang , Dong Baoxia , Chen Xiequn 
Published: February 2011

Abstract
Purpose: Although autophagy occurs in most tumor cells following DNA damage, it is still a mystery how this DNA-damaging event turns on the autophagy machinery in multiple myeloma (MM) and how the functional status of autophagy impacts on its susceptibility to death in response to DNA-damaging chemotherapy.
Experimental Design: We investigate the effects of DNA damage on autophagy in MM cells and elucidate its underlying molecular mechanism. Then, we examined the impacts of pharmacologic or genetic inhibition of autophagy on DNA damage–induced apoptosis. Furthermore, the antimyeloma activity of autophagy inhibitor in combination with DNA-damaging agents was evaluated in MM xenograft models.
Results: We showed that DNA-damaging drugs, doxorubicin and melphalan, induce caspase-dependent apoptosis and concurrently trigger Beclin 1–regulated autophagy in human MM cell lines H929 and RPMI 8226. Mechanistically, association of autophagy execution proteins Beclin 1 with class III phosphoinositide 3-kinase, which is inhibited by Bcl-2 recruitment, contributes directly to the autophagic process. Importantly, targeting suppression of autophagy by minimally toxic concentrations of pharmacologic inhibitors (hydroxychloroquine and 3-methyladenine) or short hairpin RNAs against autophagy genes, Beclin 1 and Atg5, dramatically augments proapoptotic activity of DNA-damaging chemotherapy both in vitro using MM cell lines or purified patient MM cells and in vivo in a human plasmacytoma xenograft mouse model.
Conclusion: These data can help unravel the underlying molecular mechanism of autophagy in DNA-damaged MM cells and also provide a rationale for clinical evaluation of autophagy inhibitors in combination with DNA-damaging chemotherapy in MM. Clin Cancer Res; 17(10); 3248–58. ©2011 AACR.
Anaphase Catastrophe Is a Target for Cancer Therapy
Authors: Galimberti Fabrizio , Thompson Sarah L. , Ravi Saranya , Compton Duane A. , Dmitrovsky Ethan 
Published: February 2011

Abstract
Neoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can be exploited to disrupt tumor cell growth, potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically kills tumor cells with more than 2 centrosomes. This death program can occur after genetic or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologically induced for apoptotic death of cancer cells and is, therefore, appealing to engage for cancer therapy and prevention. Clin Cancer Res; 17(6); 1218–22. ©2011 AACR.
A New Mechanism for Blocking Myeloid-Derived Suppressor Cells by CpG
Authors: Lechner Melissa G. , Epstein Alan L. 
Published: February 2011

Abstract
In this issue of Clinical Cancer Research, Zoglmeier and colleagues show that CpG, via the induction of IFN-α, matures myeloid-derived suppressor cells to abrogate immune suppression in 2 murine solid tumor models. Clin Cancer Res; 17(7); 1645–8. ©2011 AACR.
Context Dependence of Checkpoint Kinase 1 as a Therapeutic Target for Pancreatic Cancers Deficient in the BRCA2 Tumor Suppressor
Authors: Hattori Hiroyoshi , Skoulidis Ferdinandos , Russell Paul , Venkitaraman Ashok R. 
Published: February 2011

Abstract
Inherited mutations in the tumor suppressor BRCA2 are predisposed to pancreatic adenocarcinomas, which carry activating mutations in the KRAS oncogene in more than 95% of cases, as well as frequent TP53 inactivation. Here, we have established an RNA interference (RNAi) screen to identify genes whose depletion selectively inhibits the growth of cells lacking BRCA2, and then studied the effects of the genetic depletion or pharmacologic inhibition of 1 candidate, the checkpoint kinase 1 (CHK1), in the context of pancreatic cancer. Pharmacologic inhibition of CHK1 using small-molecule inhibitors (CHK1i) reduced cell growth in several cell lines depleted of BRCA2. Unexpectedly, these drugs did not suppress the growth of BRCA2-deficient pancreatic cancer cell lines from humans or gene-targeted mice expressing active Kras and trans-dominant inhibitory mutant Trp53. Remarkably, the expression of KRASG12V and TP53G154V in BRCA2-depleted HEK293 cells was sufficient to render them resistant to CHK1i (but not to mitomycin C or inhibitors of PARP1). CHK1i sensitivity was restored by gemcitabine, an S-phase genotoxin used to treat pancreatic adenocarcinoma. Thus, the growth-suppressive effect of CHK1 inhibition in BRCA2-mutant tumors can be opposed by concurrent KRAS activation and TP53 mutations typical of pancreatic adenocarcinoma, and CHK1i resistance in this setting can be overcome by gemcitabine. Our findings show that approaches that use potential therapeutic targets for cancer identified in synthetic lethal RNAi screens are affected by the genetic context of specific malignancies and combination therapy with other agents. This concept should be taken into account in the ongoing and future development of targeted cancer therapies. Mol Cancer Ther; 10(4); 670–78. ©2011 AACR.