bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of HLA-B*81-Associated Mutations in HIV-1 Gag on Viral Replication Capacity
Authors: Wright Jaclyn K. , Naidoo Vanessa L. , Brumme Zabrina L. , Prince Jessica L. , Claiborne Daniel T. , Goulder Philip J. R. , Brockman Mark A. , Hunter Eric , Ndung'u Thumbi 
Published: January 2012

ABSTRACT
HIV-1 attenuation resulting from immune escape mutations selected in Gag may contribute to slower disease progression in HIV-1-infected individuals expressing certain HLA class I alleles. We previously showed that the protective allele HLA-B*81 and the HLA-B*81-selected Gag T186S mutation are strongly associated with a lower viral replication capacity of recombinant viruses encoding Gag-protease derived from individuals chronically infected with HIV-1 subtype C. In the present study, we directly tested the effect of this mutation on viral replication capacity. In addition, we investigated potential compensatory effects of various polymorphisms, including other HLA-B*81-associated mutations that significantly covary with the T186S mutation. Mutations were introduced into a reference subtype B backbone and into patient-derived subtype C sequences in subtype B and C backbones by site-directed mutagenesis. The exponential-phase growth of mutant and wild-type viruses was assayed by flow cytometry of a green fluorescent protein reporter T cell line or by measurement of HIV-1 reverse transcriptase activity in culture supernatants. Engineering of the T186S mutation alone into all patient-derived subtype C sequences failed to yield replication-competent viruses, while in the subtype B sequence, the T186S mutation resulted in impaired replication capacity. Only the T186S mutation in combination with the T190I mutation yielded replication-competent viruses for all virus backbones tested; however, these constructs replicated slower than the wild type, suggesting that only partial compensation is mediated by the T190I mutation. Constructs encoding the T186S mutation in combination with other putative compensatory mutations were attenuated or defective. These results suggest that the T186S mutation is deleterious to HIV-1 subtype C replication and likely requires complex compensatory pathways, which may contribute to the clinical benefit associated with HLA-B*81.
Control of Innate Immune Signaling and Membrane Targeting by the Hepatitis C Virus NS3/4A Protease Are Governed by the NS3 Helix α
0
Authors: Horner Stacy M. , Park Hae Soo , Gale Michael 
Published: January 2012

ABSTRACT

Hepatitis C virus (HCV) infection is sensed in the host cell by the cytosolic pathogen recognition receptor RIG-I. RIG-I signaling is propagated through its signaling adaptor protein MAVS to drive activation of innate immunity. However, HCV blocks RIG-I signaling through viral NS3/4A protease cleavage of MAVS on the mitochondrion-associated endoplasmic reticulum (ER) membrane (MAM). The multifunctional HCV NS3/4A serine protease is associated with intracellular membranes, including the MAM, through membrane-targeting domains within NS4A and also at the amphipathic helix α
0
of NS3. The serine protease domain of NS3 is required for both cleavage of MAVS, a tail-anchored membrane protein, and processing the HCV polyprotein. Here, we show that hydrophobic amino acids in the NS3 helix α
0
are required for selective cleavage of membrane-anchored portions of the HCV polyprotein and for cleavage of MAVS for control of RIG-I pathway signaling of innate immunity. Further, we found that the hydrophobic composition of NS3 helix α
0
is essential to establish HCV replication and infection. Alanine substitution of individual hydrophobic amino acids in the NS3 helix α
0
impaired HCV RNA replication in cells with a functional RIG-I pathway, but viral RNA replication was rescued in cells lacking RIG-I signaling. Therefore, the hydrophobic amphipathic helix α
0
of NS3 is required for NS3/4A control of RIG-I signaling and HCV replication by directing the membrane targeting of both viral and cellular substrates.
Complete Genome Sequence of a Dengue Virus Serotype 4 Strain Isolated in Roraima, Brazil
Authors: Naveca Felipe G. , Souza Victor C. , Silva George A. V. , Maito Rodrigo M. , Granja Fabiana , Siqueira Thalita , Acosta Pablo O. A. 
Published: January 2012

ABSTRACT
Dengue is the most important arboviral disease worldwide. We report the complete genome sequence of a dengue virus serotype 4, genotype II strain isolated in 2010 from a patient with classical dengue fever in Boa Vista, Roraima, Brazil.
Varicella-Zoster Virus ORF12 Protein Triggers Phosphorylation of ERK1/2 and Inhibits Apoptosis
Authors: Liu XueQiao , Li Qingxue , Dowdell Kennichi , Fischer Elizabeth R. , Cohen Jeffrey I. 
Published: January 2012

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are a family of serine-threonine protein kinases involved in many cellular processes, including cell proliferation, differentiation, inflammation, and cell death. Activation of several MAPKs, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), results in stimulation of activator protein 1 (AP-1), which promotes gene transcription. Previous studies have demonstrated that varicella-zoster virus (VZV) infection activates ERK1/2, p38, and JNK to promote viral replication, but the underlying mechanism(s) is unclear. To identify viral proteins responsible for the activation of MAPK, we used a proteomic approach to screen viral proteins for AP-1 promoter activation by an AP-1–luciferase reporter assay. We found that VZV ORF12 protein, located in the tegument of virions, enhances AP-1 reporter activity. This effect of ORF12 protein was markedly inhibited by a MAPK/ERK kinase 1 and 2 (MEK1/2) inhibitor (U0126), partially blocked by a p38 inhibitor (SB202190), but not inhibited by a JNK inhibitor (SP600125). Expression of VZV ORF12 protein in cells resulted in phosphorylation of ERK1/2 and p38 but not JNK. Infection of cells with a VZV ORF12 deletion mutant resulted in reduced levels of phosphorylated ERK1/2 (p-ERK1/2) compared to infection with wild-type VZV. Furthermore, deletion of ORF12 rendered VZV-infected cells more susceptible to staurosporine-induced apoptosis. In conclusion, VZV ORF12 protein activates the AP-1 pathway by selectively triggering the phosphorylation of ERK1/2 and p38. Cells infected with a VZV ORF12 deletion mutant have reduced levels of p-ERK1/2 and are more susceptible to apoptosis than cells infected with wild-type VZV.
RNAi-Mediated Targeting of Noncoding and Coding Sequences in DNA Repair Gene Messages Efficiently Radiosensitizes Human Tumor Cells
Authors: Zheng Zhiming , Ng Wooi Loon , Zhang Xiangming , Olson Jeffrey J. , Hao Chunhai , Curran Walter J. , Wang Ya 
Published: January 2012

Abstract
Human tumor cell death during radiotherapy is caused mainly by ionizing radiation (IR)–induced DNA double-strand breaks (DSB), which are repaired by either homologous recombination repair (HRR) or nonhomologous end-joining (NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize tumor cells to IR, this approach is limited by inefficiencies of gene silencing. In this study, we show that combining an artificial miRNA (amiR) engineered to target 3′-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ factor) along with an siRNA to target the gene coding region can improve silencing efficiencies to achieve more robust radiosensitization than a single approach alone. Mechanistically, the combinatorial knockdown decreased targeted gene expression through both a reduction in mRNA stability and a blockade to mRNA translation. Together, our findings establish a general method of gene silencing that is more efficient and particularly suited for suppressing genes that are difficult to downregulate by amiR- or siRNA-based methods alone. Cancer Res; 72(5); 1221–8. ©2012 AACR.
Antigen-Specific CD4+ T Cells Regulate Function of Myeloid-Derived Suppressor Cells in Cancer via Retrograde MHC Class II Signaling
Authors: Nagaraj Srinivas , Nelson Allison , Youn Je-in , Cheng Pingyan , Quiceno David , Gabrilovich Dmitry I. 
Published: January 2012

Abstract
Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSCs to elicit CD4+ T-cell tolerance in different mouse tumor models. In contrast to CD8+ T-cell tolerance, which could be induced by MDSCs in all the tumor models tested, CD4+ T-cell tolerance could be elicited in only one of the models (MC38) in which a substantial level of MHC class II was expressed on MDSCs compared with control myeloid cells. Mechanistic investigations revealed that MDSCs deficient in MHC class II could induce tolerance to CD8+ T cells but not to CD4+ T cells. Unexpectedly, antigen-specific CD4+ T cells (but not CD8+ T cells) could dramatically enhance the immune suppressive activity of MDSCs by converting them into powerful nonspecific suppressor cells. This striking effect was mediated by direct cell–cell contact through cross-linking of MHC class II on MDSCs. We also implicated an Ets-1 transcription factor–regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4+ T cells that are antigen specific may enhance the immune suppressive activity of MDSCs, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer. Cancer Res; 72(4); 928–38. ©2012 AACR.
Twenty-Third Annual Pezcoller Symposium: Engineering Influences in Cancer Research
Authors: Friedl Peter , Hubbell Jeff , Livingston David , Mihich Enrico 
Published: January 2012

Abstract
The cross-disciplinary focus of the meeting highlighted recent progress in physical and genetic analysis and engineering of cancer disease models. As the central theme, mechanical forces affecting cell signaling, growth, differentiation, and metastasis were discussed with emphasis on the tumor microenvironment and cellular immunity, taking into account novel nanotechnology, biosensing, and intravital microscopy tools to monitor animal cancer models and human cancer. Emerging themes were the role of extracellular matrix imposing mechanical mechanisms on tumor cell function, including microenvironmental cues controlling the movement of tumor and immune cells, advanced genetic animal models for cancer that better recapitulate human disease, and preclinical and clinical molecular imaging of tumor architecture and stiffness, as well as novel nanotechnologies for anticancer drug delivery. Cancer Res; 72(4); 841–4. ©2012 AACR.
Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models
Authors: Gozgit Joseph M. , Wong Matthew J. , Moran Lauren , Wardwell Scott , Mohemmad Qurish K. , Narasimhan Narayana I. , Shakespeare William C. , Wang Frank , Clackson Tim , Rivera Victor M. 
Published: January 2012

AbstractMembers of the fibroblast growth factor receptor family of kinases (FGFR1–4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1–4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC50 values &lt;40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC50 values &lt;40 nmol/L and inhibited cell growth with GI50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10–30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL–driven models and plasma levels of ponatinib that exceed the IC50 values for FGFR1–4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers. Mol Cancer Ther; 11(3); 690–9. ©2012 AACR.
DLK1 as a Potential Target against Cancer Stem/Progenitor Cells of Hepatocellular Carcinoma
Authors: Xu Xiao , Liu Rui-Fang , Zhang Xin , Huang Li-Yu , Chen Fei , Fei Qian-Lan , Han Ze-Guang 
Published: January 2012

Abstract
Delta-like 1 homolog (DLK1; Drosophila) is a hepatic stem/progenitor cell marker in fetal livers that plays a vital role in oncogenesis of hepatocellular carcinoma (HCC). The aim of this study is to investigate whether DLK1 could serve as a potential therapeutic target against cancer stem/progenitor cells of HCC. DLK1+ and DLK1− cells were sorted by fluorescence-activated cell sorting and magnetic-activated cell sorting, respectively, and then were evaluated by flow cytometry. The biological behaviors of these isolated cells and those with DLK1 knockdown were assessed by growth curve, colony formation assay, spheroid colony formation, chemoresistance, and in vivo tumorigenicity. Adenovirus-mediated RNA interference was used to knockdown the endogenous DLK1. We found that DLK1+ population was less than 10% in almost all 17 HCC cell lines examined. DLK1+ HCC cells showed stronger ability of chemoresistance, colony formation, spheroid colony formation, and in vivo tumorigenicity compared with DLK1− cells. The DLK1+ HCC cells could generate the progeny without DLK1 expression. Furthermore, DLK1 knockdown could suppress the ability of proliferation, colony formation, spheroid colony formation, and in vivo tumorigenicity of Hep3B and Huh-7 HCC cells. Our data suggested that DLK1+ HCC cells have characteristics similar to those of cancer stem/progenitor cells. RNA interference against DLK1 can suppress the malignant behaviors of HCC cells, possibly through directly disrupting cancer stem/progenitor cells, which suggested that DLK1 could be a potential therapeutic target against the HCC stem/progenitor cells. Mol Cancer Ther; 11(3); 629–38. ©2012 AACR.
Dissecting “PI3Kness”: The Complexity of Personalized Therapy for Ovarian Cancer
Authors: Bast Robert C. , Mills Gordon B. 
Published: January 2012

Abstract
Epithelial ovarian cancers exhibit marked heterogeneity and can be divided into low-grade type I and more prevalent high-grade type II lesions that differ in stage at diagnosis, rate of growth, and susceptibility to platinum-based chemotherapy. Activation of the phosphatidylinositol 3′ kinase (PI3K) pathway occurs in a significant fraction of both types of ovarian cancer, driven predominantly by mutations in type I and amplification in type II. Available cell lines do not often reflect the genotype of type II ovarian cancers, but studies with cell lines driven by mutation suggest that blocking activated AKT is necessary, but not sufficient to inhibit cancer cell growth. Inhibition of multiple signaling pathways will likely be required to achieve effective personalized therapy for patients whose cancers exhibit “PI3Kness.” Cancer Discovery; 2(1); 16–8. ©2012 AACR.
Commentary on Hanrahan et al., p. 56.
Elevated CD14
++
CD16
−
Monocytes Predict Cardiovascular Events
Authors: Berg Katarina E. , Ljungcrantz Irena , Andersson Linda , Bryngelsson Carl , Hedblad Bo , Fredrikson Gunilla N. , Nilsson Jan , Björkbacka Harry 
Published: January 2012

Background—
Although monocytes in peripheral blood are no longer considered to be a homogeneous population, associations between distinct monocyte subsets and cardiovascular disease have not been highlighted in large epidemiological studies.

Methods and Results—

The study included 700 randomly selected subjects from the cardiovascular arm of the Malmö Diet and Cancer study. Among these, 123 subjects experienced ischemic cardiovascular events during the follow-up until December 2008. Mononuclear leukocytes frozen at the baseline investigation in 1991 to 1994 were thawed and analyzed with flow cytometry to enumerate monocyte subsets, based on CD14 and CD16 expression. The percentage and number of classical CD14
++
CD16
−
monocytes were increased in the cardiovascular-event group compared with the event-free subjects (median, 69% [interquartile range, 62% to 76%] versus 67% [59% to 72%],
P
=0.017; 344 [251 to 419] cells/μL versus 297 [212 to 384] cells/μL,
P
=0.003). The hazard ratio was 1.66 for suffering a cardiovascular event in the highest tertile of the number of CD14
++
CD16
−
monocytes compared with the lowest tertile, even after adjustment for common risk factors (HR, 1.66; 95% CI: 1.02 to 2.72). CD14
++
CD16
−
monocytes did not, however, associate with the extent of atherosclerosis at baseline. In contrast, the percentage of monocytes expressing CD16 was negatively associated to the extent of carotid atherosclerosis measured as intima-media thickness at baseline. The chemokine receptors CCR2, CX3CR1, and CCR5 were not differentially expressed between cases and controls on any of the monocyte subsets, but CCR5 expression on CD14
+
CD16
++
monocytes was negatively associated to carotid intima-media thickness.

Conclusions—

This study shows that classical CD14
++
CD16
−
monocytes can predict future cardiovascular risk independently of other risk factors in a randomly selected population.
General and Disease-Specific Psychosocial Adjustment in Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy With Implantable Cardioverter Defibrillators: A Large Cohort Study
Authors: James Cynthia A. , Tichnell Crystal , Murray Brittney , Daly Amy , Sears Samuel F. , Calkins Hugh 
Published: January 2012

Background—
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by frequent life-threatening ventricular arrhythmias, diagnosed on average in the teens to mid-50s and commonly treated by implantable cardioverter defibrillators (ICDs). As younger age and high frequency of ICD discharges are risk factors for difficulties in psychosocial adjustment, we developed a study to assess psychosocial adjustment among patients with ARVD/C and to determine risk factors for poor adjustment in this high-risk population.

Methods and Results—

Eighty-six adults enrolled in the Johns Hopkins ARVD Registry (38 male; mean age, 45.4±12.9 years), with an ICD in place for a median 3.2 years (range, 0.2 to 20.1 years), completed a set of questionnaires measuring ICD-specific anxiety (Florida Shock Anxiety Scale), device acceptance (Florida Patient Acceptance Survey), anxiety and depression (Hospital Anxiety and Depression Scale), and functional capacity (Duke Activity Status Index). Although overall device acceptance (Florida Patient Acceptance Survey mean, 76.7±15.3) was normative, patients with ARVD/C had substantially elevated body image concerns (Florida Patient Acceptance Survey subscale mean, 17.9±23.5) and device-related distress (subscale mean, 26.5±19.2), particularly among younger patients (
P
<0.01). Patients with ARVD/C had elevated ICD-specific (Florida Shock Anxiety Scale mean, 22.9±7.8) and general clinical anxiety (Hospital Anxiety and Depression Scale anxiety subscale mean, 6.2±3.9). Device-specific anxiety (Florida Shock Anxiety Scale) was predicted by younger age (
P
<0.0001), poorer functional capacity (
P
=0.016), having an ICD shock (
P
=0.003), and shorter time since ICD implant (
P
=0.007). Participants with poor device adjustment had an increased likelihood of clinically significant anxiety (
P
=0.006) and depression (
P
=0.008).

Conclusions—
Patients with ARVD/C are at elevated risk for anxiety, and young patients face challenges with device acceptance. Risk factors for poor device adjustment may be used clinically to identify patients at high-risk of psychological distress.
Long-Term Propensity Score–Matched Comparison of Percutaneous Closure of Patent Foramen Ovale With Medical Treatment After Paradoxical Embolism
Authors: Wahl Andreas , Jüni Peter , Mono Marie-Luise , Kalesan Bindu , Praz Fabien , Geister Laura , Räber Lorenz , Nedeltchev Krassen , Mattle Heinrich P. , Windecker Stephan , Meier Bernhard 
Published: January 2012

Background—
Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment.

Methods and Results—

Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score–matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ratio=0.43; 95% confidence interval=0.20–0.94;
P
=0.033). The treatment effect was driven by a decrease in the risk of transient ischemic attack of 5% versus 14%, respectively (hazard ratio=0.31; 95% confidence interval=0.10–0.94;
P
=0.039). The risk of all-cause (6% in both groups) and cardiovascular (3% in both groups) mortality appeared to be identical.

Conclusion—
In this long-term observational, propensity score–matched study, percutaneous PFO closure was more effective than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with PFO-related transient ischemic attack or stroke.
Observations of Urban Heat Island Influence on Lake-Breeze Frontal Movement
Authors: Keeler Jason M. , Kristovich David A. R. 
Published: January 2012

AbstractPredictions of lake and sea breezes are particularly important in large coastal population centers because of the circulations’ influence on heat-wave relief, energy use, precipitation, and dispersion of pollutants. While recent numerical modeling studies have suggested that sea or lake breezes should move more slowly through urban areas than in the surrounding suburbs because of urban heat island (UHI) circulations, there have been few quantitative observational studies to evaluate these results. This study utilizes high-resolution Weather Surveillance Radar-1988 Doppler (WSR-88D) observations to determine the effect of the UHI on lake-breeze frontal movement through Chicago, Illinois, and nearby suburban areas. A total of 44 lake-breeze cases from the April–September 2005 period were examined. The inland movement of the lake-breeze front (LBF) was calculated by tracking “fine lines” of radar reflectivity along several cross sections perpendicular to the Lake Michigan shoreline. The average inland propagation speed of the LBF was 5.0 km h−1; there was substantial spatial and temporal variability in LBF propagation, however. Chicago’s UHI magnitude on lake-breeze days exhibited an average nighttime maximum urban–rural temperature difference near 4.5°C and an afternoon minimum near 0°C. The observed daytime UHI magnitude did not have a significant relationship with lake-breeze frontal movement through Chicago. However, the maximum magnitude of the nighttime UHI preceding lake-breeze development was found to be strongly related to a decrease in speed of LBF movement through Chicago’s southwest (inland) suburbs. This relationship is consistent with previous studies of the diurnal evolution of UHI circulations and may represent a useful method for predicting lake-breeze inland movement.