bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the Capsid Protein of Brome Mosaic Virus Affecting Encapsidation Eliminate Vesicle Induction
In Planta
: Implications for Virus Cell-to-Cell Spread
Authors: Bamunusinghe Devinka , Chaturvedi Sonali , Seo Jang-Kyun , Rao A. L. N. 
Published: June 2013

ABSTRACT

Positive-strand RNA viruses are known to rearrange the endomembrane network to make it more conducive for replication, maturation, or egress. Our previous transmission electron microscopic (TEM) analysis showed that ectopic expression of wild-type (wt) capsid protein (CP) of
Brome mosaic virus
(BMV) has an intrinsic property of modifying the endoplasmic reticulum (ER) to induce vesicles similar to those present in wt BMV infection. In this study, we evaluated the functional significance of CP-mediated vesicle induction to the BMV infection cycle
in planta
. Consequently, the cytopathologic changes induced by wt CP or its mutants defective in virion assembly due to mutations engineered in either N- or C-proximal domains were comparatively analyzed by TEM in two susceptible (
Nicotiana benthamiana
and
Chenopodium quinoa
) and one nonhost (
N. clevelandii
) plant species. The results showed that in susceptible hosts, CP-mediated ER-derived vesicle induction is contingent on the expression of encapsidation-competent CP. In contrast, unlike in
N. benthamiana
and
C. quinoa
, transient expression of wt CP in nonhost
N. clevelandii
plants eliminated vesicle induction. Additionally, comparative source-to-sink analysis of virus spread in leaves of
N. benthamiana
and
N. clevelandii
coexpressing wt BMV and
Cucumber mosaic virus
(CMV) showed that despite
trans
-encapsidation, CMV failed to complement the defective cell-to-cell movement of BMV. The significance and relation of CP-mediated vesicle induction to virus cell-to-cell movement are discussed.
Role of RNA Interference (RNAi) in Dengue Virus Replication and Identification of NS4B as an RNAi Suppressor
Authors: Kakumani Pavan Kumar , Ponia Sanket Singh , S Rajgokul K. , Sood Vikas , Chinnappan Mahendran , Banerjea Akhil C. , Medigeshi Guruprasad R. , Malhotra Pawan , Mukherjee Sunil K. , Bhatnagar Raj K. 
Published: June 2013

ABSTRACT

RNA interference (RNAi) is an important antiviral defense response in plants and invertebrates; however, evidences for its contribution to mammalian antiviral defense are few. In the present study, we demonstrate the anti-dengue virus role of RNAi in mammalian cells. Dengue virus infection of Huh 7 cells decreased the mRNA levels of host RNAi factors, namely, Dicer, Drosha, Ago1, and Ago2, and in corollary, silencing of these genes in virus-infected cells enhanced dengue virus replication. In addition, we observed downregulation of many known human microRNAs (miRNAs) in response to viral infection. Using reversion-of-silencing assays, we further showed that NS4B of all four dengue virus serotypes is a potent RNAi suppressor. We generated a series of deletion mutants and demonstrated that NS4B mediates RNAi suppression via its middle and C-terminal domains, namely, transmembrane domain 3 (TMD3) and TMD5. Importantly, the NS4B N-terminal region, including the signal sequence 2K, which has been implicated in interferon (IFN)-antagonistic properties, was not involved in mediating RNAi suppressor activity. Site-directed mutagenesis of conserved residues revealed that a Phe-to-Ala (F112A) mutation in the TMD3 region resulted in a significant reduction of the RNAi suppression activity. The green fluorescent protein (GFP)-small interfering RNA (siRNA) biogenesis of the GFP-silenced line was considerably reduced by wild-type NS4B, while the F112A mutant abrogated this reduction. These results were further confirmed by
in vitro
dicer assays. Together, our results suggest the involvement of miRNA/RNAi pathways in dengue virus establishment and that dengue virus NS4B protein plays an important role in the modulation of the host RNAi/miRNA pathway to favor dengue virus replication.
The Endosomal Pathway and the Golgi Complex Are Involved in the Infectious Bursal Disease Virus Life Cycle
Authors: Delgui Laura R. , Rodríguez José F. , Colombo María I. 
Published: June 2013

ABSTRACT

Infectious bursal disease virus
(IBDV), a double-stranded RNA virus belonging to the
Birnaviridae
family, causes immunosuppression in chickens. In this study, we defined the localization of IBDV replication complexes based on colocalization analysis of VP3, the major protein component of IBDV ribonucleoproteins (RNPs). Our results indicate that VP3 localizes to vesicular structures bearing features of early and late endocytic compartments located in the juxtanuclear region. Interfering with the endocytic pathway with a dominant negative version of Rab5 after the internalization step leads to a reduction in virus titer. Triple-immunostaining studies between VP3, the viral RNA-dependent RNA polymerase VP1, and viral double-stranded RNA (dsRNA) showed a well-defined colocalization, indicating that the three critical components of the RNPs colocalize in the same structure, likely representing replication complexes. Interestingly, recombinant expressed VP3 also localizes to endosomes. Employing Golgi markers, we found that VP3-containing vesicles were closely associated with this organelle. Depolymerization of microtubules with nocodazole caused a profound change in VP3 localization, showing a punctate distribution scattered throughout the cytoplasm. However, these VP3-positive structures remained associated with Golgi ministacks. Similarly, brefeldin A (BFA) treatment led to a punctate distribution of VP3, scattered throughout the cytoplasm of infected cells. In addition, analysis of intra- and extracellular viral infective particles after BFA treatment of avian cells suggested a role for the Golgi complex in viral assembly. These results constitute the first study elucidating the localization of IBDV replication complexes (i.e., in endocytic compartments) and establishing a role for the Golgi apparatus in the assembly step of a birnavirus.
Echovirus 1 Entry into Polarized Caco-2 Cells Depends on Dynamin, Cholesterol, and Cellular Factors Associated with Macropinocytosis
Authors: Krieger Sophie E. , Kim Chonsaeng , Zhang Lili , Marjomaki Varpu , Bergelson Jeffrey M. 
Published: June 2013

ABSTRACTEnteroviruses invade their hosts by crossing the intestinal epithelium. We have examined the mechanism by which echovirus 1 (EV1) enters polarized intestinal epithelial cells (Caco-2). Virus binds to VLA-2 on the apical cell surface and moves rapidly to early endosomes. Using inhibitory drugs, dominant negative mutants, and small interfering RNAs (siRNAs) to block specific endocytic pathways, we found that virus entry requires dynamin GTPase and membrane cholesterol but is independent of both clathrin- and caveolin-mediated endocytosis. Instead, infection requires factors commonly associated with macropinocytosis, including amiloride-sensitive Na+/H+exchange, protein kinase C, and C-terminal-binding protein-1 (CtBP1); furthermore, EV1 accumulates rapidly in intracellular vesicles with dextran, a fluid-phase marker. These results suggest a role for macropinocytosis in the process by which EV1 enters polarized cells to initiate infection.
Mortality differentials 1991−2005 by self-reported ethnicity: findings from the ONS Longitudinal Study
Authors: Scott Anne P , Timæus Ian M 
Published: June 2013

BackgroundResearch on ethnic differentials in mortality in England and Wales has focused on immigrants because, until now, studies collecting data on ethnicity have not covered sufficient deaths to investigate the subject. International migrants are selected for good health and tend to have low mortality.MethodsWe investigated all-cause mortality at ages 1−79 in 1991−2005 by self-reported ethnicity and country of birth. The data are from the Office for National Statistics Longitudinal Study of England and Wales for the cohort aged 0−64 in 1991 (n=436 195). Poisson regression was used to adjust the estimates for metropolitan residence and three indicators of socioeconomic status.ResultsWhite, Black Caribbean, Other Asian and Other immigrants all had lower mortality than Whites born in the UK. Indian, Pakistani, Bangladeshi and Chinese immigrants had lower mortality than the UK-born Whites living in similar circumstances to them. By contrast, the UK-born Black Caribbean group had higher mortality (RR=1.38, 95% CI 1.03 to 1.86) than the UK-born Whites. This excess mortality was accounted for by their low socioeconomic status. Within the Black Caribbean population, the UK-born individuals had significantly higher mortality than those born abroad whether or not the estimates were adjusted for socioeconomic status and metropolitan residence. Adjusting exposure time for undocumented emigration made little difference to the estimates.ConclusionsImmigrants are selected for good health. This has offset the impact of socioeconomic disadvantage on the mortality of minority ethnic groups. As the immigrant population ages and the UK-born minority ethnic population grows, ethnic differentials in all-cause mortality are likely to change.
HER2 and Breast Cancer Stem Cells: More than Meets the Eye
Authors: Korkaya Hasan , Wicha Max S. 
Published: June 2013

Abstract
The development of HER2 targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggest that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (CSC) population. A new study suggests that the regulation of BCSCs by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population, and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these HER2-negative tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biologic explanation for retrospective analysis of clinical trials, which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population. Cancer Res; 73(12); 3489–93. ©2013 AACR.
Putative Predictive Biomarkers of Survival in Patients with Metastatic Pancreatic Adenocarcinoma Treated with Gemcitabine and Ganitumab, an IGF1R Inhibitor
Authors: McCaffery Ian , Tudor Yanyan , Deng Hongjie , Tang Rui , Suzuki Samuel , Badola Sunita , Kindler Hedy L. , Fuchs Charles S. , Loh Elwyn , Patterson Scott D. , Chen Li , Gansert Jennifer L. 
Published: June 2013

Abstract
Purpose: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma.
Experimental Design: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated.
Results: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28–0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09–0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09–0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11–0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07–0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS.
Conclusions: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma. Clin Cancer Res; 19(15); 4282–9. ©2013 AACR.
Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
Authors: Feng Yan , Roy Amit , Masson Eric , Chen Tai-Tsang , Humphrey Rachel , Weber Jeffrey S. 
Published: June 2013

Abstract
Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure–response relationships for measures of efficacy and safety in patients with advanced melanoma.
Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady–state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional–hazards model.
Results: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P &lt; 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.
Conclusions: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. Clin Cancer Res; 19(14); 3977–86. ©2013 AACR.
Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway
Authors: McClements Lana , Yakkundi Anita , Papaspyropoulos Angelos , Harrison Hannah , Ablett Matthew P. , Jithesh Puthen V. , McKeen Hayley D. , Bennett Rachel , Donley Christopher , Kissenpfennig Adrien , McIntosh Stuart , McCarthy Helen O. , O'Neill Eric , Clarke Robert B. , Robson Tracy 
Published: June 2013

AbstractPurpose: FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC).Experimental Design: Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti–stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence.Results: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESA+/CD44+/CD24− or aldehyde dehydrogenase (ALDH)+ cell subpopulations in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01–mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy-induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling.Conclusions: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial. Clin Cancer Res; 19(14); 3881–93. ©2013 AACR.
Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner
Authors: Cerezo Michaël , Tichet Mélanie , Abbe Patricia , Ohanna Mickaël , Lehraiki Abdelali , Rouaud Florian , Allegra Maryline , Giacchero Damien , Bahadoran Philippe , Bertolotto Corine , Tartare-Deckert Sophie , Ballotti Robert , Rocchi Stéphane 
Published: June 2013

Abstract
Metformin was reported to inhibit the proliferation of many cancer cells, including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of antiproliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial–mesenchymal transition such as Slug, Snail, SPARC, fibronectin, and N-cadherin and with inhibition of MMP-2 and MMP-9 activation. Furthermore, our data indicate that this process is dependent on activation of AMPK and tumor suppressor protein p53. Finally, we showed that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment. Mol Cancer Ther; 12(8); 1605–15. ©2013 AACR.
The effect of monthly ibandronate on bone mineral density and bone turnover markers in patients with haemophilia A and B and increased risk for fracture
Authors: Vyzantiadis Timoleon-Achilleas , Charizopoulou Maria , Adamidou Fotini , Karras Spyridon , Goulis Dimitrios , Karagiannis Asterios , Garipidou Vasilia , Vakalopoulou Sofia , Anagnostis Panagiotis 
Published: June 2013

SummaryHaemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, no study has so far evaluated the effects of anti-osteoporotic therapy on BMD in haemophilia. The primary endpoint of this prospective study was to estimate the effect of 12-month therapy of oral ibandronate 150 mg/ month on BMD in patients with haemophilia A and B. Secondary endpoint was its effect on turnover markers (BTM) of bone resorption [serum C-terminal telopeptide of type 1 collagen (sCTX), tartrate-resistant acid phosphatase band 5b] and bone formation (osteocalcin and bone-specific alkaline phosphatase. Ten adult patients with T-score < −2.5 SD or Z-score < −2 and/or increased risk of fracture according to FRAX model were included. All received 1,000 mg/day calcium carbonate with 800 IU/d cholecalciferol. Males with haemophilia A (n=7) or B (n=3) (mean age 43.5 ± 13.5 years) were studied. Ibandronate resulted in an increase in lumbar BMD (from 0.886 ± 0.169 to 0.927 ± 0.176 g/cm2, 4.7%, p=0.004). No change in BMD of total hip (from 0.717 ± 0.128 to 0.729 ± 0.153 g/cm2, p=0.963) or femoral neck (0.741 ± 0.135 to 0.761 ± 0.146 g/cm2, p=0.952) was noticed. Ibandronate led to a decrease in sCTX (from 0.520 ± 0.243 to 0.347 ± 0.230 ng/ml, −29.9%, p=0.042). No change was observed in other BTM. Ibandronate was generally well-tolerated. In conclusion, ibandronate significantly improved BMD in lumbar spine and reduced bone resorption in adults with haemophilia at increased risk of fracture. Its effect on hip BMD and bone formation markers was not significant.
Increased expression of cell adhesion molecule receptors on monocyte subsets in ischaemic heart failure
Authors: Wrigley Benjamin , Tapp Luke , Shantsila Eduard , Gregory Lip 
Published: June 2013

SummaryThe objective of this study was to evaluate the expression of cell adhesion molecule (CAM) receptors (integrins) on monocyte subsets in heart failure (HF) and examine their prognostic implication. Increased levels of soluble CAMs have been observed in patients with HF, but the precise mechanism of monocyte adhesion to the vascular endothelium remains unknown. Patients with acute HF (AHF, n=51) were compared to those with stable HF (SHF, n=42) and stable coronary artery disease (CAD, n=44) without HF. Expression of integrins-receptors to intercellular adhesion molecule-1 (ICAM-1R) and vascular CAM-1 (VCAM-1R) on monocyte subsets was assessed by flow cytometry. Monocyte subsets were defined as CD14++CD16–CCR2+ (‘classical’, Mon1), CD14++CD16+CCR2+ (‘intermediate’, Mon2), and CD14+CD16++CCR2– (‘non-classical’, Mon3). Compared to patients with SHF, those with AHF had significantly higher expression of ICAM-1R on Mon2 (p=0.01). Compared to those with stable CAD, patients with SHF had a significantly higher expression of ICAM-1R on Mon2 (p=0.025). Compared to SHF, patients with AHF had a similar expression of VCAM-1R on both Mon1 and Mon3 but significantly higher expression on Mon2 (p=0.019). There were no significant differences between SHF and CAD in monocyte expression of VCAM-1R. In multivariate Cox regression analysis, VCAM-1R expression on Mon2 was associated with adverse clinical outcome (death or rehospitalisation) in AHF [HR 1.07 (1.01–1.14), p=0.029]. In conclusion, HF is associated with increased monocyte expression of integrins-receptors to both ICAM-1 and VCAM-1, being particularly linked to Mon2 subset. Expression of VCAM-1R on Mon2 may have prognostic value in patients with AHF.
Pathophysiological role of neutrophils in acute myocardial infarction
Authors: Carbone Federico , Nencioni Alessio , Mach François , Vuilleumier Nicolas , Montecucco Fabrizio 
Published: June 2013

SummaryThe pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix-degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical models with pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post-ischaemic outcomes.