Impaired Functions of Peripheral Blood Monocyte Subpopulations in Aged Humans

Aging is associated with increased susceptibility to microbial infections, and monocytes play an important role in microbial defense. In this study, we have identified and compared four subpopulations of monocytes (CD14++(high)CD16−, CD14+(low)CD16−, CD14++(high)CD16+, and CD14+(low)CD16+) in the peripheral blood of young and aged subjects with regard to their numbers, cytokine production, TLR expression, and phosphorylation of ERK1/2 in response to pam3Cys a TLR-1/2 ligand. Proportions and numbers of CD14++(high)CD16+ and CD14+(low)CD16+ monocytes were significantly increased, whereas proportions of CD14+(low)CD16− monocytes were decreased in aged subjects as compared to young subjects. In aged subjects, IL-6 production by all four subsets of monocytes was significantly decreased, whereas TNF-α production was decreased in monocyte subsets, except the CD14+(low)CD16− subset. A significantly reduced expression of TLR1 was observed in CD14++(high)CD16+ and CD14+(low)CD16+ monocyte subsets in aged subjects. Furthermore, following pam3Cys stimulation, ERK1/2 phosphorylation was significantly lower in CD14+(low)CD16+, CD14++(high)CD16+, and CD14+(low)CD16− subsets of monocytes from aged subjects. This is the first study of four subpopulations of monocytes in aging, which demonstrates that their functions are differentially impaired with regard to the production of cytokines, expression of TLR, and signaling via the ERK–MAPK pathway. Finally, changes in the number of monocyte subsets, and impairment of TLR1 expression, TNF-α production, and EK1/2 phosphorylation was more consistent in CD16+ monocyte subsets regardless of expression of CD14high or CD14+low, therefore highlighting the significance of further subdivision of monocytes into four subpopulations

CD16 Expression on Monocytes in Healthy Individuals but Not Schistosome-Infected Patients Is Positively Associated with Levels of Parasite-Specific IgG and IgG1

Human IgG1 antibody responses are associated with protection against Schistosoma haematobium infection and are now a target for schistosome vaccine development. This study aimed to investigate the relationship between total IgG and the IgG subclasses and the monocyte IgG receptor, known as FcγRIIIa or CD16, in schistosome exposed people. Systemic levels of schistosome-specific anti-adult worm total IgG and IgG subclass titres were measured by ELISA in 100 individuals from an S. haematobium endemic area in Zimbabwe and, using parametric statistical methods and regression analysis, related to the levels of CD16 expression on individuals' circulating monocytes, determined via flow cytometry. Monocyte CD16 expression rose with parasite-specific total IgG and IgG1 in healthy participants, but not in schistosome infected patients. Similar to parasite-specific IgG and IgG1, CD16 expression in healthy individuals is associated with protection against schistosome infection. This relationship indicates a mechanistic link between the innate and adaptive immune responses to helminth infection in protection against infection. Further understanding the elements of a protective immune response in schistosomiasis may aid in efforts to develop a protective vaccine against this disease.This work was supported by the World Health Organisation and the Wellcome Trust grant WT082028MA, the Thrasher Research Fund and the Medical Research Council grant LJA-544

The Determinants of Foreign Currency Hedging: Does Foreign Currency Debt Induce a Bias?

"In this paper we use UK data to present strong empirical evidence that explains the mixed results in previous studies with respect to the effect of financial distress on the demand for corporate hedging. We build on recent studies that have identified a strong link between foreign currency (FC) debt use and leverage. Given this relationship, we show that using leverage variables as proxies for financial distress and the failure to distinguish between FC debt users and non-users causes misleading inference. More specifically, when we partition our sample of FC hedgers into firms that use and do not use foreign debt, we show that leverage variables are significantly related to the FC hedging decision for firms that use FC debt either in isolation or in combination with FC derivatives but not for firms that only use FC derivatives. This suggests that FC debt users are influencing these results. However, we also find that other financial distress cost proxies with no obvious link to FC debt use are significant determinants in the corporate demand for FC hedging, including derivatives use." Copyright (c) 2007 The Authors Journal compilation (c) 2007 Blackwell Publishing Ltd.

A New Approach to Improving the Efficiency of FEL Oscillator Simulations

During the last year we have been benchmarking FEL oscillator simulation codes against the measured performance of the three Jefferson Lab oscillator FELs. While one might think that a full 4D simulation is de facto the best predictor of performance, the simulations are computationally intensive, even when analytical approximations to the electron bunch longitudinal distribution are used. In this presentation we compare the predictions of the 4D FEL interaction codes Genesis and Medusa, in combination with the optical code OPC, with those using a combination of the 2D & 3D versions of these codes, which can be run quickly on a single CPU core desktop computer

Correction to: High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer.

The original article [1] contains an error in Fig. 2 whereby Fig. 2D has mistakenly been omitted. Fig. 2 can be viewed in its entirety - including Fig. 2D - in this Correction article

High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer.

Backgroundα3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models.MethodsThe whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology.ResultsWe showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues.ConclusionLXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype

Comparative effectiveness of trimodal therapy versus radical cystectomy for localized muscle-invasive urothelial carcinoma of the bladder

INTRODUCTION & OBJECTIVES: The only randomized controlled trial comparing trimodal therapy (TMT) vs. radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB) failed to meet its accrual target. We sought to examine the comparative effectiveness of TMT vs. RC for muscle-invasive UCB in an observational cohort study. MATERIAL & METHODS: Within the National Cancer Data Base (2004-2011), we identified 12,843 individuals who received TMT or RC for definitive treatment of cN0M0 muscle-invasive UCB. Inverse probability of treatment weighting (IPTW) adjusted Kaplan-Meier and Cox regression analyses with timevarying covariate were used to compare overall survival (OS) of patients who received TMT vs. RC. Exploratory analyses according to patient characteristics were also performed. RESULTS: Overall, 1,257 (9.8%) and 11,586 (90.2%) patients received TMT and RC, respectively. IPTW-adjusted Kaplan-Meier curves showed that median OS was similar between TMT and RC groups (39.6 [95% CI, 33.7-45.5] vs. 43.0 [95% CI, 40.9-45.1] months; P=0.290; Figure 1). In IPTW-adjusted Cox regression analysis with time-varying covariate, TMT was associated with a significant adverse effect on OS after 25 months of follow-up (HR=1.37;95%CI=[1.16-1.59];P\u3c0.001). In exploratory analyses (Figure 2), there was no significant difference between TMT and RC with regard to long-term OS in individuals aged ≥70 (HR=1.21;95%CI=[0.83-1.60];P=0.225), of female gender (HR=1.28;95%CI=[0.83-1.74];P=0.170), with Charlson comorbidity index≥1 (HR=1.10;95%CI=[0.83-1.38];P=0.439) and/or ≥cT3 disease (HR=1.16; 95%CI=[0.80-1.52];P=0.338). CONCLUSIONS: We generally observed that TMT was associated with worse long-term OS compared to RC for muscle-invasive UCB. However, selected subgroups of patients may choose TMT over RC to avoid surgical toxicities with minimal impact on OS. (Figure Presented)

<i>In Vivo</i> Protein Dynamics on the Nanometer Length Scale and Nanosecond Time Scale

Selectively labeled GroEL protein was produced in living deuterated bacterial cells to enhance its neutron scattering signal above that of the intracellular milieu. Quasi-elastic neutron scattering shows that the in-cell diffusion coefficient of GroEL was (4.7 ± 0.3) × 10^–12 m²/s, a factor of 4 slower than its diffusion coefficient in buffer solution. Internal protein dynamics showed a relaxation time of (65 ± 6) ps, a factor of 2 slower compared to the protein in solution. Comparison to the literature suggests that the effective diffusivity of proteins depends on the length and time scale being probed. Retardation of in-cell diffusion compared to the buffer becomes more significant with the increasing probe length scale, suggesting that intracellular diffusion of biomolecules is nonuniform over the cellular volume. The approach outlined here enables investigation of protein dynamics within living cells to open up new lines of research using “in-cell neutron scattering” to study the dynamics of complex biomolecular systems