The Dynamical Cluster Approximation: Non-Local Dynamics of Correlated Electron Systems

We recently introduced the dynamical cluster approximation(DCA), a new technique that includes short-ranged dynamical correlations in addition to the local dynamics of the dynamical mean field approximation while preserving causality. The technique is based on an iterative self-consistency scheme on a finite size periodic cluster. The dynamical mean field approximation (exact result) is obtained by taking the cluster to a single site (the thermodynamic limit). Here, we provide details of our method, explicitly show that it is causal, systematic, $\Phi$-derivable, and that it becomes conserving as the cluster size increases. We demonstrate the DCA by applying it to a Quantum Monte Carlo and Exact Enumeration study of the two-dimensional Falicov-Kimball model. The resulting spectral functions preserve causality, and the spectra and the CDW transition temperature converge quickly and systematically to the thermodynamic limit as the cluster size increases.Comment: 19 pages, 13 postscript figures, revte

Determining atmospheric electric fields using MGMR3D

Cosmic-ray particles impinging on the atmosphere induce high-energy particle cascades in air, an Extensive Air Shower (EAS), emitting coherent radio emission. This emission is affected by the presence of strong electric fields during thunderstorm conditions. To reconstruct the atmospheric electric field from the measured radio footprint of the EAS we use an analytic model for the calculation of the radio emission, MGMR3D. In this work we make an extensive comparison between the results of a microscopic model for radio emission, CoREAS, to obtain an improved parametrization for MGMR3D in the presence of atmospheric electric fields, as well as confidence intervals. The approach to extract the electric field structure is applied successfully to an event with a complicated radio footprint measured by LOFAR during thunderstorm conditions. This shows that, with the improved parametrization, MGMR3D can be used to extract the structure of the atmospheric electric field.Comment: The paper is accepted for publication in Physical Review

A Machine Learning Approach to Measure and Monitor Physical Activity in Children to Help Fight Overweight and Obesity

Physical Activity is important for maintaining healthy lifestyles. Recommendations for physical activity levels are issued by most governments as part of public health measures. As such, reliable measurement of physical activity for regulatory purposes is vital. This has lead research to explore standards for achieving this using wearable technology and artificial neural networks that produce classifications for specific physical activity events. Applied from a very early age, the ubiquitous capture of physical activity data using mobile and wearable technology may help us to understand how we can combat childhood obesity and the impact that this has in later life. A supervised machine learning approach is adopted in this paper that utilizes data obtained from accelerometer sensors worn by children in free-living environments. The paper presents a set of activities and features suitable for measuring physical activity and evaluates the use of a Multilayer Perceptron neural network to classify physical activities by activity type. A rigorous reproducible data science methodology is presented for subsequent use in physical activity research. Our results show that it was possible to obtain an overall accuracy of 96 % with 95 % for sensitivity, 99 % for specificity and a kappa value of 94 % when three and four feature combinations were used

Assessing the role of tumour-associated macrophage subsets in breast cancer subtypes using digital image analysis

Purpose: The number of M1-like and M2-like tumour-associated macrophages (TAMs) and their ratio can play a role in breast cancer development and progression. Early clinical trials using macrophage targeting compounds are currently ongoing. However, the most optimal detection method of M1-like and M2-like macrophage subsets and their clinical relevance in breast cancer is still unclear. We aimed to optimize the assessment of TAM subsets in different breast cancer subtypes, and therefore related TAM subset numbers and ratio to clinicopathological characteristics and clinical outcome. Methods: Tissue microarrays of 347 consecutive primary Luminal-A, Luminal-B, HER2-positive and triple-negative tumours of patients with early-stage breast cancer were serially sectioned and immunohistochemically stained for the pan-macrophage marker CD68 and the M2-like macrophage markers CD163, CSF-1R and CD206. TAM numbers were quantified using a digital image analysis algorithm. M1-like macrophage numbers were calculated by subtracting M2-like TAM numbers from the total TAM number. Results: M2-like markers CD163 and CSF-1R showed a moderate positive association with each other and with CD68 (r ≥ 0.47), but only weakly with CD206 (r ≤ 0.06). CD68 + , CD163 + and CSF-1R + macrophages correlated with tumour grade in Luminal-B tumours (P < 0.001). Total or subset TAM numbers did not correlate with disease outcome in any breast cancer subtype. Conclusion: In conclusion, macrophages and their subsets can be detected by means of a panel of TAM markers and are related to unfavourable clinicopathological characteristics in Luminal-B breast cancer. However, their impact on outcome remains unclear. Preferably, this should be determined in prospective series

Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model

PURPOSE: The reoperation rate for breast-conserving surgery is as high as 15-30% due to residual tumor in the surgical cavity after surgery. In vivo tumor-targeted optical molecular imaging may serve as a red-flag technique to improve intraoperative surgical margin assessment and to reduce reoperation rates. Cysteine cathepsins are overexpressed in most solid tumor types, including breast cancer. We developed a cathepsin-targeted, quenched fluorescent activity-based probe, VGT-309, and evaluated whether it could be used for tumor detection and image-guided surgery in syngeneic tumor-bearing mice. METHODS: Binding specificity of the developed probe was evaluated in vitro. Next, fluorescent imaging in BALB/c mice bearing a murine breast tumor was performed at different time points after VGT-309 administration. Biodistribution of VGT-309 after 24 h in tumor-bearing mice was compared to control mice. Image-guided surgery was performed at multiple time points tumors with different clinical fluorescent camera systems and followed by ex vivo analysis. RESULTS: The probe was specifically activated by cathepsins X, B/L, and S. Fluorescent imaging revealed an increased tumor-to-background contrast over time up to 15.1 24 h post probe injection. In addition, VGT-309 delineated tumor tissue during image-guided surgery with different optical fluorescent imaging camera systems. CONCLUSION: These results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques

Considering the biology of late recurrences in selecting patients for extended endocrine therapy in breast cancer

Extended endocrine therapy can reduce recurrences occurring more than 5 years after diagnosis (late recurrences) in estrogen receptor (ER)-positive breast cancer. Given the side effects of endocrine therapy, optimal patient selection for extended treatment is crucial. Enhanced understanding of late recurrence biology could optimize patient selection in this setting. We therefore summarized the current knowledge of late recurrence biology, clinical trials on extended endocrine therapy, and tools for predicting late recurrence and benefit from treatment extension. Extending 5 years of tamoxifen therapy with 5 years of tamoxifen or an aromatase inhibitor (AI) reduces late recurrence risk by 2-5%, but results of extending AI-based therapy are inconsistent. Although several clinicopathological parameters and multigene assays are prognostic for late recurrence, selection tools predicting benefit from extended endocrine therapy are sparse. Therefore, we additionally performed a pooled analysis using 2231 mRNA profiles of patients with ER-positive/human epidermal growth factor receptor 2 negative breast cancer. Gene Set Enrichment Analysis was applied on genes ranked according to their association with early and late recurrence risk. Higher expression of estrogen-responsive genes was associated with a high recurrence risk beyond 5 years after diagnosis when patients had received no systemic therapy. Although 5 years of endocrine therapy reduced this risk, this effect disappeared after treatment cessation. This suggests that late recurrences of tumors with high expression of estrogen-responsive genes are likely ER-driven. Long-term intervention in this pathway by means of extended endocrine therapy might reduce late recurrences in patients with tumors showing high expression of estrogen-responsive genes

Proteomics of Human Dendritic Cell Subsets Reveals Subset-Specific Surface Markers and Differential Inflammasome Function.

Dendritic cells (DCs) play a key role in orchestrating adaptive immune responses. In human blood, three distinct subsets exist: plasmacytoid DCs (pDCs) and BDCA3+ and CD1c+ myeloid DCs. In addition, a DC-like CD16+ monocyte has been reported. Although RNA-expression profiles have been previously compared, protein expression data may provide a different picture. Here, we exploited label-free quantitative mass spectrometry to compare and identify differences in primary human DC subset proteins. Moreover, we integrated these proteomic data with existing mRNA data to derive robust cell-specific expression signatures with more than 400 differentially expressed proteins between subsets, forming a solid basis for investigation of subset-specific functions. We illustrated this by extracting subset identification markers and by demonstrating that pDCs lack caspase-1 and only express low levels of other inflammasome-related proteins. In accordance, pDCs were incapable of interleukin (IL)-1β secretion in response to ATP

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

Background Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival. Methods From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001). Conclusions HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future

PLAYgrounds: Effect of a PE playground program in primary schools on PA levels during recess in 6 to 12 year old children. Design of a prospective controlled trial

Background The relative number of children meeting the minimal required dose of daily physical activity remains execrably low. It has been estimated that in 2015 one out of five children will be overweight. Therefore, low levels of physical activity during early childhood may compromise the current and future health and well-being of the population, and promoting physical activity in younger children is a major public health priority. This study is to gain insight into effects of a Physical Education based playground program on the PA levels during recess in primary school children aged 6-12. Methods/design The effectiveness of the intervention program will be evaluated using a prospective controlled trial design in which schools will be matched, with a follow-up of one school year. The research population will consist of 6-12 year old primary school children. The intervention program will be aimed at improving physical activity levels and will consist of a multi-component alteration of the schools' playground. In addition, playground usage will be increased through altered time management of recess times, as well as a modification of the Physical Education content. Discussion The effects of the intervention on physical activity levels during recess (primary outcome measure), overall daily physical activity and changes in physical fitness (secondary outcome measures) will be assessed. Results of this study could possibly lead to changes in the current playground system of primary schools and provide structured health promotion for future public health. Trial registration Netherlands Trial Register (NTR): NTR238

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone