Quantitative photoacoustic tomography: experimental phantom studies

Photoacoustic tomography (PAT) is a promising non-invasive imaging modality exhibiting high resolution, good contrast and specificity to light-absorbing molecules (chromophores). One of the outstanding challenges the technique faces is that PAT images, though dependent on optical absorption, are not its direct representation because they are coloured by the unknown light fluence. Theoretical studies have succeeded in quantifying optical absorption and chromophore concentration by employing model-based inversions (MBI) that can deal with the non-linearity of the problem and the fluence-related distortion. However, experimental translation has been scarce. The aim was to perform quantitative PAT (qPAT) in a rigorous experimental phantom study to show that highly-resolved 3D estimation of chromophore distributions can be achieved. The first consideration was finding a tissue-relevant and stable matrix material and chromophores. Thermoplastic PVCP was fully assessed. Its stability, intrinsic optical properties, thermoelastic efficiency and low-frequency acoustic properties were suitable. The limitation was the lack of photostability of embedded pigments. Separately, we fully characterised aqueous solutions of sulphate salts and found them to be suitable chromophores for qPAT and potential surrogates for oxy- and deoxyhemoglobin. For a phantom made of sub-mm tubes filled with sulphate solutions in an intralipid-rich background, 3D high resolution estimates of chromophore concentrations were obtained through an efficient diffusion-approximation MBI. Uncertainties in optical inputs of the MBI were tackled by assessing in silico their effect on quantification accuracy and then mitigated in the designed experiment through careful measurements. A faithful representation of the multiwavelength photoacoustic tomography images was sought by employing broadband, near-omnidirectional and high-sensitivity sensors and a detection configuration and reconstruction that overcame the limited-view problem. Estimation of the chromophore ratio, analogous to the much sought-after blood oxygenation, gave a mean absolute error of 3.4 p.p., whilst normalised estimates of the two main chromophore distributions gave errors of 13.2% and 17.2%

GSK3-mediated raptor phosphorylation supports amino acid-dependent Q2 mTORC1-directed signalling

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser(859). We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation

The effect of loading direction on strain localisation in wire arc additively manufactured Ti–6Al–4V

Ti–6Al–4V microstructures produced by high deposition rate Wire Arc Additive Manufacturing (WAAM) can be both heterogeneous and anisotropic. Key features of the as-built microstructures include; large columnar ß grains, an α transformation texture inherited from the β solidification texture, grain boundary (GB) α colonies, and Heat Affected Zone (HAZ) banding. The effect of this heterogeneity on the local strain distribution has been investigated using Digital Image Correlation (DIC) in samples loaded in tension; parallel (WD), perpendicular (ND) and at 45° (45ND) to the deposited layers. Full-field surface strain maps were correlated to the underlying local texture. It is shown that loading perpendicular to the columnar β grains leads to a diffuse heterogeneous deformation distribution, due to the presence of regions containing hard, and soft, α microtextures within different parent β grains. The ‘soft’ regions correlated to multi-variant α colonies that did not contain a hard α variant unfavourably orientated for basal or prismatic slip. Far more severe strain localisation was seen in 45° ND loading at ‘soft’ β grain boundaries, where single variant α GB colonies favourably orientated for slip had developed during transformation. In comparison, when loaded parallel to the columnar ß grains, the strain distribution was relatively homogeneous and the HAZ bands did not show any obvious influence on strain localisation at the deposit layer-scale. However, when using high-resolution DIC, as well as more intense shear bands being resolved at the β grain boundaries during 45° ND loading, microscale strain localisation was observed in HAZ bands below the yield point within the thin white-etching α colony layer

SRC inhibition prevents P-cadherin mediated signaling and function in basallike breast cancer cells

© The Author(s). 2018. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior. METHODS: P-cadherin and SRC expression was evaluated in a series of invasive Breast Cancer and contingency tables and chi-square tests were performed. Cell-cell adhesion measurements were performed by Atomic Force Microscopy, where frequency histograms and Gaussian curves were applied. 2D and 3D cell migration and invasion, proteases secretion and self-renew potential were evaluated in vitro. Student's t-tests were used to determine statistically significant differences. The cadherin/catenin complex interactions were evaluated by in situ proximity-ligation assay, and statistically significant results were determined by using Mann-Whitney test with a Bonferroni correction. In vivo xenograft mouse models were used to evaluate the impact of dasatinib on tumor growth and survival. ANOVA test was used to evaluate the differences in tumor size, considering a confidence interval of 95%. Survival curves were estimated by the Kaplan-Meier's method, using the log-rank test to assess significant differences for mice overall survival. RESULTS: Our data demonstrated that P-cadherin overexpression is significantly associated with SRC activation in breast cancer cells, which was also validated in a large series of primary tumor samples. SRC activity suppression with dasatinib significantly prevented the in vitro functional effects of P-cadherin overexpressing cells, as well as their in vivo tumorigenic and metastatic ability, by increasing mice overall survival. Mechanistically, SRC inhibition affects P-cadherin downstream signaling, rescues the E-cadherin/p120-catenin complex to the cell membrane, recovering cell-cell adhesion function. CONCLUSIONS: In conclusion our findings show that targeting P-cadherin/SRC signaling and functional activity may open novel therapeutic opportunities for highly aggressive and poor prognostic basal-like breast cancer.This work was funded by Laço Grant 2014, by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 – Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by FCT - Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior under the projects PTDC/SAU-GMG/120049/2010-FCOMP-01-0124-FEDER-021209, PEst-C/SAU/LA0003/2013, NORTE-01-0145-FEDER-000029 and POCI-01-0145-FEDER-016390. FCT funded the research grants of ASR (SFRH/BPD/75705/2011), ARN (SFRH/BD/100380/2014), BS (SFRH/BPD/104208/2014), AFV (SFRH/BPD/90303/2012), as well as JP with Programa IFCT 2013 (FCT Investigator). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274)info:eu-repo/semantics/publishedVersio

Absorbance based light emitting diode optical sensors and sensing devices

The ever increasing demand for in situ monitoring of health, environment and security has created a need for reliable, miniaturised sensing devices. To achieve this, appropriate analytical devices are required that possess operating characteristics of reliability, low power consumption, low cost, autonomous operation capability and compatibility with wireless communications systems. The use of light emitting diodes (LEDs) as light sources is one strategy, which has been successfully applied in chemical sensing. This paper summarises the development and advancement of LED based chemical sensors and sensing devices in terms of their configuration and application, with the focus on transmittance and reflectance absorptiometric measurements

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales

Healthy Teens @ School: Evaluating and disseminating transdiagnostic preventive interventions for eating disorders and obesity for adolescents in school settings

Background The worldwide prevalence of overweight and obesity is at alarming levels. Nearly one in three children in Europe is overweight or obese. Disordered eating and body image concerns are equally widespread and increase risk for more chronic and severe weight-related problems. Research has shown that online interventions that address both healthy weight regulation and body image can reduce risk for eating disorders and obesity simultaneously and are feasible to implement in school settings. To date, evaluation and dissemination of such programs in Europe is scant. Methods The Healthy Teens @ School study is a multi-country cluster-randomized controlled trial (RCT) comparing the effectiveness of an unguided, online, multi-level intervention for promoting a healthy lifestyle and reducing problematic eating behavior, eating disorder and obesity risk among students aged 14 to 19 years with control condition. As part of the Horizon 2020 funded project ICare (GA No. 634757) the trial is conducted in Austria and Spain. Cluster randomization by school is used. The intervention is an adapted version of an evidence-based program developed in the USA (StayingFit). Participants of the intervention group are assigned to one of two possible program tracks based on the results of the initial online-assessment: Overweight adolescents are assigned to the “Weight Management” track emphasizing balanced eating and exercise for weight maintenance, and all other individuals are assigned to the “Healthy Habits” track which aims at promoting healthy habits related to e.g., nutrition, physical activity, sleep. The participants of both tracks work on ten modules (one 20–30 min module per week) during school hours and/or at home. Assessments are conducted at pre- and post-intervention, and at 6- and 12-months after baseline assessment. The primary outcome is intuitive eating, secondary outcomes are eating disorder symptomatology, body image concerns, body mass index, food intake, physical activity, self-esteem, stress coping, depression, and anxiety. Following the initial assessment, individuals in the control group do not have access to the prevention program but continue as normal and are only prompted to the assessments at all time points. At the end of the 12-month study they will get access to the program. Discussion The results from this study will add to the understanding of how to address eating and weight related problems in adolescents and will shed light on the feasibility of implementing online prevention programs in school routine in Austria and Spain. As part of the larger ICare project this RCT will determine how an adapted version of StayingFit is disseminated within Europe

Modelling approaches for mixed forests dynamics prognosis. Research gaps and opportunities

Aim of study: Modelling of forest growth and dynamics has focused mainly on pure stands. Mixed-forest management lacks systematic procedures to forecast the impact of silvicultural actions. The main objective of the present work is to review current knowledge and forest model developments that can be applied to mixed forests.Material and methods: Primary research literature was reviewed to determine the state of the art for modelling tree species mixtures, focusing mainly on temperate forests.Main results: The essential principles for predicting stand growth in mixed forests were identified. Forest model applicability in mixtures was analysed. Input data, main model components, output and viewers were presented. Finally, model evaluation procedures and some of the main model platforms were described.Research highlights: Responses to environmental changes and management activities in mixed forests can differ from pure stands. For greater insight into mixed-forest dynamics and ecology, forest scientists and practitioners need new theoretical frameworks, different approaches and innovative solutions for sustainable forest management in the context of environmental and social changes.Keywords: dynamics, ecology, growth, yield, empirical, classification

Reimbursed medication adherence enhancing interventions in 12 european countries:Current state of the art and future challenges

Background: Medication non-adherence jeopardises the effectiveness of chronic therapies and negatively affects financial sustainability of healthcare systems. Available medication adherence-enhancing interventions (MAEIs) are utilised infrequently, and even more rarely reimbursed. The aim of this paper was to review reimbursed MAEIs across selected European countries. Methods: Data on reimbursed MAEIs were collected from European countries at the ENABLE Cost Action expert meeting in September 2021. The identified MAEIs were analysed and clustered according to their characteristics, direct vs. indirect relation to adherence, and the targeted adherence phase. Results: Out of 12 contributing countries, 10 reported reimbursed MAEIs, 28 in total, of which 20 were identified as MAEIs targeting adherence directly. Reimbursed MAEIs were most often performed by either doctors (n = 6), nurses (n = 6), or pharmacists (n = 3). The most common types of MAEIs were education (n = 6), medication regimen management (n = 5), and adherence monitoring feedback (n = 4). Only seven reimbursed MAEIs were technology-mediated, whereas 11 addressed two interlinked phases of medication adherence, i.e., implementation and persistence. Conclusion: Our review highlights the scarcity of reimbursed MAEIs across the selected European countries, and calls for their more frequent use and reimbursement