Evaluating the evidence for targeting FOXO3a in breast cancer:a systematic review

Background: Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics. Methods: Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment. Results: Increased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells. Discussion: FOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation

Tunable Semiconducting Polymer Nanoparticles with INDT-Based Conjugated Polymers for Photoacoustic Molecular Imaging.

Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

Operational Significance of Discord Consumption: Theory and Experiment

Coherent interactions that generate negligible entanglement can still exhibit unique quantum behaviour. This observation has motivated a search beyond entanglement for a complete description of all quantum correlations. Quantum discord is a promising candidate. Here, we demonstrate that under certain measurement constraints, discord between bipartite systems can be consumed to encode information that can only be accessed by coherent quantum interactions. The inability to access this information by any other means allows us to use discord to directly quantify this `quantum advantage'. We experimentally encode information within the discordant correlations of two separable Gaussian states. The amount of extra information recovered by coherent interaction is quantified and directly linked with the discord consumed during encoding. No entanglement exists at any point of this experiment. Thus we introduce and demonstrate an operational method to use discord as a physical resource.Comment: 10 pages, 3 figures, updated with Nature Physics Reference, simplified proof in Appendi

Contributions of scale: What we stand to gain from Indigenous and local inclusion in climate-health monitoring and surveillance systems

Understanding how climate change will affect global health is a defining challenge this century. This is predicated, however, on our ability to combine climate and health data to investigate the ways in which variations in climate, weather, and health outcomes interact. There is growing evidence to support the value of place- and community-based monitoring and surveillance efforts, which can contribute to improving both the quality and equity of data collection needed to investigate and understand the impacts of climate change on health. The inclusion of multiple and diverse knowledge systems in climate-health surveillance presents many benefits, as well as challenges. We conducted a systematic review, synthesis, and confidence assessment of the published literature on integrated monitoring and surveillance systems for climate change and public health. We examined the inclusion of diverse knowledge systems in climate-health literature, focusing on: 1) analytical framing of integrated monitoring and surveillance system processes 2) key contributions of Indigenous knowledge and local knowledge systems to integrated monitoring and surveillance systems processes; and 3) patterns of inclusion within these processes. In total, 24 studies met the inclusion criteria and were included for data extraction, appraisal, and analysis. Our findings indicate that the inclusion of diverse knowledge systems contributes to integrated climate-health monitoring and surveillance systems across multiple processes of detection, attribution, and action. These contributions include: the definition of meaningful problems; the collection of more responsive data; the reduction of selection and source biases; the processing and interpretation of more comprehensive datasets; the reduction of scale dependent biases; the development of multi-scale policy; long-term future planning; immediate decision making and prioritization of key issues; as well as creating effective knowledge-information-action pathways. The value of our findings and this review is to demonstrate how neither scientific, Indigenous, nor local knowledge systems alone will be able to contribute the breadth and depth of information necessary to detect, attribute, and inform action along these pathways of climate-health impact. Rather, it is the divergence or discordance between the methodologies and evidences of different knowledge systems that can contribute uniquely to this understanding. We critically discuss the possibility of what we, mainly local communities and experts, stand to lose if these processes of inclusion are not equitable. We explore how to shift the existing patterns of inclusion into balance by ensuring the equity of contributions and justice of inclusion in these integrated monitoring and surveillance system processes

Detection of subtelomere imbalance using MLPA: validation, development of an analysis protocol, and application in a diagnostic centre

BACKGROUND: Commercial MLPA kits (MRC-Holland) are available for detecting imbalance at the subtelomere regions of chromosomes; each kit consists of one probe for each subtelomere. METHODS: For validation of the kits, 208 patients were tested, of which 128 were known to be abnormal, corresponding to 8528 genomic regions overall. Validation samples included those with trisomy 13, 18 and 21, microscopically visible terminal deletions and duplications, sex chromosome abnormalities and submicroscopic abnormalities identified by multiprobe FISH. A robust and sensitive analysis system was developed to allow accurate interpretation of single probe results, which is essential as breakpoints may occur between MLPA probes. RESULTS: The validation results showed that MLPA is a highly efficient technique for medium-throughput screening for subtelomere imbalance, with 95% confidence intervals for positive and negative predictive accuracies of 0.951-0.996 and 0.9996-1 respectively. A diagnostic testing strategy was established for subtelomere MLPA and any subsequent follow-up tests that may be required. The efficacy of this approach was demonstrated during 15 months of diagnostic testing when 455 patients were tested and 27 (5.9%) abnormal cases were detected. CONCLUSION: The development of a robust, medium-throughput analysis system for the interpretation of results from subtelomere assays will be of benefit to other Centres wishing to implement such an MLPA-based service

Does proactive personality matter in leadership transitions? Effects of proactive personality on new leader identification and responses to new leaders and their change agendas

Despite the growing frequency of leadership transitions and their significant impact on team and organizational performance, little research has examined why and how teams develop an identification with a new leader or their subsequent receptiveness to the new leader’s change initiatives. Drawing from the contrast and congruence effects and the theoretical perspectives of leader identification, this study empirically tests a model in which the congruence of new leaders’ and their teams’ proactive personalities foster new leader identification, as well as the team’s behavioral responses to the new leader’s change agenda. This effect is strongest when the new leader’s proactive personality is higher than that of the former leader’s proactive personality (positive contrast). Our findings of a four-wave “before-and-after” transition survey of 155 hotel employees and 51 new leaders, achieved through polynomial regression analyses, proved very insightful. Essentially, we found that the congruence between a new leader’s and his/her team’s proactive personalities and the positive contrast between a former leader’s and the new leader’s proactive personalities enhanced new leader identification and the team’s shared identification with the new leader’s change agenda, and, thereby led the team to exhibit more behavioral engagement with, and voice behavior about, the new leader’s change agenda

Adult-onset hyperinsulinaemic hypoglycaemia in clinical practice: diagnosis, aetiology and management.

OBJECTIVE: In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period. DESIGN: Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed. RESULTS: Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I-IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 (YY1) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden. CONCLUSION: Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease