T cells but not NK cells are associated with a favourable outcome for resected colorectal liver metastases

T cells, but not NK cells, are preferentially recruited to colorectal liver metastases. NK cells within colorectal metastases have an intrahepatic and potentially tolerogenic, rather than a peripheral, phenotype. Similar to primary tumours, the magnitude of the T cell infiltrate in colorectal metastases is positively associated with surviva

Functional brain imaging studies of youth depression: A systematic review

AbstractBackgroundThere is growing interest in understanding the neurobiology of major depressive disorder (MDD) in youth, particularly in the context of neuroimaging studies. This systematic review provides a timely comprehensive account of the available functional magnetic resonance imaging (fMRI) literature in youth MDD.MethodsA literature search was conducted using PubMED, PsycINFO and Science Direct databases, to identify fMRI studies in younger and older youth with MDD, spanning 13–18 and 19–25years of age, respectively.ResultsTwenty-eight studies focusing on 5 functional imaging domains were identified, namely emotion processing, cognitive control, affective cognition, reward processing and resting-state functional connectivity. Elevated activity in “extended medial network” regions including the anterior cingulate, ventromedial and orbitofrontal cortices, as well as the amygdala was most consistently implicated across these five domains. For the most part, findings in younger adolescents did not differ from those in older youth; however a general comparison of findings in both groups compared to adults indicated differences in the domains of cognitive control and affective cognition.ConclusionsYouth MDD is characterized by abnormal activations in ventromedial frontal regions, the anterior cingulate and amygdala, which are broadly consistent with the implicated role of medial network regions in the pathophysiology of depression. Future longitudinal studies examining the effects of neurodevelopmental changes and pubertal maturation on brain systems implicated in youth MDD will provide a more comprehensive neurobiological model of youth depression

Lickometry: A novel and sensitive method for assessing functional deficits in rats after stroke

The need for sensitive, easy to administer assessments of long-term functional deficits is crucial in pre-clinical stroke research. In the present study, we introduce lickometry (lick microstructure analysis) as a precise method to assess sensorimotor deficits up to 40 days after middle cerebral artery occlusion in rats. Impairments in drinking efficiency compared to controls, and a compensatory increase in the number of drinking clusters were observed. This highlights the utility of this easy to administer task in assessing subtle, long-term deficits, which could be likened to oral deficits in patients

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor

The Notch receptor signalling pathway plays an important role in breast development, regulation of stem cells and differentiation of luminal progenitor cells. The pathway also plays a significant role in breast cancer development and progression. However, which of the Notch receptors that regulate breast cancer stem cells is unknown. We assessed stem cell activity in breast cancer cell lines and nine primary human tumour samples. In vitro and in vivo breast cancer stem cell activity was enriched using selection of anoikis resistant cells or cells expressing the membrane phenotype ESA(+)/CD44(+)/CD24(low). We compared the activation of Notch receptors in the breast cancer stem cell-enriched population to luminally differentiated cells and studied the effects of pathway inhibition, both in vitro and in vivo. We find that Notch4 signalling activity is 8-fold higher in the breast cancer stem cell-enriched cells compared to the differentiated cells while Notch1 activation is 4-fold lower in breast cancer stem cells. Furthermore, pharmacological or genetic Notch inhibition markedly reduced breast cancer stem cell activity in vitro, and significantly reduced tumour formation in vivo. Importantly, cells with Notch4 knock-down using specific shRNA formed fewer mammosphere colonies than Notch1 knock-down cells. In vivo Notch1 knock-down, like pharmacological inhibition, reduced the number and size of tumours but Notch4 knock-down suppressed tumour initiation completely. Our findings indicate that Notch4-targeted therapies will be more effective than targeting Notch1 in suppressing breast cancer recurrence initiated by breast cancer stem cells

Protocol for a mixed-methods investigation of quality improvement in early childhood education and care in Australia

International recognition of the early years as a crucial foundational period has led to the design and implementation of quality rating and improvement systems (QRIS) that define, communicate, and monitor the components of quality in early childhood education and care (ECEC). The aim of these policies is to achieve effective quality assurance and improvement through a system-oriented approach to assessment and evaluation. Informed by ecological systems theory, this paper outlines a three-phase, mixed-methods design for researching a national sample of child care centres that showed overall improvement on the Australian National Quality Standard (NQS) assessment and rating (A&R) criteria. The study samples are drawn from a national dataset of centre-based child care services with two or more A&R rounds and an initial rating of Working Towards NQS (N = 1,935). The results of this study will provide insights into the macro-, exo-, meso- and micro-systems level factors and strategies that support quality in ECEC services

MRI and gravimetric studies of hydrology in drip irrigated heaps and its effect on the propagation of bioleaching microorganisms

Heap bioleaching performance is dependent on the contacting of the leach solution with the ore bed, hence on the system hydrodynamics. In this study two experimental setups were used to examine hydrodynamics associated with irrigation from a single drip emitter, one of the most common methods of heap irrigation. A specialist magnetic resonance imaging (MRI) method which is insensitive to the metal content of the ore was used to examine the liquid flow into an ore bed in the immediate vicinity of an irrigation point. The distribution of liquid in, microbial colonisation of and mineral recovery from a bioleach of a large scale 132 kg “ore slice” were subsequently monitored using sample ports positioned along the breadth and height of the reactor. In both systems the lateral movement of the liquid increased with bed depth, though preferential flow was evident. The majority of the liquid flow was in the region directly below the irrigation point and almost no liquid exchange occurred in the areas of lowest liquid content at the upper corners of the bed in which fluid exchange was driven by capillary action. The MRI studies revealed that the liquid distribution was unchanging following an initial settling of the ore bed and that, at steady state, the majority (~60%) of the liquid flowed directly into established large channels. The limited lateral movement of the liquid had a significant impact on the local leaching efficiencies and microbial colonisation of the ore with cell concentrations in the regions of lowest liquid content lying below the detection limit. Hence poor lateral liquid distribution with drip irrigation, and the associated impact on colonisation was identified as a significant disadvantage of this irrigation approach. Further, the need to optimise fluid exchange throughout the ore bed was identified as key for optimisation of leaching performance

The role of digital technologies in supporting quality improvement in Australian early childhood education and care settings

This national study explored the role of digital technologies in early childhood education and care settings and whether they could contribute to quality improvement as reported by educators and assessors of quality in Australia. In this paper, data from Stage 2 of the Quality Improvement Research Project were used, which comprised 60 Quality Improvement Plans from educators linked with 60 Assessment and Rating reports from the assessors who visited early childhood centres as part of the administration of the National Quality Standards by each of Australia’s State and Territory jurisdictions. Bronfenbrenner’s ecological systems theory (Bronfenbrenner, U. (1995).Developmental ecology through space and time: A future perspective. In P. Moen, G.H. Elder, Jr., & K. Lüscher (Eds.), Examining lives in context: Perspectives on the ecologyof human development (pp. 619 – 647). American Psychological Association. https://doi.org/10.1037/10176-018; Bronfenbrenner & Ceci, Bronfenbrenner and Ceci, Psychological Review 101:568 – 586, 1994) was adopted to facilitate a systemic and dynamic view on the use of digital technologies in these 60 ECEC settings. References (e.g. comments/ suggestions/ examples) made by the educators about the implementation of digital technologies were counted and thematically analysed. Results revealed the strong role new technologies (e.g. documentation and management platforms, tablets, apps, etc.) play in the majority of ECEC settings and especially in relation to three of the seven Quality Areas: Educational programme and practice (Quality Area 1); Collaborative partnerships with families and communities (Quality Area 6) and Governance and leadership (Quality Area 7). Future directions for research are suggested and implications for embracing a more holistic, integrated and broad view on the use of digital technologies are discussed

Mapping the leap: Differences in quality improvement in relation to assessment rating outcomes

Introduction: Australia’s National Quality Standard (NQS) outlines the criteria to assess the quality of early childhood services. A four-point rating scale: (i) Exceeding NQS; (ii) Meeting NQS; (iii) Working Toward NQS; and (iv) Significant Improvement Required is applied to services following a regular assessment and rating process. Settings rated as Working Toward are reassessed within 12 months. Most settings achieved a one-step improvement in this Time 2 reassessment, moving to a Meeting rating but some settings made a two-step improvement, moving to an Exceeding rating. The QIP is a key document used by authorities to assess the quality of a service. Methods: A grounded theory, data driven approach was taken to deepen understanding of quality rating improvements in long day care services in Australia of quality rating improvements by early childhood education and care [ECEC] services in Australia. This study, part of the second phase of a three phase study involved a document analysis of the Time 2 Quality Improvement Plans (QIPs) of a representative sample of Long Day Care (LDC) services (n = 60) from all Australian states and territories to determine what factors may have contributed to these different levels of improvement, with a focus on Quality Area 1 (QA1) (Educational programs and practices) and Quality Area 7 (QA7) (Governance and leadership). The study utilized the semantic analysis tool Leximancer 4.5. Leximancer 4.5 statistically analyses the semantic relationships between concepts in documents by measuring word proximity and correlation. The software creates visual maps of concepts and their connections to each other in texts. Concepts located near one another on the map are more likely to be contextually related. This tool is particularly useful when there are multiple, complex documents to analyze, reducing the potential biases that can arise from documents that use language with which these researchers are very familiar with. Results: The analysis found clear differences between the Time 2 QIPs of services who had made a two-step rating improvement and those who made a one-step improvement. Two-step (Exceeding NQS) category improvers for QA1 placed attention in their QIPs on improvement to the program and overall practice, with an orientation to the role of the educational leader. Two-step (Exceeding NQS) category improvers for QA7 seemed to be more oriented to a systemic view of the processes encompassed by QA7; how the management of the service and information supports the work of educators, with stronger links made between leadership roles (the manager and nominated supervisor) and the work of educators. Discussion: The QIPs demonstrated how the intentional and systemic processes in these quality areas related to practice, management, and leadership

The effect of chewing gum on physiological and self-rated measures of alertness and daytime sleepiness

The proposition that chewing gum can improve alertness was investigated via both physiological and self-rated measures. The Pupillographic Sleepiness Test (PST) provided a measure of pupillary unrest (PUI); a physiological index of daytime sleepiness. Chewing gum reduced the extent of sleepiness as measured by both PUI and self-rated sleepiness. Specifically, in comparison with sham chewing and no chewing controls, the chewing gum condition significantly limited the increase in pupillary unrest following the 11-minute PST within a darkened laboratory: a finding indicating moderation of the daytime sleepiness increase for the chewing gum condition. In addition, there was some evidence that chewing gum (relative to the no-chewing condition only) moderated the increase in a self-rated measure of sleepiness (Stanford Sleepiness Scale). However, there was no evidence that chewing gum moderated the decrease in self-rated alertness (Bond-Lader Visual Analogue Mood Scale). Although the precise mechanism underpinning the effect of chewing gum is unclear, the reduction in daytime sleepiness may be underpinned via heightened cerebral activity following the chewing of gum or the arousing effects of mint flavour