Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner

Population genetic structuring of methicillin-resistant Staphylococcus aureus clone EMRSA-15 within UK reflects patient referral patterns

Antibiotic resistance forms a serious threat to the health of hospitalised patients, rendering otherwise treatable bacterial infections potentially life-threatening. A thorough understanding of the mechanisms by which resistance spreads between patients in different hospitals is required in order to design effective control strategies. We measured the differences between bacterial populations of 52 hospitals in the United Kingdom and Ireland, using whole genome sequences from 1085 MRSA clonal complex 22 isolates collected between 1998 and 2012. The genetic differences between bacterial populations were compared with the number of transferred patients between hospitals and their regional structure. The MRSA populations within single hospitals, regions, and countries were genetically distinct from the rest of the bacterial population at each of these levels. Hospitals from the same patient referral regions showed more similar MRSA populations, as did hospitals sharing many patients. Furthermore, the bacterial population from different time-periods within the same hospital were generally more similar to each other than contemporaneous bacterial populations from different hospitals. We conclude that, while a large part of the dispersal and expansion of MRSA takes place among patients seeking care in single hospitals, inter-hospital spread of resistant bacteria is by no means a rare occurrence. Hospitals are exposed to constant introductions of MRSA on a number of levels: 1) most MRSA is received from hospitals that directly transfer large numbers of patients, while 2) fewer introductions happen between regions or 3) across national borders, reflecting lower numbers of transferred patients. A joint coordinated control effort between hospitals, is therefore paramount for the national control of MRSA, antibiotic-resistant bacteria, and other hospital-associated pathogens.This work was supported by grants from the UKCRC Translational Infection Research Initiative, and the Medical Research Council (Grant Number G1000803) with contributions to the Grant from the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research on behalf of the Department of Health, and the Chief Scientist Office of the Scottish Government Health Directorate (to SJP); and by Wellcome Trust grant number 098051 and 089472 awarded to the Wellcome Trust Sanger Institute and BGS respectively. MET is a Clinician Scientist Fellow, supported by the Academy of Medical Sciences and The Health Foundation, and by the NIHR Cambridge Biomedical Research Centre. We thank the British Society of Antimicrobial Chemotherapy (BSAC) bacteraemia resistance surveillance programme for supplying bacterial isolates

Long-Term Effects of Metacognitive Strategy Instruction on Student Academic Performance:A Meta-Analysis

Meta-analyses have shown the positive effects of strategy instruction on student performance; however, little meta-analytical research has been conducted on its long-term effects. We examined the long-term effects of 48 metacognitive strategy instruction interventions on student academic performance. The results show a very small increase of the effect at long-term compared with the posttest effects. The instruction effect at posttest increased from Hedges’ g = 0.50 to 0.63 at follow-up test. Moderator analyses showed that low SES students benefited the most at long-term. Furthermore, instructions including the cognitive strategy ‘rehearsal’ had lower long-term effects compared to interventions without this component. Other specific strategies (within categories metacognitive, cognitive, management, or motivational) did not moderate the overall positive long-term effect of metacognitive strategy instructions. Particular attributes of the intervention –subject domain, measurement instrument, duration, time between posttest and follow-up test, and cooperation – neither had an impact on the follow-up effect

Floffy: Designing an Outdoor Robot for Children

In our research we utilized the domain of entertainment robotics to educate children on the principles of environmental awareness by playful means outdoors. Our research revolved around the iterative design of Floffy: the environmental robot, which was essentially a playful toy robot that would respond positively to interaction that was beneficial for the environment and the child’s own well being and negatively to interaction or behaviour that was detrimental to the surroundings. We conducted an explorative, informal evaluation of Floffy with two small groups of children and they rated their experience with it positively. Our results show that there is potential in utilizing entertainment robots to educate children on serious and critical issues such as saving our environment and being sustainable

Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre

Background Study aimed to characterise treatment and outcomes for patients with hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC) within a large regional cancer centre, as a benchmark for evaluating real-world impact of novel therapies. Methods Retrospective longitudinal cohort, using electronic patient records of adult females with a first diagnosis of HR+/HER2- MBC January 2012–March 2018. Results One hundred ninety-six women were identified with HR+/HER2- MBC. Median age was 67 years, 85.2% were post-menopausal and median time between primary diagnosis and metastasis was 5.4 years. Most (75.1%) patients received endocrine therapy as first line systemic treatment (1st LoT); use of 1st LoT chemotherapy halved between 2012 and 2017. Patients receiving 1st LoT chemotherapy were younger and more likely to have visceral metastasis (p < 0.01). Median OS was 29.5 months and significantly greater for patients with exclusively non-visceral metastasis (p < 0.01). The adjusted hazard ratio for death of patients with visceral (or CNS) metastasis was 1.91 relative to those with exclusively non-visceral metastasis. Conclusions Diverse endocrine therapies predominate as 1st LoT for patients with HR+/HER2- MBC, chemotherapy being associated with more aggressive disease in younger patients, emphasising the importance of using effective and tolerable therapies early

A guided, internet-based stress management intervention for university students with high levels of stress:Feasibility and acceptability study

BackgroundTransitioning to adulthood and challenges in university life can result in increased stress levels among university students. Chronic and severe stress is associated with deleterious psychological and physiological effects. Digital interventions could succeed in approaching and helping university students who might be at risk; however, the experiences of students with internet-based stress management interventions are insufficiently understood.ObjectiveThis study aims to explore the feasibility; acceptability; and changes in perceived stress, depressive symptoms, and quality of life from baseline to posttest assessment of a 5-session, internet-based stress management intervention guided by an e-coach, developed for university students experiencing high levels of stress.MethodsA single-arm study was conducted. Students were recruited from different channels, mainly from a web survey. Students were eligible if they (1) scored ≥20 on the Perceived Stress Scale-10, (2) were aged ≥18 years, and (3) were studying at one of the participating universities. Feasibility and acceptability of the intervention were investigated using several indications, including satisfaction (Client Satisfaction Questionnaire-8) and usability (System Usability Scale-10). We also investigated the indicators of intervention adherence using use metrics (eg, the number of completed sessions). Our secondary goal was to explore the changes in perceived stress (Perceived Stress Scale-10), depressive symptoms (Patient Health Questionnaire-9), and quality of life (EQ-5D-5L scale) from baseline to posttest assessment. In addition, we conducted semistructured interviews with intervention completers and noncompleters to understand user experiences in depth. For all primary outcomes, descriptive statistics were calculated. Changes from baseline to posttest assessment were examined using 2-tailed paired sample t tests or the Wilcoxon signed rank test. Qualitative data were analyzed using thematic analysis.ResultsOf 436 eligible students, 307 (70.4%) students started using the intervention. Overall, 25.7% (79/307) completed the core sessions (ie, sessions 1-3) and posttest assessment. A substantial proportion of the students (228/307, 74.3%) did not complete the core sessions or the posttest assessment. Students who completed the core sessions reported high satisfaction (mean 25.78, SD 3.30) and high usability of the intervention (mean 86.01, SD 10.25). Moreover, this group showed large reductions in perceived stress (Cohen d=0.80) and moderate improvements in depression score (Cohen d=0.47) and quality of life (Cohen d=-0.35) from baseline to posttest assessment. Qualitative findings highlight that several personal and intervention-related factors play a role in user experience.ConclusionsThe internet-based stress management intervention seems to be feasible, acceptable, and possibly effective for some university students with elevated stress levels. However, given the high dropout rate and qualitative findings, several adjustments in the content and features of the intervention are needed to maximize the user experience and the impact of the intervention.Trial Registration: Netherlands Trial Register 8686; https://onderzoekmetmensen.nl/nl/trial/20889.International Registered Report Identifier (IRRID): RR2-10.1016/j.invent.2021.100369.</p

An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

Epithelia are continuously self-renewed, but how epithelial integrity is maintained during the morphological changes that cells undergo in mitosis is not well understood. Here, we show that as epithelial cells round up when they enter mitosis, they exert tensile forces on neighboring cells. We find that mitotic cell–cell junctions withstand these tensile forces through the mechanosensitive recruitment of the actin-binding protein vinculin to cadherin-based adhesions. Surprisingly, vinculin that is recruited to mitotic junctions originates selectively from the neighbors of mitotic cells, resulting in an asymmetric composition of cadherin junctions. Inhibition of junctional vinculin recruitment in neighbors of mitotic cells results in junctional breakage and weakened epithelial barrier. Conversely, the absence of vinculin from the cadherin complex in mitotic cells is necessary to successfully undergo mitotic rounding. Our data thus identify an asymmetric mechanoresponse at cadherin adhesions during mitosis, which is essential to maintain epithelial integrity while at the same time enable the shape changes of mitotic cells

Not just a matter of size:a hospital-level risk factor analysis of MRSA bacteraemia in Scotland

Background: Worldwide, there is a wealth of literature examining patient-level risk 6 factors for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. At the hospital-level it is generally accepted that MRSA bacteraemia is more common in larger hospitals. In Scotland, size does not fully explain all the observed variation among hospitals. The aim of this study was to identify risk factors for the presence and rate of MRSA bacteraemia cases in Scottish mainland hospitals. Specific hypotheses regarding hospital size, type and connectivity were examined. Methods: Data from 198 mainland Scottish hospitals (defined as having at least one inpatient per year) were analysed for financial year 2007-08 using logistic regression (Model 1: presence/absence of MRSA bacteraemia) and Poisson regression (Model 2: rate of MRSA bacteraemia). The significance of risk factors representing various measures of hospital size, type and connectivity were investigated. Results: In Scotland, size was not the only significant risk factor identified for the presence and rate of MRSA bacteraemia. The probability of a hospital having at least one case of MRSA bacteraemia increased with hospital size only if the hospital exceeded a certain level of connectivity. Higher levels of MRSA bacteraemia were associated with the large, highly connected teaching hospitals with high ratios of patients to domestic staff. Conclusions: A hospital’s level of connectedness within a network may be a better measure of a hospital’s risk of MRSA bacteraemia than size. This result could be used to identify high risk hospitals which would benefit from intensified infection control measures

Patient Referral Patterns and the Spread of Hospital-Acquired Infections through National Health Care Networks

Rates of hospital-acquired infections, such as methicillin-resistant Staphylococcus aureus (MRSA), are increasingly used as quality indicators for hospital hygiene. Alternatively, these rates may vary between hospitals, because hospitals differ in admission and referral of potentially colonized patients. We assessed if different referral patterns between hospitals in health care networks can influence rates of hospital-acquired infections like MRSA. We used the Dutch medical registration of 2004 to measure the connectedness between hospitals. This allowed us to reconstruct the network of hospitals in the Netherlands. We used mathematical models to assess the effect of different patient referral patterns on the potential spread of hospital-acquired infections between hospitals, and between categories of hospitals (University medical centers, top clinical hospitals and general hospitals). University hospitals have a higher number of shared patients than teaching or general hospitals, and are therefore more likely to be among the first to receive colonized patients. Moreover, as the network is directional towards university hospitals, they have a higher prevalence, even when infection control measures are equally effective in all hospitals. Patient referral patterns have a profound effect on the spread of health care-associated infections like hospital-acquired MRSA. The MRSA prevalence therefore differs between hospitals with the position of each hospital within the health care network. Any comparison of MRSA rates between hospitals, as a benchmark for hospital hygiene, should therefore take the position of a hospital within the network into account

Actual and preferred place of death of home-dwelling patients in four European countries: making sense of quality indicators

Background: Dying at home and dying at the preferred place of death are advocated to be desirable outcomes of palliative care. More insight is needed in their usefulness as quality indicators. Our objective is to describe whether " the percentage of patients dying at home'' and "the percentage of patients who died in their place of preference'' are feasible and informative quality indicators. Methods and Findings: A mortality follow-back study was conducted, based on data recorded by representative GP networks regarding home-dwelling patients who died non-suddenly in Belgium (n = 1036), the Netherlands (n = 512), Italy (n = 1639) or Spain (n = 565). "The percentage of patients dying at home'' ranged between 35.3% (Belgium) and 50.6% (the Netherlands) in the four countries, while "the percentage of patients dying at their preferred place of death'' ranged between 67.8% (Italy) and 86.0% (Spain). Both indicators were strongly associated with palliative care provision by the GP (odds ratios of 1.55-13.23 and 2.30-6.63, respectively). The quality indicator concerning the preferred place of death offers a broader view than the indicator concerning home deaths, as it takes into account all preferences met in all locations. However, GPs did not know the preferences for place of death in 39.6% (the Netherlands) to 70.3% (Italy), whereas the actual place of death was known in almost all cases. Conclusion: GPs know their patients' actual place of death, making the percentage of home deaths a feasible indicator for collection by GPs. However, patients' preferred place of death was often unknown to the GP. We therefore recommend using information from relatives as long as information from GPs on the preferred place of death is lacking. Timely communication about the place where patients want to be cared for at the end of life remains a challenge for GPs