FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

From Springer Nature via Jisc Publications RouterHistory: received 2020-06-29, accepted 2021-03-15, registration 2021-04-23, pub-electronic 2021-05-28, online 2021-05-28, collection 2021-12Publication status: PublishedFunder: Royal College of Surgeons of England (RCS); doi: https://doi.org/10.13039/501100000297Abstract: Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival

A participatory approach to iteratively adapting game design workshops to empower autistic youth

IntroductionAutistic people face systemic barriers to fair employment. Informal learning may promote the self-determination transition-age autistic youth need to overcome and/or transform these barriers. This report focuses on the iterative process of developing video game design workshops guided by feedback from autistic students about instructional strategies they found engaging. This study is part of a three-year-long NSF-funded program of research that seeks to empower autistic youth to move toward successful careers by teaching educators how to more effectively guide them.MethodsIn the Summer of 2021, educators at an award-winning NYC-based, not-for-profit, education program, Tech Kids Unlimited (TKU) collaborated with researchers, including autistic students, to iteratively develop and assess two online game design workshops for transition-age autistic youth. Participants selected which workshop they were available for (Workshop 1: n = 18; M age = 16.72  years; Workshop 2: n = 16; M age = 16.56  years). Students in Workshop 2  had more varied support needs and were less motivated to learn video game design than students in Workshop 1. Students completed assessments before and after each workshop and rated their interest in specific workshop activities after each activity. Guided by data from Workshop 1, we revised instructional strategies before conducting Workshop 2.ResultsWe found little evidence for our hypothesis that attentional style would impact educational engagement. However, video game design self-efficacy and self-determination were often positively associated with engagement. Two industry speakers, one of whom was autistic, were among the highest-rated activities. As hypothesized, video game design self-efficacy and self-determination (and unexpectedly) spatial planning improved from pre- to post-test following Workshop 1. Despite our efforts to use what we learned in Workshop 1 to improve in Workshop 2, Workshop 2 did not lead to significant improvements in outcomes. However, students highlighted instructional strategies as a strength of Workshop 2 more often than they had for Workshop 1. Educators highlighted the importance of group “temperature checks,” individualized check-ins, social–emotional support for students and educators, and fostering a positive atmosphere.DiscussionFindings suggest that interactive multimodal activities, stimulating discussions, and opportunities to engage with neurodivergent industry professionals may engage and empower diverse autistic youth

Institutional Hybridity and Cultural Isomorphism in Contemporary Policing

Recent work on policing has increasingly acknowledged the influence of a broad array of changes upon both the structure and culture of police organizations. Generally, however, literature and research have tended to focus attention onto those elements of the broader police environment that effect such developments, whereas little commentary, to date, has been directed towards those features which impact across the broader public sector. Through drawing on the concepts of ‘hybrid professionalism’ [Noordegraaf M (2015) Hybrid professionalism and beyond: (new) forms of public professionalism in changing organizational and societal contexts. Journal of Professions and Organization 2: 187–206] and ‘institutional isomorphism’ [DiMaggio PJ and Powell WW (1983) The iron cage revisited: Institutional isomorphism and collective rationality in organizational fields. American Sociological Review 48: 147–160], this conceptual paper will argue that the impact of neoliberal ideology on the contemporary public sector has created a police organization for which professionalism increasingly denotes generic management skills that are common across different occupations and different police roles. In particular, it will be suggested that such institutional isomorphism may drive ideational responses commensurate with cultural change within police organizations. In short, therefore, the paper will make the case that, in parallel with changes already identified by other academics, broader structural changes may lead to a narrower and more generic set of cultural responses within contemporary police organizations

Measurement of the energy asymmetry in tt¯ j production at 13 TeV with the ATLAS experiment and interpretation in the SMEFT framework

A measurement of the energy asymmetry in jet-associated top-quark pair production is presented using 139fb-1 of data collected by the ATLAS detector at the Large Hadron Collider during pp collisions at s=13TeV. The observable measures the different probability of top and antitop quarks to have the higher energy as a function of the jet scattering angle with respect to the beam axis. The energy asymmetry is measured in the semileptonic tt¯ decay channel, and the hadronically decaying top quark must have transverse momentum above 350GeV. The results are corrected for detector effects to particle level in three bins of the scattering angle of the associated jet. The measurement agrees with the SM prediction at next-to-leading-order accuracy in quantum chromodynamics in all three bins. In the bin with the largest expected asymmetry, where the jet is emitted perpendicular to the beam, the energy asymmetry is measured to be - 0.043 ± 0.020 , in agreement with the SM prediction of - 0.037 ± 0.003. Interpreting this result in the framework of the Standard Model effective field theory (SMEFT), it is shown that the energy asymmetry is sensitive to the top-quark chirality in four-quark operators and is therefore a valuable new observable in global SMEFT fits

Studies of new Higgs boson interactions through nonresonant HH production in the b¯bγγ fnal state in pp collisions at √s = 13 TeV with the ATLAS detector

A search for nonresonant Higgs boson pair production in the b ¯bγγ fnal state is performed using 140 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. This analysis supersedes and expands upon the previous nonresonant ATLAS results in this fnal state based on the same data sample. The analysis strategy is optimised to probe anomalous values not only of the Higgs (H) boson self-coupling modifer κλ but also of the quartic HHV V (V = W, Z) coupling modifer κ2V . No signifcant excess above the expected background from Standard Model processes is observed. An observed upper limit µHH < 4.0 is set at 95% confdence level on the Higgs boson pair production cross-section normalised to its Standard Model prediction. The 95% confdence intervals for the coupling modifers are −1.4 < κλ < 6.9 and −0.5 < κ2V < 2.7, assuming all other Higgs boson couplings except the one under study are fxed to the Standard Model predictions. The results are interpreted in the Standard Model efective feld theory and Higgs efective feld theory frameworks in terms of constraints on the couplings of anomalous Higgs boson (self-)interactions

Measurement of the energy response of the ATLAS calorimeter to charged pions from W±→ τ±(→ π±ντ) ντ events in Run 2 data

The energy response of the ATLAS calorimeter is measured for single charged pions with transverse momentum in the range 10 < pT< 300 GeV. The measurement is performed using 139 fb - 1 of LHC proton–proton collision data at s=13 TeV taken in Run 2 by the ATLAS detector. Charged pions originating from τ-lepton decays are used to provide a sample of high-pT isolated particles, where the composition is known, to test an energy regime that has not previously been probed by in situ single-particle measurements. The calorimeter response to single-pions is observed to be overestimated by ∼ 2 % across a large part of the pT spectrum in the central region and underestimated by ∼ 4 % in the endcaps in the ATLAS simulation. The uncertainties in the measurements are ≲ 1 % for 15 < pT< 185 GeV in the central region. To investigate the source of the discrepancies, the width of the distribution of the ratio of calorimeter energy to track momentum, the energies per layer and response in the hadronic calorimeter are also compared between data and simulation