MTSS1 is a critical epigenetically regulated tumor suppressor in CML

Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1 overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI resistant CML stem cells in patients

Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

Holographic Thermalization

Using the AdS/CFT correspondence, we probe the scale-dependence of thermalization in strongly coupled field theories following a quench, via calculations of two-point functions, Wilson loops and entanglement entropy in d=2,3,4. In the saddlepoint approximation these probes are computed in AdS space in terms of invariant geometric objects - geodesics, minimal surfaces and minimal volumes. Our calculations for two-dimensional field theories are analytical. In our strongly coupled setting, all probes in all dimensions share certain universal features in their thermalization: (1) a slight delay in the onset of thermalization, (2) an apparent non-analyticity at the endpoint of thermalization, (3) top-down thermalization where the UV thermalizes first. For homogeneous initial conditions the entanglement entropy thermalizes slowest, and sets a timescale for equilibration that saturates a causality bound over the range of scales studied. The growth rate of entanglement entropy density is nearly volume-independent for small volumes, but slows for larger volumes.Comment: 39 pages, 24 figure

Stratification of diabetes in the context of comorbidities, using representation learning and topological data analysis

\ua9 2023, The Author(s). Diabetes is a heterogenous, multimorbid disorder with a large variation in manifestations, trajectories, and outcomes. The aim of this study is to validate a novel machine learning method for the phenotyping of diabetes in the context of comorbidities. Data from 9967 multimorbid patients with a new diagnosis of diabetes were extracted from Clinical Practice Research Datalink. First, using BEHRT (a transformer-based deep learning architecture), the embeddings corresponding to diabetes were learned. Next, topological data analysis (TDA) was carried out to test how different areas in high-dimensional manifold correspond to different risk profiles. The following endpoints were considered when profiling risk trajectories: major adverse cardiovascular events (MACE), coronary artery disease (CAD), stroke (CVA), heart failure (HF), renal failure (RF), diabetic neuropathy, peripheral arterial disease, reduced visual acuity and all-cause mortality. Kaplan Meier curves were plotted for each derived phenotype. Finally, we tested the performance of an established risk prediction model (QRISK) by adding TDA-derived features. We identified four subgroups of patients with diabetes and divergent comorbidity patterns differing in their risk of future cardiovascular, renal, and other microvascular outcomes. Phenotype 1 (young with chronic inflammatory conditions) and phenotype 2 (young with CAD) included relatively younger patients with diabetes compared to phenotypes 3 (older with hypertension and renal disease) and 4 (older with previous CVA), and those subgroups had a higher frequency of pre-existing cardio-renal diseases. Within ten years of follow-up, 2592 patients (26%) experienced MACE, 2515 patients (25%) died, and 2020 patients (20%) suffered RF. QRISK3 model’s AUC was augmented from 67.26% (CI 67.25–67.28%) to 67.67% (CI 67.66–67.69%) by adding specific TDA-derived phenotype and the distances to both extremities of the TDA graph improving its performance in the prediction of CV outcomes. We confirmed the importance of accounting for multimorbidity when risk stratifying heterogenous cohort of patients with new diagnosis of diabetes. Our unsupervised machine learning method improved the prediction of clinical outcomes

Native-English-Speaking Teachers:Disconnections Between Theory, Research, and Practice

Native-English-speaking teachers (NESTs) have long been in demand for perceived benefits of the skills they bring to the classroom. However, the notion that native speakers provide the best models of the target language and thus make the best teachers of the language has been criticised in the literature. This article reports on the disconnection between academic literature on NESTs and the realities they report. Drawing on data from an investigation into NEST schemes globally, the article suggests that lived classroom experiences of NESTs are complex, They are also often bilingual, experienced, and qualified, and regard local English teachers (LETs) they work with as experts and in control of how English is practised in the classroom. These characteristics contrast with much of the academic literature, which explores the concept of native speakerism, which tends to view NESTs negatively. The article proposes that one reason for the disconnection between theory and practice is the parallel lives of researchers and teachers, whether NESTs or LETs. Thus, each group’s realities and concerns are not always understood by the other. The article suggests that a substantial group of bilingual and bicultural NESTs consider the country where work home, so future theorisations of NESTs and native speakerism should take account of these teachers

Shaping electron wave functions in a carbon nanotube with a parallel magnetic field

A magnetic field, through its vector potential, usually causes measurable changes in the electron wave function only in the direction transverse to the field. Here we demonstrate experimentally and theoretically that in carbon nanotube quantum dots, combining cylindrical topology and bipartite hexagonal lattice, a magnetic field along the nanotube axis impacts also the longitudinal profile of the electronic states. With the high (up to 17T) magnetic fields in our experiment the wave functions can be tuned all the way from "half-wave resonator" shape, with nodes at both ends, to "quarter-wave resonator" shape, with an antinode at one end. This in turn causes a distinct dependence of the conductance on the magnetic field. Our results demonstrate a new strategy for the control of wave functions using magnetic fields in quantum systems with nontrivial lattice and topology.Comment: 5 figure

Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34<sup>+</sup>38<sup>lo/−</sup>), are significantly lower than in CML progenitor cells (total CD34<sup>+</sup>) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34<sup>+</sup> and primitive CD34<sup>+</sup>38<sup>lo/−</sup> cells accumulated significantly higher levels of sLDL when compared with non-CML CD34<sup>+</sup> cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication

The relationship between the perception of distributed leadership in secondary schools and teachers' and teacher leaders' job satisfaction and organizational commitment

This study investigates the relation between distributed leadership, the cohesion of the leadership team, participative decision-making, context variables, and the organizational commitment and job satisfaction of teachers and teacher leaders. A questionnaire was administered to teachers and teacher leaders (n=1770) from 46 large secondary schools. Multiple regression analyses and path analyses revealed that the study variables explained significant variance in organizational commitment. The degree of explained variance for job satisfaction was considerably lower compared to organizational commitment. Most striking was that the cohesion of the leadership team and the amount of leadership support was strongly related to organizational commitment, and indirectly to job satisfaction. Decentralization of leadership functions was weakly related to organizational commitment and job satisfaction

Systematic evaluation of patient-reported outcome (PRO) protocol content and reporting in UK cancer clinical trials: the EPiC study protocol.

Emerging evidence suggests that patient-reported outcome (PRO)-specific information may be omitted in trial protocols and that PRO results are poorly reported, limiting the use of PRO data to inform cancer care. This study aims to evaluate the standards of PRO-specific content in UK cancer trial protocols and their arising publications and to highlight examples of best-practice PRO protocol content and reporting where they occur. The objective of this study is to determine if these early findings are generalisable to UK cancer trials, and if so, how best we can bring about future improvements in clinical trials methodology to enhance the way PROs are assessed, managed and reported.Trials in which the primary end point is based on a PRO will have more complete PRO protocol and publication components than trials in which PROs are secondary end points.Completed National Institute for Health Research (NIHR) Portfolio Cancer clinical trials (all cancer specialities/age-groups) will be included if they contain a primary/secondary PRO end point. The NIHR portfolio includes cancer trials, supported by a range of funders, adjudged as high-quality clinical research studies. The sample will be drawn from studies completed between 31 December 2000 and 1 March 2014 (n=1141) to allow sufficient time for completion of the final trial report and publication. Two reviewers will then review the protocols and arising publications of included trials to: (1) determine the completeness of their PRO-specific protocol content; (2) determine the proportion and completeness of PRO reporting in UK Cancer trials and (3) model factors associated with PRO protocol and reporting completeness and with PRO reporting proportion.The study was approved by the ethics committee at University of Birmingham (ERN_15-0311). Trial findings will be disseminated via presentations at local, national and international conferences, peer-reviewed journals and social media including the CPROR twitter account and UOB departmental website (http://www.birmingham.ac.uk/cpro0r)