Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.

Advancing gender inclusivity for Two-Spirit, trans, nonbinary and other gender-diverse blood and plasma donors.

BACKGROUND AND OBJECTIVES: Two-Spirit, trans, nonbinary and other gender-diverse (2STGD) donors face challenges in donation. While many blood operators aim to address these challenges, to date, no empirical study with these donors has been conducted to guide their efforts. This paper reports 2STGD donors' views on a two-step approach asking donors their gender and sex assigned at birth (SAAB), and expanding gender options in donor registration. MATERIALS AND METHODS: A qualitative community-based study was conducted with 2STGD donors (n = 85) in Canada. Semi-structured, in-depth interviews were conducted from July to October 2022, audio-recorded and transcribed. Data were analysed using a thematic analytic framework. RESULTS: Participants were divided on their views of a two-step approach asking gender and SAAB. Themes underlying views in favour of this approach included the following: demonstrating validation and visibility, and treating 2STGD donors and cisgender donors alike. Themes underlying views not in favour or uncertain included potential for harm, compromising physical safety, and invalidation. All participants were in favour of expanding gender options if blood operators must know donors' gender. CONCLUSION: Results indicate that a two-step approach for all donors is not recommended unless the blood operator must know both a donor's gender and SAAB to ensure donor and/or recipient safety. Gender options should be expanded beyond binary options. Ongoing research and evidence synthesis are needed to determine how best to apply donor safety measures to nonbinary donors.

Involving lived experience in regional efforts to address gambling-related harms: going beyond 'window dressing' and 'tick box exercises'.

BACKGROUND: Lived Experience (LE) involvement has been shown to improve interventions across diverse sectors. Yet LE contributions to public health approaches to address gambling-related harms remain underexplored, despite notable detrimental health and social outcomes linked to gambling. This paper analyses the potential of LE involvement in public health strategy to address gambling-related harms. It focuses on the example of a UK city-region gambling harms reduction intervention that presented multiple opportunities for LE input. METHODS: Three focus groups and 33 semi-structured interviews were conducted to hear from people with and without LE who were involved in the gambling harms reduction intervention, or who had previous experience of LE-informed efforts for addressing gambling-related harms. People without LE provided reflections on the value and contributions of others' LE to their work. Data analysis combined the Framework Method with themes developed inductively (from people's accounts) and deductively (from the literature, including grey literature). RESULTS: Four themes were identified: (1) personal journeys to LE involvement; (2) the value added by LE to interventions for addressing gambling-related harms; (3) emotional impacts on people with LE; and (4) collective LE and diverse lived experiences. Two figures outlining LE involvement specific to gambling harms reduction in the UK, where public health efforts aimed at addressing gambling-related harms coexist with industry-funded programmes, are proposed. CONCLUSIONS: Integrating a range of LE perspectives in a public health approach to gambling harms reduction requires local access to involvement for people with LE via diverse routes that are free from stigma and present people with LE with options in how they can engage and be heard in decision-making, and how they operate in relation to industry influence. Involving LE in gambling harms reduction requires enabling people to develop the affective and critical skills necessary to navigate complex emotional journeys and a challenging commercial and policy environment.

What works in advocating for food advertising policy change across an english region - a realist evaluation.

BACKGROUND: With increasing recognition of the role of commercial determinants of health, local areas in England have sought to restrict the advertising of products high in fat, salt and sugar (HFSS) on council-owned spaces, as part of wider strategies to reduce obesity. While there is some evidence of the impact of such policy change on behaviour, little is known about what works in the process of implementing this policy change. METHODS: Guided by a realist evaluation framework that explores the interaction between context, mechanism and outcomes, this study aims to investigate the factors that influence the restriction of outdoor advertising of HFSS products in one region in England. It refines a programme theory co-produced with stakeholders from 14 local authorities within a region and uses multiple data sources from each area with an in-depth examination of four case study sites. Data sources include longitudinal realist interviews, focus groups and surveys with policy advocates and policy stakeholders. Data were analysed retroductively to understand the causal link between context, mechanism and outcomes. RESULTS: Outcomes were driven by five dominant mechanisms: a strategic and staggered approach to stakeholder engagement, gathering intelligence, identifying policy champions, building relationships, reframing the issue; and two secondary mechanisms of amplifying the issue and increasing public will. These led to varied outcomes with no changes in formal policy position within the evaluation period but draft policy guidance in place and changes in political will demonstrated. Dominant context factors influencing change included having a named and resourced policy advocate in place supported by an external Community of Improvement and having existing aligned local objectives. Organisational complexity and change, financial concerns, lack of local examples, ideological positions and the pandemic were also influencing contextual factors. CONCLUSION: Effecting policy change in this area requires the commitment of an extended period and the valuing of short-term policy outcomes, such as increasing political will. The importance of a resourced and well-supported policy advocate to lead this work is fundamental and the commercially sensitive nature of this policy change means that a complex interplay of mechanisms is required which may be dominated by a strategically staggered approach to stakeholder engagement.

The conceptualization and development of critical health literacy in children: a scoping review.

The cognitive and social practices associated with critical health literacy, such as critical appraisal of health messages and participation in political processes to address wider determinants of health, are of lifelong benefit. Understanding how and where critical health literacy development can be supported early in the life course may improve health outcomes now and in the future. This scoping review focuses on how critical health literacy in children is conceptualized and the supportive environments available for its development. Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines are used in reporting. Evidence retrieved was eligible for inclusion if it contained a substantive conceptual or empirical study of critical health literacy in populations aged 7-11 (middle childhood). From the included 18 peer-reviewed and grey literature sources, schools are identified as the setting most associated with the development of critical health literacy in the target age group. However, the action-oriented dimension of critical health literacy is rarely supported in the school setting. The review concludes that further research is needed to clarify how and where to support children to develop critical health literacy in and outside of school settings.

Co-producing principles to guide health research: an illustrative case study from an eating disorder research clinic.

BACKGROUND: There is significant value in co-produced health research, however power-imbalances within research teams can pose a barrier to people with lived experience of an illness determining the direction of research in that area. This is especially true in eating disorder research, where the inclusion of co-production approaches lags other research areas. Appealing to principles or values can serve to ground collaborative working. Despite this, there has not been any prior attempt to co-produce principles to guide the work of a research group and serve as a basis for developing future projects. METHODS: The aim of this piece of work was to co-produce a set of principles to guide the conduct of research within our lived experience led research clinic, and to offer an illustrative case for the value of this as a novel co-production methodology. A lived experience panel were recruited to our eating disorder research group. Through an iterative series of workshops with the members of our research clinic (composed of a lived experience panel, clinicians, and researchers) we developed a set of principles which we agreed were important in ensuring both the direction of our research, and the way in which we wanted to work together. RESULTS: Six key principles were developed using this process. They were that research should aim to be: 1) real world-offering a clear and concrete benefit to people with eating disorders, 2) tailored-suitable for marginalised groups and people with atypical diagnoses, 3) hopeful-ensuring that hope for recovery was centred in treatment, 4) experiential-privileging the 'voice' of people with eating disorders, 5) broad-encompassing non-standard therapeutic treatments and 6) democratic-co-produced by people with lived experience of eating disorders. CONCLUSIONS: We reflect on some of the positives as well as limitations of the process, highlighting the importance of adequate funding for longer-term co-production approaches to be taken, and issues around ensuring representation of minority groups. We hope that other health research groups will see the value in co-producing principles to guide research in their own fields, and will adapt, develop, and refine this novel methodology.

It important that when researchers are trying to understand illnesses they do this together with people who have experienced them. This can be difficult, because researchers often take over­even if everyone is meant to be working as a team. We are a group of people trying to understand eating disorders and help people who have them get better. In our group there are some people that have experienced an eating disorder, health workers and researchers.We thought it might be helpful if we could start by working out what things were most important to us as a group, and then try to stick by them. We talked a lot together to come up with a list of principles.The six principles we thought were the most important were that research should make a difference to people's lives, see people as individuals, be hopeful, make sure that people have a voice, look at things that aren't traditional therapies, and always work together as equals.There are some issues with what we did; we found it hard to get a good mix of people in our group, and we were lucky in having enough money to pay people to do what we wanted to do, which is not always true. Despite this, we still hope that other teams might look at what we have done, and see if they could build on it, or change it, so it would work for them.

RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.

Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.

Settings for the development of health literacy: A conceptual review.

Advances in conceptualizing settings in health promotion include understanding settings as complex and interlinked systems with a core commitment to health and related outcomes such as health literacy. Traditional settings for the development of health literacy include health care environments and schools. There is a need to identify and conceptualize non-traditional and emerging settings of twenty-first-century everyday life. The aim of this conceptual review is to inform a conceptual model of a "non-traditional" setting for the development of health literacy. The model uses the example of the public library to propose four equity-focused antecedents required in a setting for the development of health literacy: the setting acknowledges the wider determinants of health, is open access, involves local communities in how it is run, and facilitates informed action for health. The review concludes that a settings approach to the development of health literacy can be conceptualized as part of a coordinated "supersetting approach," where multiple settings work in synergy with each other.

Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high-frequency stimulation.

AIMS: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS. METHODS AND RESULTS: Sixty-three atrial sites were tested with HFS in four Langendorff-perfused porcine hearts. A 3.5 mm tip quadripolar ablation catheter was used to stimulate and deliver HFS to the left and right atrial epicardium, within the local atrial refractory period. Tissue samples from sites triggering atrial ectopy/AF (ET) sites and non-ET sites were stained with choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), for quantification of parasympathetic and sympathetic nerves, respectively. The average cross-sectional area (CSA) of nerves was also calculated. Histomorphometry of six ET sites (9.5%) identified by HFS evoking at least a single atrial ectopic was compared with non-ET sites. All ET sites contained ChAT-immunoreactive (ChAT-IR) and/or TH-immunoreactive nerves (TH-IR). Nerve density was greater in ET sites compared to non-ET sites (nerves/cm2: 162.3 ± 110.9 vs. 69.65 ± 72.48; P = 0.047). Overall, TH-IR nerves had a larger CSA than ChAT-IR nerves (µm2: 11 196 ± 35 141 vs. 2070 ± 5841; P < 0.0001), but in ET sites, TH-IR nerves were smaller than in non-ET sites (µm2: 6021 ± 14 586 vs. 25 254 ± 61 499; P < 0.001). CONCLUSIONS: ET sites identified by HFS contained a higher density of smaller nerves than non-ET sites. The majority of these nerves were within the atrial myocardium. This has important clinical implications for devising an effective therapeutic strategy for targeting autonomic triggers of AF.

Public Libraries as Supportive Environments for Children's Development of Critical Health Literacy.

Critical health literacy enables individuals to use cognitive and social resources for informed action on the wider determinants of health. Promoting critical health literacy early in the life-course may contribute to improved health outcomes in the long term, but children's opportunities to develop critical health literacy are limited and tend to be school-based. This study applies a settings-based approach to analyse the potential of public libraries in England to be supportive environments for children's development of critical health literacy. The study adopted institutional ethnography as a framework to explore the public library as an everyday setting for children. A children's advisory group informed the study design. Thirteen children and 19 public library staff and community stakeholders were interviewed. The study results indicated that the public library was not seen by children, staff, or community stakeholders as a setting for health. Its policies and structure purport to develop health literacy, but the political nature of critical health literacy was seen as outside its remit. A supersetting approach in which children's everyday settings work together is proposed and a conceptual model of the public library role is presented.

Digital Health Intervention Design and Deployment for Engaging Demographic Groups Likely to Be Affected by the Digital Divide: Protocol for a Systematic Scoping Review.

BACKGROUND: Digital health interventions refer to interventions designed to support health-related knowledge transfer and are delivered via digital technologies, such as mobile apps. Digital health interventions are a double-edged sword: they have the potential to reduce health inequalities, for example, by making treatments available remotely to rural populations underserved by health care facilities or by helping to overcome language barriers via in-app translation services; however, if not designed and deployed with care, digital health interventions also have the potential to increase health inequalities and exacerbate the effects of the digital divide. OBJECTIVE: The aim of this study is to review ways to mitigate the digital divide through digital health intervention design, deployment, and engagement mechanisms sensitive to the needs of digitally excluded populations. METHODS: This protocol outlines the procedure for a systematic scoping review that follows the methodology recommended by the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidance. The following databases will be searched for primary research studies published in English from October 1, 2011, to October 1, 2021: Cochrane Library, Epistemonikos, NICE Evidence, PROSPERO, PubMed (with MEDLINE and Europe PMC), and Trip. In addition, the following sources of gray literature will be searched: Conference Proceedings Citation Index, Health Management Information Consortium, International HTA Database, OpenGrey, The Grey Literature Report, Google Scholar Basic Search UK, MedNar Deep Web Search Engine, and Carrot2. We will select publications that meet the following inclusion criteria: primary research papers that evaluated digital health interventions that describe features of digital health intervention design and deployment that enable or hinder access to and engagement with digital health interventions by adults from demographic groups likely to be affected by the digital divide (eg, older age, minority ethnic groups, lower income, and lower education level). A random selection of 25 publications identified from the search will be double screened by four reviewers. If there is >75% agreement for included/excluded publications, the team will continue to screen all the identified publications. For all included publications, study characteristics will be extracted by one author and checked for agreement by a second author, with any disagreements resolved by consensus among the study team. Consultation digital health intervention design and deployment, and digital health intervention users will also be conducted in parallel. RESULTS: The review is underway and is anticipated to be completed by September 2022. CONCLUSIONS: The results will have implications for researchers and policy makers using digital health interventions for health improvement peripandemic and post pandemic, and will inform best practices in the design and delivery of digital health interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/32538.

Involving Children in Health Literacy Research.

Despite the volume and breadth of health literacy research related to children, children's involvement in that research is rare. Research with children is challenging, but the principles of involvement and engagement underpin all health promotion work, including health literacy. This commentary reflects on the process of setting up a Children's Advisory Group to consult on an institutional ethnography study of health literacy work from children's standpoint. The Children's Advisory Group contributed feedback on the study ethics and design and piloted methods for rapport-building and data collection, including livestreamed draw-and-describe and modified Interview to the Double. Consulting with the Children's Advisory Group highlighted the importance of listening to children and recognizing and valuing children's imaginative contributions to methods for involving children in health literacy research. Insights from this commentary can be used to foreground equity-focused approaches to future research and practice with children in the field of health literacy.

Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart.

BACKGROUND: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helper and CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross-priming DC in post-myocardial infarction immunopathology through presentation of self-antigen from necrotic cardiac cells to cytotoxic CD8+ T cells. METHODS: We induced type 2 myocardial infarction-like ischemic injury in the heart by treatment with a single high dose of the ß-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function. RESULTS: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a-/- mice deficient in DC cross-priming are protected from persistent immune-mediated myocardial damage and decline of cardiac function, likely because of dampened activation of cytotoxic CD8+ T cells. CONCLUSION: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of postischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent postischemic immunopathology and heart failure.

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9 ± 4.1-67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude - 106.9%, S-endpoint gradient + 54.9%, S point - 39.4%, RS ratio + 38.6% and (-dV/dt)max - 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates.

North American temperate conifer (Tsuga canadensis) reveals a complex physiological response to climatic and anthropogenic stressors.

Rising atmospheric CO2 (ca) is expected to promote tree growth and lower water loss via changes in leaf gas exchange. However, uncertainties remain if gas-exchange regulation strategies are homeostatic or dynamical in response to increasing ca, as well as evolving climate and pollution inputs. Using a suite of tree ring-based δ13C-derived physiological parameters (Δ13C, ci, iWUE) and tree growth from a mesic, low elevation stand of canopy-dominant Tsuga canadensis in north-eastern USA, we investigated the influence of rising ca, climate and pollution on, and characterised the dynamical regulation strategy of, leaf gas exchange at multidecadal scales. Isotopic and growth time series revealed an evolving physiological response in which the species shifted its leaf gas-exchange strategy dynamically (constant ci; constant ci/ca; constant ca - ci) in response to rising ca, moisture availability and site conditions over 111 yr. Tree iWUE plateaued after 1975, driven by greater moisture availability and a changing soil biogeochemistry that may have impaired a stomatal response. Results suggested that trees may exhibit more complex physiological responses to the changing environmental conditions over multidecadal periods, and complicating the parameterisation of Earth system models and the estimation of future carbon sink capacity and water balance in midlatitude forests and elsewhere.

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo.

Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity.

Acute leukemias are aggressive malignancies of developmentally arrested hematopoietic progenitors. We sought here to explore the possibility that changes in hematopoietic stem/progenitor cells during development might alter the biology of leukemias arising from this tissue compartment. Using a mouse model of acute T cell leukemia, we found that leukemias generated from fetal liver (FL) and adult bone marrow (BM) differed dramatically in their leukemia stem cell activity with FL leukemias showing markedly reduced serial transplantability as compared to BM leukemias. We present evidence that this difference is due to NOTCH1-driven autocrine IGF1 signaling, which is active in FL cells but restrained in BM cells by EZH2-dependent H3K27 trimethylation. Further, we confirmed this mechanism is operative in human disease and show that enforced IGF1 signaling effectively limits leukemia stem cell activity. These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer.

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.

RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1, along with transcription factors TAL1 and NOTCH1, as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including insulin-like growth factor 1 receptor (IGF1R) and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL.

IGF1R Derived PI3K/AKT Signaling Maintains Growth in a Subset of Human T-Cell Acute Lymphoblastic Leukemias.

Insulin-like growth factor 1 receptor (IGF1R) is a prevalent signaling pathway in human cancer that supports cell growth/survival and thus contributes to aggressive biological behavior. Much work has gone into development of IGF1R inhibitors; however, candidate agents including small molecule tyrosine kinase inhibitors and blocking antibodies have yet to fulfill their promise clinically. Understanding cellular features that define sensitivity versus resistance are important for effective patient selection and anticipation of outgrowth of a resistant clone. We previously identified an important role for IGF signaling in T-cell acute lymphoblastic leukemia (T-ALL) relying primarily upon genetically defined mouse models. We present here an assessment of IGF1R dependence in human T-ALL using a broad panel of 27 established cell lines that capture a spectrum of the genetic variation that might be encountered in clinical practice. We observed that a subset of cell lines are sensitive to IGF1R inhibition and are characterized by high levels of surface IGF1R expression and PTEN positivity. Interestingly, lentiviral expression or knock-down of PTEN in PTEN-negative/positive cell lines, respectively, had limited effects on their response to IGF1R inhibition, suggesting that PTEN contributes to, but does not define IGF dependence. Additionally, we characterize downstream PI3K/AKT signaling as dominant over RAS/RAF/MEK/ERK in mediating growth and/or survival in this context. Finally, we demonstrate that IGF and interleukin-7 (IL-7) fulfill non-overlapping roles in supporting T-ALL growth. These findings are significant in that they reveal cellular features and downstream mechanisms that may determine the response of an individual patient's tumor to IGF1R inhibitor therapy.

Giant reversible anisotropy changes at room temperature in a (La,Sr)MnO3/Pb(Mg,Nb,Ti)O3 magneto-electric heterostructure.

In a model artificial multiferroic system consisting of a (011)-oriented ferroelectric Pb(Mg,Nb,Ti)O3 substrate intimately coupled to an epitaxial ferromagnetic (La,Sr)MnO3 film, electric field pulse sequences of less than 6 kV/cm induce large, reversible, and bistable remanent strains. The magnetic anisotropy symmetry reversibly switches from a highly anisotropic two-fold state to a more isotropic one, with concomitant changes in resistivity. Anisotropy changes at the scale of a single ferromagnetic domain were measured using X-ray microscopy, with electric-field dependent magnetic domain reversal showing that the energy barrier for magnetization reversal is drastically lowered. Free energy calculations confirm this barrier lowering by up to 70% due to the anisotropic strain changes generated by the substrate. Thus, we demonstrate that an electric field pulse can be used to 'set' and 'reset' the magnetic anisotropy orientation and resistive state in the film, as well as to lower the magnetization reversal barrier, showing a promising route towards electric-field manipulation of multifunctional nanostructures at room temperature.