Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1.

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.

Developing a Trauma-Informed and Recovery-Oriented Alternative to 'Aggression Management' Training for a Metropolitan and Rural Mental Health Service.

For clinicians working in mental health services, 'aggression management' training is generally prioritised, and often mandated. Traditional 'aggression management' training has the potential to reinforce the perception that violence and aggression are inevitable, and thus defensive and coercive practices are needed. This paper outlines the principles and processes that underpinned the development of two training programs designed as recovery-oriented and trauma-informed alternatives to traditional 'aggression management' training. The focus of the paper is on exploring how 'aggression management' training can be aligned with best practice principles. The programs were developed in a metropolitan and rural mental health service and aimed to reduce the need for defensive and coercive practices by promoting therapeutic engagement. A key feature of both programs is an orientation towards safety rather than risk. By embedding the principles of recovery and trauma-informed care in their development and orienting training towards enhancing safety, clinicians are provided with a new way of conceptualising and responding to 'aggression'. Experiential methods in the delivery of the training, and the co-design and co-delivery with peer (consumer) educators were important in supporting attitudinal change. To promote safety, the language and content of training programs must reflect contemporary principles and approaches such as trauma-informed care and recovery. This paper illustrates that to be effective, these principles and approaches must not just be described, but modelled in the development, design, and delivery of the training.

Workplace experiences of mental health consumer peer workers in New South Wales, Australia: a survey study exploring job satisfaction, burnout and turnover intention.

BACKGROUND: Consumer peer workers are individuals with lived experience of mental health issues and recovery who are employed to use their lived experience to support others. The consumer peer workforce has expanded substantially in recent years. While some research has explored the workplace experiences of peer workers, no previous studies have explored job satisfaction, burnout or turnover intention for this workforce. METHODS: Consumer peer workers in New South Wales, Australia were invited to complete a survey designed to explore their workplace experiences. The survey included measures of job satisfaction, burnout, turnover intention, job demands and job resources, and satisfaction with supervision, professional development and opportunities for career progression. Questions also explored positive and negative aspects of positions. Analyses included exploration of the relationships between of job satisfaction, burnout, turnover intention, job demands and job resources as well as tabulation of common positive and negative aspects of positions. Results were also compared with findings from a previous study exploring workplace experiences of other mental health workers. RESULTS: A total of 67 peer workers participated in the study. Overall job satisfaction, burnout (disengagement and exhaustion) and turnover intention for peer workers was not significantly different to other mental health workers. Job satisfaction, disengagement, exhaustion and turnover intention were all significantly inter-related. Job resources of social support, job control, feedback, and rewards and recognition were associated with positive workplace experiences and the job demand of "physical environment" was most substantially associated with poorer workplace experiences. The most common positive aspect of positions was "connecting with consumers" and the most common negative aspect of positions was "attitudes of clinicians / workplace culture". Access to supervision from a senior peer worker was associated with more positive workplace experiences. CONCLUSIONS: This research demonstrates that while consumer peer workers do not appear to experience poorer job satisfaction or higher levels of burnout or turnover intention than other mental health workers, a range of challenges do exist. Efforts to further expand the peer workforce (especially senior peer worker roles) and to promote more positive attitudes and workplace cultures are likely to promote better workplace experiences for peer workers.

EGFR Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma.

PURPOSE: Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. EXPERIMENTAL DESIGN: Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (n = 14) and validation set (n = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in vivo glioma models. RESULTS: EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping, which augmented the cytotoxicity. EGFR amplification-associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in nonamplified models. CONCLUSIONS: EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.

ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, due in part to the propensity of lung cancer to metastasize. Aberrant epithelial-to-mesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT cell-cell adhesion is reduced allowing cells to dissociate and invade. Of the EMT-associated transcription factors, ZEB1 uniquely promotes NSCLC disease progression. Here we apply two independent screens, BioID and an Epigenome shRNA dropout screen, to define ZEB1 interactors that are critical to metastatic NSCLC. We identify the NuRD complex as a ZEB1 co-repressor and the Rab22 GTPase-activating protein TBC1D2b as a ZEB1/NuRD complex target. We find that TBC1D2b suppresses E-cadherin internalization, thus hindering cancer cell invasion and metastasis.

Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma.

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Stigmatization and self-determination of preregistration nurses: A path analysis.

The concept of stigma and the stigmatizing behaviours of health-care professionals can have a profound influence on people with mental illness. A key construct that has been identified as influencing our behaviours is self-determination. As such, in the present study, we attempted to examine the connection and influence of motivational measures on the stigmatization of preregistration nurses. Data were collected once using three surveys that measured the motivational responses and stigmatizing behaviours of preregistration nurses after an approved mental health clinical placement. Using a path analysis, the results indicated that psychological needs significantly influenced preregistration nurses' self-determination towards work. In addition, self-determination was a significant influence on the stigmatization behaviours of preregistration nurses. The results of the present study provide initial empirical evidence that supports the importance of professional self-determination and the potential connection of quality care, as illustrated with the low stigmatizing behaviours of preregistration nurses who are more self-determined towards their work/career. Because of the significant results of the present study, it is recommended that future research is needed that uses self-determination theory as a lens to understand the application and importance within the field of nurse education.

Examination of a therapeutic-recreation based clinical placement for undergraduate nursing students: A self-determined perspective.

Nursing students across the globe are expected to undertake clinical placements. To date, there have been no studies that have examined the potential educational benefits for undergraduate nursing students engaged in a mental health clinical placement grounded in self-determination theory. The present study examined the experiences of undergraduate students engaged in a mental health clinical placement termed Recovery Camp. An ethnographic methodology within a case study approach was used. The researchers were immersed in the clinical placement, which took place at a YMCA camp facility. Participants were 20 3rd year undergraduate nursing students. To gain insight and understanding, the researchers used interviews, observations, and reflective journals. The constant-comparative method was used to analyse the data. Emergent themes identified from systematic analysis were: (a) social connection and (b) experiential learning. Recovery Camp facilitated a sense of inclusion and positive/supportive behaviour. It also enhanced student learning and understanding of symptoms of mental illness. Findings from this study support and extend findings for the use of therapeutic-recreation based work placement experiences in the clinical education of future nurses. Findings demonstrated a link between this type of placement and undergraduate student's development of deeper knowledge of symptoms and experiences associated with mental illness.

Preparing Nursing Students for Mental Health Care: The Impact of a Recovery-oriented Clinical Placement.

The provision of mental health care has recently focused on the concept of recovery-oriented care. Clinical placements are important for imparting recovery-oriented knowledge and skills to students. However, it has been determined that not all clinical placements are beneficial for future nursing professionals. The aim of this study was to examine what elements of professional learning were facilitated by engagement in a recovery- and recreation-based clinical placement for pre-registration nursing students called Recovery Camp. Qualitative data were collected through individual interviews and reflective journals of pre-registration nurses. Findings from this study indicate that Recovery Camp enhanced students' understanding of stigma, developed their professional knowledge and applied skills, and helped them gain insight into the role a consumer plays in his/her own recovery journey. Placements that allow pre-registration nurses the opportunity to authentically engage with people with a lived experience of mental illness may assist in the effective development of future professionals in meeting their diverse needs.

Innovative Mental Health Clinical Placement: Developing Nurses' Relationship Skills.

Engagement in clinical placements is mandatory for all pre-registration nursing programs. Although clinical placements can be valuable, recent literature illustrates that placements within a mental health setting can vary in their educational development. The aim of the current study was to examine the potential learning benefit of 20 pre-registration nursing students in an innovative, university-accredited mental health clinical placement called Recovery Camp. Recovery Camp is a 5-day immersive clinical placement, grounded in therapeutic recreation, which involves all participants engaging in a variety of activities focused on enhancing personal recovery. Qualitative data were collected using individual interviews, reflective journals, and researcher field notes. Analysis of data was conducted using an inductive thematic approach. Analysis of data revealed five themes: (a) Initial Anxiety/Nervousness, (b) Diffusion of Power, (c) Student Perceptions of Consumers, (d) Interaction and Communication, and (e) Resource Shift as a Result of Camp. Developing the professional learning of pre-registration nurses through immersion in effective clinical placements is paramount. Findings demonstrate that pre-registration nurses may benefit from clinical placements that provide immersive and collaborative experiences that allow for the development of relationship-oriented skills that can facilitate person-centered care. [Journal of Psychosocial Nursing and Mental Health Services, 55(2), 36-43.].

Goal Setting Among People Living with Mental Illness: A Qualitative Analysis of Recovery Camp.

People living with mental illness (consumers) often experience difficulty in achieving life goals, particularly those important for their recovery. An innovative approach to address consumers' goals for recovery can be found in the form of therapeutic recreation (TR) initiatives. Recovery Camp is a five-day TR program, bringing together people with a serious mental illness, undergraduate health students, and staff members. This article aims to examine the types of goals set by consumers in the context of Recovery Camp, and to what extent the self-identified goals were attained. The consumers (n  =  27) were invited to set goals that they wished to achieve during the week. On the final day of Recovery Camp, each participant rated the degree to which they felt that each of their goals was achieved or not. The goals were themed using content analysis, revealing four key themes: connectedness, developing healthy habits, challenging oneself, and recovery. All goals were, to some extent, attained. The results suggest people with a mental illness are able to both set and evaluate the self-identified goals in the context of a TR initiative. A collaborative recovery approach indicates that goal planning should be undertaken in direct consultation with the consumer.

Effect of immersive workplace experience on undergraduate nurses' mental health clinical confidence.

Preregistration education needs to ensure that student nurses are properly trained with the required skills and knowledge, and have the confidence to work with people who have a mental illness. With increased attention on non-traditional mental health clinical placements, further research is required to determine the effects of non-traditional mental health clinical placements on mental health clinical confidence. The aim of the present study was to investigate the impact of a non-traditional mental health clinical placement on mental health nursing clinical confidence compared to nursing students undergoing traditional clinical placements. Using the Mental Health Nursing Clinical Confidence Scale, the study investigated the relative effects of two placement programmes on the mental health clinical confidence of 79 nursing students. The two placement programmes included a non-traditional clinical placement of Recovery Camp and a comparison group that attended traditional clinical placements. Overall, the results indicated that, for both groups, mental health placement had a significant effect on improving mean mental health clinical confidence, both immediately upon conclusion of placement and at the 3-month follow up. Students who attended Recovery Camp reported a significant positive difference, compared to the comparison group, for ratings related to communicating effectively with clients with a mental illness, having a basic knowledge of antipsychotic medications and their side-effects, and providing client education regarding the effects and side-effects of medications. The findings suggest that a unique clinical placement, such as Recovery Camp, can improve and maintain facets of mental health clinical confidence for students of nursing.

Recovery Camp: Assisting consumers toward enhanced self-determination.

Mental health consumers are often socially isolated and may lack the basic leisure competencies which serve as a critical building block for community (re)integration. Therapeutic recreation (TR), as a treatment modality for people with mental illness, is yet to be fully embraced in the Australian health-care setting, despite having a strong historical foundation in North America. A team of academics created a TR experience, termed Recovery Camp, which was designed to collectively engage consumers and future health professionals drawn from a range of discipline areas. The 2014 Recovery Camp was staged over a five day period and involved 28 adult consumers living with mental illness. Consumers undertook a diverse range of experiential recreation activities engineered to facilitate individual engagement and to encourage the development of positive therapeutic relationships and teamwork. The camp atmosphere was deliberately community-based and recovery-oriented, valuing the lived experience of mental illness. Using a 2 × 3 design involving a camp and comparison group, the study sought to examine the influence of a TR programme on the self-determination of individuals with a mental illness. Those who participated in the Recovery Camp reported an increase in awareness of self and perceived choice post-camp, relative to the comparison group. While this difference remained significant for awareness of self at three-month follow-up, there was no significant difference in perceived choice between the two groups at follow-up. Study findings serve to support the role of recreation within a recovery framework to positively change the health-related behaviour of mental health consumers.

The Effect of Respite Services on Carers of Individuals With Severe Mental Illness.

Many individuals with severe mental illness (SMI) require the support of an informal carer, such as a family member or close friend, to assist with everyday living. The difficulties and altered life circumstances experienced by individuals with SMI result in carers taking on significant responsibilities. The current study aimed to address the benefits to carers of several days relief from their caring responsibilities. Carers (N = 9) of a cohort of individuals with SMI who attended a therapeutic recreation initiative, Recovery Camp, were surveyed in late May 2015. A custom-designed instrument using open and closed questions was administered. Data were analyzed using the constant-comparative method. Participants reported negative health effects that they directly associated with their caring responsibilities. The experience of having a break when their care recipient attended Recovery Camp was positive for all participants, highlighting the need for respite services. Further research is required to explore the specific respite needs of individuals who provide care to those with SMI to reduce the burden experienced by these vulnerable populations. [Journal of Psychosocial Nursing and Mental Health Services, 54 (12), 33-38.].

Perceived Control among People with Severe Mental Illness: A Comparative Study.

BACKGROUND: Given the importance of perceived control to mental health and recovery, research is needed to determine strategies to increase perceived control for people with a mental illness. AIM: Investigate the implications of a therapeutic recreation program on the perceived control of people with a mental illness. METHOD: Participants of an intervention group (n=27) and comparison group (n=18) completed the Perceived Control Across Domains Scale at three time intervals. Subscale and total scores were analysed. RESULTS AND DISCUSSION: Significant variation occurred in the perceived control areas of substance use, personal cognition and personal empowerment. IMPLICATIONS: A unique nurse led therapeutic recreation initiative, such as Recovery Camp, can improve and maintain facets of perceived control among people with mental illness.

Nursing students' reflections on the learning experience of a unique mental health clinical placement.

INTRODUCTION: There exists a need for innovative thinking to identify new clinical placement opportunities for nursing students. Recovery-based clinical placements for mental health nurse students remain unique and require investigation. AIM: To examine the learning experience of Bachelor of Nursing students who undertook an innovative mental health clinical placement known as Recovery Camp. DESIGN: This study incorporated qualitative analysis of written reflections. Using Braun and Clarke's (2006) six phases of thematic analysis the corpus of student reflections were reviewed by three members of the research team independent to each other. FINDINGS: Four themes emerged. The theme of Pre-placement Expectations incorporates participant foci on pre-conceptions of Recovery Camp. The theme of Student Learning incorporates the ways in which participants recognised the experience of Recovery Camp influenced learning. Reflections themed under the title Placement Setting include discussion of the Recovery Camp as a clinical placement. The theme of Future Practice incorporates students' reflections on how they plan to practice as nurses as a result the learning experiences of Recovery Camp. CONCLUSIONS: An immersive clinical placement such as Recovery Camp can influence students' perceptions of people with mental illness, have a positive impact on student learning and influence students' decisions about future practice. The learning experience of nursing students whom attend unique, recovery-orientated clinical placements can be both positive and educative.

Can a clinical placement influence stigma? An analysis of measures of social distance.

BACKGROUND: The way people who experience mental illness are perceived by health care professionals, which often includes stigmatising attitudes, can have a significant impact on treatment outcomes and on their quality of life. OBJECTIVE: To determine whether stigma towards people with mental illness varied for undergraduate nursing students who attended a non-traditional clinical placement called Recovery Camp compared to students who attended a 'typical' mental health clinical placement. DESIGN: Quasi-experimental. PARTICIPANTS: Seventy-nine third-year nursing students were surveyed; n=40 attended Recovery Camp (intervention), n=39 (comparison group) attended a 'typical' mental health clinical placement. METHODS: All students completed the Social Distance Scale (SDS) pre- and post-placement and at three-month follow-up. Data analysis consisted of a one-way repeated measures analysis of variance (ANOVA) exploring parameter estimates between group scores across three time points. Two secondary repeated measures ANOVAs were performed to demonstrate the differences in SDS scores for each group across time. Pairwise comparisons demonstrated the differences between time intervals. RESULTS: A statistically significant difference in ratings of stigma between the intervention group and the comparison group existed. Parameter estimates revealed that stigma ratings for the intervention group were significantly reduced post-placement and remained consistently low at three-month follow-up. There was no significant difference in ratings of stigma for the comparison group over time. CONCLUSIONS: Students who attended Recovery Camp reported significant decreases in stigma towards people with a mental illness over time, compared to the typical placement group. Findings suggest that a therapeutic recreation based clinical placement was more successful in reducing stigma regarding mental illness in undergraduate nursing students compared to those who attended typical mental health clinical placements.

Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression.

UNLABELLED: The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. SIGNIFICANCE: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo-YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5-CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival.

The effectiveness of extrication collars tested during the execution of spine-board transfer techniques.

BACKGROUND CONTEXT: In the prehospital stages of emergency care, cervical collars are (supposedly) used to aid rescuers in maintaining in-line stabilization of the spinal column as patients with potential or actual injuries are shifted onto a spine board to achieve full spinal immobilization. Unfortunately, not a single study has examined the effectiveness of cervical collars to control motion during the execution of spine-board transfer techniques. PURPOSE: To evaluate the controlling effect of three cervical collars during the execution of spine-board transfer techniques. STUDY DESIGN: This was a repeated measures investigation in which a cadaveric model was used to test the effectiveness of the Ambu (Ambu, Inc., Linthicum, MD), Aspen (Aspen Medical Products, Inc., Long Beach, CA) and Miami J (Jerome Medical, Moorestown, NJ) collars during the execution of the log-roll (LR) maneuver and the lift-and-slide (LS) technique. METHODS: Six medical professionals executed the LR and the LS on five cadavers. An electromagnetic tracking device was used to capture angular movements generated at the C5-C6 vertebral segment during the execution of both transfer techniques. The types of motion that were analyzed in this study were flexion-extension, lateral flexion and axial rotation motion. To test the three cervical collars, an experimental lesion (ie, a complete segmental instability) was created at the aforementioned spinal level of the cadavers and sensors from the electromagnetic tracking device were affixed to the specified vertebrae to record the motion generated at the site of the lesion. RESULTS: Statistical tests did not reveal a significant interaction between the independent variables of this study (ie, transfer technique and collar type), lending no support to the notion that there may be a combination of collar and transfer technique that could theoretically offer added protection to the patient. Although there was a decrease in the amount of motion generated in every one of the planes of motion as a result of wearing each of the three collars, none of the changes that emerged proved to be significantly different. A significant difference was noted between the LR and LS techniques when the amount of lateral flexion and axial rotation motion generated with each of the procedures were compared. In both cases, execution of the LR maneuver resulted in significantly more motion. CONCLUSIONS: The data presented here suggest that the collars tested in this study are functionally similar. It is recommended that this study be repeated with a larger sample size.