Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma.

ABSTRACT: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor-associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.

A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth.

Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in vitro and in vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

Clinical Effects of the 'Crisis Toolbox' (CTB): A Brief, Skills Based, Intervention Delivered in a Crisis Resolution and Home Treatment Team.

Access to psychological interventions for people under Crisis Resolution and Home Treatment Teams (CRHTTs) is limited. The Crisis Toolbox (CTB) is a skills-based intervention designed to increase access using flexible methods of delivery. This study aimed to evaluate the clinical effects of the CTB. A retrospective service evaluation of 399 participants who accessed the CTB between November 2020 and February 2021 was employed. Sessional measures comprising the Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Scale (GAD-7) were recorded across three time points. Overall, there were significantly decreasing trends in PHQ-9 (ß = - 1.6, p < 0.001) and GAD-7 scores (ß = - 1.5, p < 0.001) in participants who accessed the CTB. The magnitude and direction of specific trends differed according to age, diagnosis, and neurodiversity. The CTB could help reduce depression and anxiety in people experiencing crisis. Randomised controlled trials are now required to test its acceptability, feasibility, and effectiveness.

Nurse ethicists: Innovative resource or ideological aspiration?

In recent years, there have been growing calls for nurses to have a formal advanced practice role as nurse ethicists in hospital contexts. Initially proposed in the cultural context of the USA where nurse ethicists have long been recognised, the idea is being advocated in other judications outside of the USA such as the UK, Australia and elsewhere. Such calls are not without controversy, however. Underpinning this controversy are ongoing debates about the theoretical, methodological and political dimensions of clinical ethics support services generally, and more recently where nurses might 'fit' within such a service. In considering whether nurse ethicists ought to have a place in clinical ethics support services, a number of questions arise such as: Is such a role warranted? If so, what credentials should nurses assuming the title of 'nurse ethicist' be required to have? What standards of practice ought nurse ethicists be required to uphold? What is the ultimate role and function of nurse ethicists in hospital contexts? And in what contexts might a nurse ethicist be most useful? In this essay, brief attention will be given to addressing these questions. It will be concluded that, as a minimum, nurses wishing to assume an advanced nursing practice role as a nurse ethicist must have substantive grounding in the foundational knowledge of the disciplines of both moral philosophy and nursing ethics. They must also not lose sight of the ultimate goal of nursing ethics, notably, to promote and advance ethical nursing practice and the provision of 'good' nursing care.

Acceptability of the 'Crisis Toolbox': a skills-based intervention delivered in a Crisis Resolution and Home Treatment Team during COVID-19.

Crisis Resolution and Home Treatment Teams (CRHTTs) provide 24-hour, seven day per week support for people in crisis. The COVID-19 pandemic has placed significant demand on urgent care and increased the need for brief interventions in CRHTT settings with flexible methods of delivery. This evaluation aimed to examine client satisfaction with the 'Crisis Toolbox' (CTB), a brief, skills-based intervention delivered in one CRHTT during COVID-19. All participants who received the CTB completed a satisfaction questionnaire. Descriptive statistics were calculated to quantify acceptability and qualitative themes were generated using thematic analysis. Fifty-eight people participated, all of whom reported high levels of satisfaction with the CTB. Four qualitative themes also emerged relating to 'Active ingredients of the CTB', 'The therapeutic relationship', 'Service-user preferences' and 'Expectations and continuity of care'. The CTB appears to be a valued intervention. Further research is now needed to assess its clinical impact and effect on operational indicators.

Fostering trusting relationships with older immigrants hospitalised for end-of-life care.

BACKGROUND: Trust has been identified as a vital value in the nurse-patient relationship. Although increasingly the subject of empirical inquiries, the specific processes used by nurses to foster trust in nurse-patient relationships with older immigrants of non-English speaking backgrounds hospitalised for end-of-life care have not been investigated. AIMS: To explore and describe the specific processes that nurses use to foster trust and overcome possible cultural mistrust when caring for older immigrants of non-English speaking backgrounds hospitalised for end-of-life care. RESEARCH DESIGN: A qualitative descriptive approach was used. Twenty-two registered nurses were recruited from four metropolitan health services in Melbourne, Australia. Ethical considerations: Research approval was granted by the Human Research Ethics Committees of the host institution and four participating health services. FINDINGS: Thematic analysis revealed that fostering trust encompassed the following three commensurate stages: establishing trust, strengthening trust and sustaining trust. Underpinning the successful achievement of these stages was the nurses' moral commitment (reflected in their intentional, conscious and conscientious approach) to fostering trust as an essential ingredient of quality end-of-life care. DISCUSSION: This study has shown that while professional competencies are important to providing quality end-of-life care to older immigrant patients of non-English speaking backgrounds, it is a nurse's moral commitment to fostering trust that may ultimately lay the foundations for a trusting quality care relationship to be established and sustained. CONCLUSION: This study has captured the processes used by nurses to foster trust as an essential element of quality end-of-life care in older immigrants. The characteristics of trust and the different factors influencing its expression in diverse cultural contexts are, however, under-researched. Accordingly, gaps remain in the knowledge and understanding of the specific cultural nuances and manifestations of trust across and within different cultures. This is an area that is germane to further cross-cultural and international collaborative scholarly inquiry and research.

Characterization of the Pro-Inflammatory Cytokine IL-1ß on Butyrate Oxidation in Colorectal Cancer Cells.

Cancer, in part, is driven, by alterations in cellular metabolism that promote cell survival and cell proliferation. Identifying factors that influence this shift in cellular metabolism in cancer cells is important. Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that has been reported to be elevated in colorectal cancer patients. While much is known toward the effect of dietary nutrients on regulating inflammation and the inflammatory response, which includes cytokines such as IL-1ß, far less is understood how cytokines impact nutrient fate to alter cancer cell metabolism. Butyrate, a nutrient derived from the fermentation of dietary fiber in the colon, is the preferential exogenous energetic substrate used by non-cancerous colonocytes, but is used less efficiently by colorectal cancer cells. To test whether IL-1ß alters colonocyte energy metabolism, we measured butyrate oxidation in HCT116 colorectal cancer cells with and without IL-1ß. We hypothesize that IL-1ß will push cancerous colonocytes away from the utilization and oxidation of butyrate. In this study, we demonstrate that pretreatment of colorectal cancer cells with IL-1ß diminished butyrate oxidation and NADH levels. This effect was blocked with the interleukin receptor antagonist A (IL-1RA). Moreover, IL-1ß suppressed basal mitochondrial respiration and lowered the mitochondrial spare capacity. By using inhibitors to block downstream targets of the interleukin-1 receptor pathway, we show that p38 is required for the IL-1ß-mediated decrease in butyrate oxidation. These data provide insight into the metabolic effects induced by IL-1ß in colorectal cancer, and identify relevant targets that may be exploited to block the effects of this cytokine. J. Cell. Biochem. 118: 1614-1621, 2017. © 2016 Wiley Periodicals, Inc.

Inattentional blindness and failures to rescue the deteriorating patient in critical care, emergency and perioperative settings: Four case scenarios.

BACKGROUND: Failure to identify and respond to clinical deterioration is an important measure of patient safety, hospital performance and quality of care. Although studies have identified the role of patient, system and human factors in failure to rescue events, the role of 'inattentional blindness' as a possible contributing factor has been overlooked. OBJECTIVES: To explore the nature and possible patient safety implications of inattentional blindness in critical care, emergency and perioperative nursing contexts. METHODS: Analysis of four case scenarios drawn from a naturalistic inquiry investigating how nurses identify and manage gaps (discontinuities) in care. Data were collected via in-depth interviews from a purposeful sample of 71 nurses, of which 20 were critical care nurses, 19 were emergency nurses and 16 were perioperative nurses. Case scenarios were identified, selected and analysed using inattentional blindness as an interpretive frame. RESULTS: The four case scenarios presented here suggest that failures to recognise and act upon patient observations suggestive of clinical deterioration could be explained by inattentional blindness. In all but one of the cases reported, vital signs were measured and recorded on a regular basis. However, teams of nurses and doctors failed to 'see' the early signs of clinical deterioration. The high-stress, high-complexity nature of the clinical settings in which these cases occurred coupled with high cognitive workload, noise and frequent interruptions create the conditions for inattentional blindness. CONCLUSIONS: The case scenarios considered in this report raise the possibility that inattentional blindness is a salient but overlooked human factor in failure to rescue events across the critical care spectrum. Further comparative cross-disciplinary research is warranted to enable a better understanding of the nature and possible patient safety implications of inattentional blindness in critical care nursing contexts.

Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc.

Recognising and responding to 'cutting corners' when providing nursing care: a qualitative study.

AIMS AND OBJECTIVES: The aim of this study is to report on a key finding of a larger study investigating the 'gaps' in patient care that registered nurses encounter during the course of their practice. A key finding of this larger study was that 'cutting corners' was a gap discerned by nurses. BACKGROUND: 'Cutting corners' has been characterised as a 'violation' and threat to patient safety, although there is a paucity of research on this issue. DESIGN: Naturalistic inquiry using a qualitative exploratory descriptive approach. METHODS: Data were collected from a purposeful sample of 71 registered nurses from emergency department, critical care, perioperative, rehabilitation and transitional care and neurosciences settings in Australia and analysed using content and thematic analysis strategies. RESULTS: Cutting corners was a common practice that encompassed (1) the partial or complete omission of patient care, (2) delays in providing care and (3) the failure to do things correctly. Corners were cut in patient assessment, essential nursing care, the care of central venous catheters and medication administration. The practice of cutting corners was perceived as contributing to preventable adverse events. CONCLUSIONS: The study found that cutting corners created gaps that contributed to unfinished nursing care and preventable adverse events. The findings of the study raise the possibility that cutting corners is a salient but underinvestigated characteristic of nursing practice. Further research and inquiry are needed to deepen understanding of cutting corners and its impact on patient safety. RELEVANCE TO CLINICAL PRACTICE: Identifying the nature and implications of cutting corners when providing nursing care is an important contributing factor to improving patient safety and quality care.

'Moral distress'--time to abandon a flawed nursing construct?

Moral distress has been characterised in the nursing literature as a major problem affecting nurses in all healthcare systems. It has been portrayed as threatening the integrity of nurses and ultimately the quality of patient care. However, nursing discourse on moral distress is not without controversy. The notion itself is conceptually flawed and suffers from both theoretical and practical difficulties. Nursing research investigating moral distress is also problematic on account of being methodologically weak and disparate. Moreover, the ultimate purpose and significance of the research is unclear. In light of these considerations, it is contended that the notion of moral distress ought to be abandoned and that concerted attention be given to advancing inquiries that are more conducive to improving the quality and safety of moral decision-making, moral conduct and moral outcomes in nursing and healthcare domains.

Nurses' experiences of ethical preparedness for public health emergencies and healthcare disasters: a systematic review of qualitative evidence.

Little is known about nurses' direct experiences of ethical preparedness for dealing with catastrophic public health emergencies and healthcare disasters or the ethical quandaries that may arise during such events. A systematic literature review was undertaken to explore and synthesize qualitative research literature reporting nurses' direct experiences of being prepared for and managing the ethical challenges posed by catastrophic public health emergencies and healthcare disasters. Twenty-six research studies were retrieved for detailed examination and assessed by two independent reviewers for methodological validity prior to inclusion in the review. Of these, 12 studies published between 1973 and 2011 were deemed to meet the inclusion criteria and were critically appraised. The review confirmed there is a significant gap in the literature on nurses' experiences of ethical preparedness for managing public health emergencies and healthcare disasters, and the ethical quandaries they encounter during such events. This finding highlights the need for ethical considerations in emergency planning, preparedness, and response by nurses to be given more focused attention in the interests of better informing the ethical basis of emergency disaster management.

Andragogy in Practice: Applying a Theoretical Framework to Team Science Training in Biomedical Research.

This study is the first to apply the theoretical principles of Malcolm Knowles' theory of andragogy to evaluate data collected from learners who participated in team science training workshops in a biomedical research setting. Briefly, andragogy includes six principles: the learner's self-concept, the role of experience, readiness to learn, orientation to learning, the learner's need to know, and intrinsic motivation. Using an embedded study design, the primary focus was on qualitative data, with quantitative data complementing the qualitative findings. The deductive analysis demonstrated that approximately 85% of the qualitative data could be connected to at least one andragogical principle. Participant responses to positive evaluation questions were largely related to two principles: readiness to learn and problem-based learning orientation. Participant responses to negative questions were largely connected to two different principles: the role of experience and self-direction. Inductive analysis found an additional theme: meeting biological needs. Quantitative survey results supported the qualitative findings. The study findings demonstrate that andragogy can serve as a valuable construct to integrate into the development of effective team science training for biomedical researchers.

Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models. METHODS: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted. RESULTS: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice. CONCLUSIONS: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.

Academic freedom and the obligation to ensure morally responsible scholarship in nursing.

Academic freedom is generally regarded as being of critical importance to the development, improved understanding, and dissemination of new knowledge in a field. Although of obvious importance to the discipline of nursing, the nature, extent and value of academic freedom and the controversies surrounding it have rarely been considered in the nursing literature. It is a key aim of this paper to redress this oversight by providing a brief examination of: (i) the principle of academic freedom; (ii) the distinction between academic freedom, freedom of speech, and the academic freedom to publish; (iii) the problem of ideological judgments being dressed up as scientific or discipline judgments to supports 'bad' conclusions; and (iv) the standards that might otherwise be appealed to for determining whether maverick manuscripts supporting morally abhorrent conclusions should be accepted for publication. It is suggested that the tenets of academic freedom require robust international debate, with due attention being given to such issues as the development of an international declaration on academic freedom to publish in nursing, how to ensure a robust rebuttal system in nursing journals to counter specious scholarship, and how to better promote the letters pages of nursing journals as a venue for facilitating debate on controversial issues.

Bioethics, cultural differences and the problem of moral disagreements in end-of-life care: a terror management theory.

Cultural differences in end-of-life care and the moral disagreements these sometimes give rise to have been well documented. Even so, cultural considerations relevant to end-of-life care remain poorly understood, poorly guided, and poorly resourced in health care domains. Although there has been a strong emphasis in recent years on making policy commitments to patient-centred care and respecting patient choices, persons whose minority cultural worldviews do not fit with the worldviews supported by the conventional principles of western bioethics face a perpetual struggle in getting their care needs met in a meaningful, safe, and healing way. In this essay, attention is given to exploring why cultural differences exist, why they matter, and how health care providers should treat them in order to reduce the incidence and impact of otherwise preventable harmful moral outcomes in end-of-life care. In addressing these questions, a novel application of the renowned terror management theory will be made.

Promises and Challenges of Immunogenic Chemotherapy in Multiple Myeloma.

Immunological tolerance of myeloma cells represents a critical obstacle in achieving long-term disease-free survival for multiple myeloma (MM) patients. Over the past two decades, remarkable preclinical efforts to understand MM biology have led to the clinical approval of several targeted and immunotherapeutic agents. Among them, it is now clear that chemotherapy can also make cancer cells "visible" to the immune system and thus reactivate anti-tumor immunity. This knowledge represents an important resource in the treatment paradigm of MM, whereas immune dysfunction constitutes a clear obstacle to the cure of the disease. In this review, we highlight the importance of defining the immunological effects of chemotherapy in MM with the goal of enhancing the clinical management of patients. This area of investigation will open new avenues of research to identify novel immunogenic anti-MM agents and inform the optimal integration of chemotherapy with immunotherapy.

Nursing and justice as a basic human need.

This paper explores the idea that justice is a basic human need akin to those famously depicted in Maslow's hierarchy of human needs and, as such, warrants recognition as a core element in representative ideas about nursing. Early nurse theorists positioned the principles and practice of nursing as having their origins in 'universal human needs'. The principle of deriving nursing care from human needs was thought to provide a guide not only for promoting health, but for preventing disease and illness. The nursing profession has had a longstanding commitment to social justice as a core professional value and ideal, obligating nurses to address the social conditions that undermine people's health. The idea of justice as a universal human need per se and its possible relationship to people's health outcomes has, however, not been considered. One reason for this is that justice in nursing discourse has more commonly been associated with law and ethics, and the legal and ethical responsibilities of nurses in relation to individualized patient care and, more recently, changing systems of care to improve health and health outcomes. Although this association is not incorrect, it is incomplete. A key aim of this paper is to redress this oversight and to encourage a broader conceptualization of justice as necessary for human survival, health and development, not merely as a professional value, or legal or ethical principle for guiding human conduct.