H-Content Is Not Predictive of Perfluorocarbon Ocular Endotamponade Cytotoxicity in Vitro

In recent years, cases of retinal toxicity occurred in some European, Middle Eastern, and South American countries following the use of perfluorocarbon liquids (PFCLs) on vitreoretinal surgeries owing to impurities in the product. Moreover, Spanish ophthalmologists reported several toxic cases on the use of perfluoro-n-octane Ala Octa (Alamedics, Dornstadt, Germany), raising the necessity of reviewing the current validated methods used for assessing the safety of PFCLs. We proved that in samples of PFCLs contaminated on purpose with impurities previously detected in Ala Octa devices, the determination of the so-called H-content using a 1H NMR quantitative assay implemented with the electronic reference to access in vivo concentrations 2 technology failed to demonstrate a correlation between the H-content and in vitro cytotoxicity test in ARPE-19 and BALB 3T3 cell lines. Therefore, direct information on the safety of PFCLs was provided only by the cytotoxicity test in vitro validated according to ISO 10993-5, and the H-content was not predictive of perfluorocarbon ocular endotamponade cytotoxicity in vitr

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.National Institutes of Health (U.S.) (Grant P01 CA066996)National Institutes of Health (U.S.) (Grant R01 HL082945)National Cancer Institute (U.S.) (Grant P30-CA14051

CD81 Is Essential for the Re-entry of Hematopoietic Stem Cells to Quiescence following Stress-Induced Proliferation Via Deactivation of the Akt Pathway

A protein that is thought to orchestrate the distribution of other signaling molecules on the cell membrane, CD81, is critical to maintaining the functional integrity of hematopoietic stem cells during their regeneration

Socially assistive robots in health and social care: acceptance and cultural factors. Results from an exploratory international online survey

Aim: This study explored the views of an international sample of registered nurses and midwives working in health and social care concerning socially assistive robots (SARs), and the relationship between dimensions of culture and rejection of the idea that SARs had benefits in these settings. Methods: An online survey was used to obtain rankings of (among other topics) the extent to which SARs have benefits for health and social care. It also asked for free text responses regarding any concerns about SARs. Results: Most respondents were overwhelmingly positive about SARs' benefits. A small minority strongly rejected this idea, and qualitative analysis of the objections raised by them revealed three major themes: things might go wrong, depersonalization, and patient‐related concerns. However, many participants who were highly accepting of the benefits of SARs expressed similar objections. Cultural dimensions of long‐term orientation and uncertainty avoidance feature prominently in technology acceptance research. Therefore, the relationship between the proportion of respondents from each country who felt that SARs had no benefits and each country's ratings on long‐term orientation and uncertainty avoidance were also examined. A significant positive correlation was found for long‐term orientation, but not for uncertainty avoidance. Conclusion: Most respondents were positive about the benefits of SARs, and similar concerns about their use were expressed both by those who strongly accepted the idea that they had benefits and those who did not. Some evidence was found to suggest that cultural factors were related to rejecting the idea that SARs had benefits

Obstacles to compassion-giving among nursing and midwifery managers: an international study

Aim: To explore nursing and midwifery managers’ views regarding obstacles to compassion-giving across country cultures. Background: The benefit of compassionate leadership is being advocated, but despite the fact that healthcare is invariably conducted within culturally diverse workplaces, the interconnection of culture, compassion and leadership is rarely addressed. Furthermore, evidence on how cultural factors hinder the expression of compassion among nursing and midwifery managers is lacking. Methods: Cross-sectional, exploratory, international online survey involving 1 217 participants from 17 countries. Managers’ responses on open-ended questions related to barriers for providing compassion were entered and thematically analysed through NVivo. Results: Three key themes related to compassion-giving obstacles emerged across countries: 1. related to the managers’ personal characteristics and experiences; 2. system-related; 3. staff-related. Conclusions: Obstacles to compassion-giving among managers vary across countries. An understanding of the variations across countries and cultures of what impedes compassion to flourish in healthcare is important. Implications for nursing practice and policy: Nursing mangers should wisely use their power by adopting leadership styles that promote culturally competent and compassionate workplaces with respect for human rights. Policymakers should identify training and mentoring needs to enable the development of managers’ practical wisdom. Appropriate national and international policies should facilitate the establishment of standards and guidelines for compassionate leadership, in the face of distorted organisational cultures and system-related obstacles to compassion-giving

Enactment of compassionate leadership by nursing and midwifery managers: results from an international online survey

Aim To explore the views of an international sample of nursing and midwifery managers concerning attributes that they associate with compassionate management. Method A cross- sectional online survey. Using a snowballing sampling method, 1217 responses were collected from nursing and midwifery managers in 17 countries. A total of complete 933 responses to a question related to which actions and behaviours indicated that a manager was exercising compassionate leadership were analysed for this paper. First, content analysis of the responses was conducted, and second, a relative distribution of the identified themes for the overall sample and for each participating country was calculated. Results Six main themes were identified describing the attributes of a compassionate leader: (1) Virtuous support, (2) Communication, (3) Personal virtues of the manager, (4) Participatory communication, (5) Growth/flourishing/ nurturing and (6) Team cohesion. The first three themes mentioned above collectively accounted for 63% of the responses, and can therefore be considered to be the most important characteristics of compassionate management behaviour. Conclusion The key indicators of compassionate management in nursing and midwifery which were identified emphasise approachability, active and sensitive listening, sympathetic responses to staff members’ difficulties (especially concerning child and other caring responsibilities), active support of and advocacy for the staff team and active problem solving and conflict resolution. While there were differences between the countries’ views on compassionate healthcare management, some themes were widely represented among different countries’ responses, which suggest key indicators of compassionate management that apply across culture

The importance of being a compassionate leader: the views of nursing and midwifery managers from around the world

Introduction: Despite the importance of compassionate leadership in health care, many of the existing publications do not account for the effect of culture. The aim of this study is to explore the views of nursing and midwifery managers from different countries in relation to the definition, advantages, and importance of compassion. Methodology: A cross-sectional, descriptive, exploratory online survey was conducted across 17 countries, containing both closed and open-ended questions. Data from N = 1,217 respondents were analyzed using a directed hybrid approach focusing only on qualitative questions related to compassion-giving. Results: Four overarching themes capture the study’s results: (1) definition of compassion, (2) advantages and importance of compassion for managers, (3) advantages and importance of compassion for staff and the workplace, and (4) culturally competent and compassionate leadership. Discussion: Innovative research agendas should pursue further local qualitative empirical research to inform models of culturally competent and compassionate leadership helping mangers navigate multiple pressures and be able to transculturally resonate with their staff and patients

Forkhead Transcription Factors (FoxOs) Promote Apoptosis of Insulin-Resistant Macrophages During Cholesterol-Induced Endoplasmic Reticulum Stress

OBJECTIVE—Endoplasmic reticulum stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to endoplasmic reticulum stress–associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in type 2 diabetes. However, the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21cip1. and p16INK4a, and Forkhead transcriptional factor 1 (Foxo1), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration