The Environment: Alive, Whole, Interconnected and Interacting

Nurses frequently care for individuals whose conditions are related to destructive environmental influences. Although the environment is a central construct in the nursing paradigm, its definition is client oriented, circumscribed, and does not adequately explain situations emanating from the larger physical, social, cultural, political, or economic spheres of the environment. This research described an expanded, ideal, environmental nursing domain derived from selected upstream scholars whose work has addressed broad environmental dimensions. Using the concept of future search, once this idealized environmental domain is envisioned, the nursing profession can begin to discover the knowledge base that is needed in order to created an expanded environmental world view. Combined qualitative data collection methods of individual field interviews using feminist approaches, and a focus group consisting of scholars who have addressed broad environmental dimensions related to nursing were used in this study. Data analysis was performed by using the constant comparative method which consisted of concurrent data collection and analysis. The participants described an ideal environment as the entire planet which is alive, whole, interconnected and interacting. Within this planetary environment are numerous dynamic patterns, dimensions, and levels that are interconnected and have open or indefinite boundaries. Because of the interconnections and interactions, any part of the planet that is unhealthy affects the entire planet adversely. Recommended nursing actions included the use of nursing and ecofeminist paradigms to liberate the nursing profession and the environment from oppressive conditions. Steps to achieving liberation consisted of including the environment as the nursing client and redirecting nursing actions from downstream to upstream environmental activities. The findings of this study have the potential for freeing nurses to expand their actions beyond the present limited environmental arena of the individual person. Using this enlarged conceptualization of the environment, nursing researchers, educators, and practitioners can address health issues within broad environmental dimensions in order to facilitate human well-being

Bestimmung der koronaren Gefäßverkalkungen: Vergleich der Mehrzeilen-Detektor Computertomographie und der Elektronenstrahl Computertomographie

Die Diagnose einer koronaren Atherosklerose durch die Bestimmung der koronaren Verkalkungen zur Abschätzung des Risikos eines zukünftigen kardialen Ereignisses erfährt seit einigen Jahren eine zunehmende Verbreitung. Bisher wurden dazu dezidierte Elektronenstrahl Computertomographen eingesetzt. Neuerdings können koronare Kalzifikationen auch mit Mehrzeilen-Detector CT Geräten erfasst und quantifiziert werden. Die Bestimmung der koronaren Kalzifikationen mit der Mehrzeilen-Detector- gegenüber der Elektronstrahlen-CT hat den Vorteil, dass die Untersuchung kostengünstiger und an weit mehr Standorten durchgeführt werden kann. Koronare Kalzifikationen wurden bisher mit einem proprietären Algorithmus (Agatston Score) quantifiziert. Der Übergang zur Quantifizierung von koronaren Kalzifikationen mit modernen CT Geräten erfordert Quantifizierungsalgorithmen, die von allen CT Gerätetypen gleichermaßen durchgeführt werden können und eine hohe Reproduzierbarkeit haben. Im Rahmen der vorliegenden Studie wurden die Elektonenstrahl- und Mehrzeilen-Detector Computertomographie sowie verschiedene Quantifizierungsalgorithmen (Agatston Score, Volumen, Masse, Dichte und Anzahl der Läsionen) in einem Patientenkollektiv (n=100), bei dem das Ausmaß der koronaren Atherosklerose bestimmt werden sollte, miteinander verglichen. Bei einem Teil der Patienten (n=59) wurde zudem eine Herzkatheteruntersuchung durchgeführt. Bei diesen Patienten konnte die Genauigkeit der verschiedenen Quantifizierungsalgorithmen zur Bestimmung einer koronaren Herzkrankheit ermittelt werden. Die Korrelation zwischen Elektronenstrahl- und Mehrzeilen-Detector CT war für alle Quantifizierungsalgorithmen sehr hoch (0.901-0.993). Aufgrund des unterschiedlichen Untersuchungsprotokolls kam es allerdings zu einem systematischen Fehler mit konstant höheren Werten in der Mehrzeilen-Detector CT. Zusammenfassend konnte gezeigt werden, dass koronare Kalzifikationen mit vergleichbarer Sensitivität und Genauigkeit mit der Elektronenstrahl- und Mehrzeilen-Detector-CT erfasst werden können. Da die Quantifizierung der koronaren Kalzifikationen mit der Masse am besten mit allen Geräten zu reproduzieren war, sollte dieser Algorithmus in der Zukunft in weiteren Studien verwendet werden, die zum Ziel haben, den prognostischen Wert von koronaren Kalzifikationen zu bestimme

Kiri tundmatule, Tönningen

http://tartu.ester.ee/record=b1860573~S1*es

ABCB5-Targeted chemoresistance reversal inhibits merkel cell carcinoma growth

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy. © 2016 The Author

IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response

Objective: Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear. Research design and methods: The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation. Results: IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified $CD4^+$ T cells [IL-21 pOrf plasmid–treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and $FoxP3^−$ cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice. Conclusions: IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation

Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma

About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins

Dendritic cells license regulatory B cells to produce IL-10 and mediate suppression of antigen-specific CD8 T cells

Regulatory B cells (Bregs) suppress and reduce autoimmune pathology. However, given the variety of Breg subsets, the role of Bregs in the pathogenesis of type 1 diabetes is still unclear. Here, we dissect this fundamental mechanism. We show that natural protection from type 1 diabetes in nonobese diabetic (NOD) mice is associated with increased numbers of IL-10-producing B cells, while development of type 1 diabetes in NOD mice occurs in animals with compromised IL-10 production by B cells. However, B cells from diabetic mice regain IL-10 function if activated by the innate immune receptor TLR4 and can suppress insulin-specific CD8 T cells in a dendritic cell (DC)-dependent, IL-10-mediated fashion. Suppression of CD8 T cells is reliant on B-cell contact with DCs. This cell contact results in deactivation of DCs, inducing a tolerogenic state, which in turn can regulate pathogenic CD8 T cells. Our findings emphasize the importance of DC–Breg interactions during the development of type 1 diabetes

Nestin depletion induces melanoma matrix metalloproteinases and invasion

Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-β), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence