Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia ...remain poorly understood. Here, we demonstrate an oncogenic KrasG12D-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. KrasG12D-dependent production of GM-CSF in vivo is required for the recruitment of Gr1+CD11b+ myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of KrasG12D-PDECs, and, consistent with the role of GM-CSF in Gr1+CD11b+ mobilization, this effect is mediated by CD8+ T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity.
► Oncogenic KrasG12D upregulates the production of GM-CSF in pancreatic ductal cells ► GM-CSF is required for accumulation of Gr1+CD11b+ cells in neoplastic pancreata ► Gr1+CD11b+ cells counteract CD8+ T cell-mediated suppression of neoplastic growth ► KrasG12D-GM-CSF axis may promote pancreatic cancer by undermining antitumor immunity
Aims
This study aimed to identify the nursing stress factors, which affect turnover intention in hospital nurses.
Background
Nursing stress is known to be an important predictor of turnover intention ...in nurses. Although nurses experience various sources of stress across work environments, cultures, and generations, little is known about the stress factors affecting turnover intention in nurses.
Design
A descriptive cross‐sectional design was employed.
Methods
A total of 329 nurses were recruited through convenience sampling from 27 hospitals in South Korea. Data were collected from May to November 2018 using a questionnaire.
Results
Among the stress factors, stress from patients and their families, workload stress, stress from conflicts with supervisors, and stress from conflicts with peers were associated with turnover intention in hospital nurses. These variables explained 40.0% of the variance in turnover intention among hospital nurses.
Conclusions
Stress from interpersonal relationships with patients and their families, supervisors, and peers may have a considerable impact on turnover intention. To reduce nursing turnover intention, coping strategies to reduce stress from patients and their families should be established. It is necessary to provide programmes that foster interpersonal relationship skills in the workplace. Nurse managers may encourage communication among nurses to establish positive relationships.
SUMMARY STATEMENT
What is already known about the topic?
Nurses' turnover continues to remain a challenging issue across work environments, cultures, and generations.
Nursing stress has a great impact on turnover intention in hospital nurses. However, little is known about the stress factors that affect turnover intention in nurses.
What this paper adds?
Among the nursing stress factors, stress from patients and families had a strong effect on turnover intention in hospital nurses, followed by stress from workload, conflicts with supervisors, and conflicts with peers.
The implications of this paper:
Our findings suggest that stress from interpersonal relationships might have a considerable impact on turnover intention.
Coping strategies to reduce stress from patients and family need to be first established to reduce the turnover intention in hospital nurses.
Nurse managers should be aware of the effects of interpersonal relationships on turnover intention and encourage communication among nurses to establish positive relationships.
Macroautophagy/autophagy is a lysosome-dependent catabolic process for the turnover of proteins and organelles in eukaryotes. Autophagy plays an important role in immunity and inflammation, as well ...as metabolism and cell survival. Diverse immune and inflammatory signals induce autophagy in macrophages through pattern recognition receptors, such as toll-like receptors (TLRs). However, the physiological role of autophagy and its signaling mechanisms in microglia remain poorly understood. Microglia are phagocytic immune cells that are resident in the central nervous system and share many characteristics with macrophages. Here, we show that autophagic flux and expression of autophagy-related (Atg) genes in microglia are significantly suppressed upon TLR4 activation by lipopolysaccharide (LPS), in contrast to their stimulation by LPS in macrophages. Metabolomics analysis of the levels of phosphatidylinositol (PtdIns) and its 3-phosphorylated form, PtdIns3P, in combination with bioinformatics prediction, revealed an LPS-induced reduction in the synthesis of PtdIns and PtdIns3P in microglia but not macrophages. Interestingly, inhibition of PI3K, but not MTOR or MAPK1/3, restored autophagic flux with concomitant dephosphorylation and nuclear translocation of FOXO3. A constitutively active form of FOXO3 also induced autophagy, suggesting FOXO3 as a downstream target of the PI3K pathway for autophagy inhibition. LPS treatment impaired phagocytic capacity of microglia, including MAP1LC3B/LC3-associated phagocytosis (LAP) and amyloid β (Aβ) clearance. PI3K inhibition restored LAP and degradation capacity of microglia against Aβ. These findings suggest a unique mechanism for the regulation of microglial autophagy and point to the PI3K-FOXO3 pathway as a potential therapeutic target to regulate microglial function in brain disorders.
Abbreviations: Atg: autophagy-related gene; Aβ: amyloid-β; BafA1: bafilomycin A
1
; BECN1: beclin 1, autophagy related; BMDM: bone marrow-derived macrophage; CA: constitutively active; CNS: central nervous system; ZFYVE1/DFCP1: zinc finger, FYVE domain containing 1; FOXO: forkhead box O; ELISA:enzyme-linked immunosorbent assay; HBSS: Hanks balanced salt solution; LAP: LC3-associated phagocytosis; MAP1LC3B: microtubule-associated protein 1 light chain 3; LPS: lipopolysaccharide; LY: LY294002; MTOR: mechanistic target of rapamycin kinase; Pam
3
CSK
4
: N-palmitoyl-S-dipalmitoylglyceryl Cys-Ser-(Lys)
4
; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PLA: proximity ligation assay; Poly(I:C): polyinosinic-polycytidylic acid; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB1: ribosomal protein S6 kinase, polypeptide 1; TLR: Toll-like receptor; TNF: tumor necrosis factor; TFEB: transcription factor EB; TSPO: translocator protein.
All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. ...However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions.
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•Gut epithelia mount innate immunity by sensing bacterial-derived uracil•Uracil induces DUOX-dependent intestinal ROS generation•Uracil from allochthonous pathogenic bacteria induces homeostatic inflammation•Long-term uracil release from colitogenic pathobionts causes chronic inflammation
Different gut bacteria have distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, determining homeostasis or pathogenesis in gut-microbe interactions.
Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic ...restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.
AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA
1
: bafilomycin A
1
; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor
The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this ...study was to investigate the potential antitumor effects of a messenger RNA‐HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell‐mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor‐implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV‐treated mice. Furthermore, tumor expansion was significantly reduced upon TC‐1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV‐related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.
Abstract Objectives This study investigated the role of fractional myocardial mass (FMM), a vessel-specific myocardial mass, in the evaluation of physiological severity of stenosis. Using computed ...tomography angiography, the study investigated fractional myocardial mass, a concept of myocardial mass subtended by specific vessel, which could reduce anatomical-physiological mismatch. Background Discordance between anatomical stenosis and physiological severity is common but remains poorly understood. Methods This multicenter study enrolled 463 patients with 724 lesions, who underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography with fractional flow reserve (FFR) measurement. FMM was assessed by allometric scaling analysis of arterial tree length and myocardial mass from CCTA. Results FFR <0.80, a criteria for vessel-specific physiological stenosis, was found in 281 vessels (39%). FMM decreased consistently according to the vessel downstream (p < 0.001, all). The frequency of FFR <0.80 increased in proportion to FMM and inverse proportion to angiographic minimal luminal diameter (MLD) (p < 0.001). In per-vessel analysis, FMM per MLD (FMM/MLD) showed good correlation with FFR (r = 0.61) and was superior to diameter stenosis (DS) for FFR <0.80 by receiver operating characteristic and reclassification analysis (C-statistics = 0.84 versus 0.74, net reclassification improvement NRI = 0.63, integrated discrimination improvement IDI = 0.18; p < 0.001, all). The optimal cutoff of FMM/MLD was 29 g/mm, with sensitivity = 75%, specificity = 77%, positive predictive value = 68%, negative predictive value = 83%, and accuracy = 77%. Addition of FMM/MLD to DS could further discriminate vessels with FFR <0.80 (C-statistic = 0.86 vs. 0.84, NRI = 0.34, IDI = 0.03; p < 0.005, all). In per-range classification analysis, agreement between FFR and FMM/MLD maintained >80% when the severity of disease was away from cutoff. Conclusions FMM/MLD could find physiological severity of coronary artery with higher accuracy than anatomical stenosis. FMM may explain the anatomical-physiological discordance.
Split‐liver transplantation (SLT) should be cautiously considered because the right trisection (RTS) graft can be a marginal graft in adult recipients. Herein, we analyzed the outcomes of RTS‐SLT in ...Korea, where >75% of adult liver transplantations are performed with living donor liver transplantation. Among 2462 patients who underwent deceased donor liver transplantations (DDLTs) from 2005 to 2014, we retrospectively reviewed 86 (3.5%) adult patients who received a RTS graft (RTS‐SLT group). The outcomes of the RTS‐SLT group were compared with those of 303 recipients of whole liver (WL; WL‐DDLT group). Recipient age, laboratory Model for End‐Stage‐Liver Disease (L‐MELD) score, ischemia time, and donor‐to‐recipient weight ratio (DRWR) were not different between the 2 groups (P > 0.05). However, malignancy was uncommon (4.7% versus 36.3%), and the donor was younger (25.2 versus 42.7 years) in the RST‐SLT group than in the WL‐DDLT group (P < 0.05). The technical complication rates and the 5‐year graft survival rates (89.0% versus 92.8%) were not different between the 2 groups (P > 0.05). The 5‐year overall survival (OS) rate (63.1%) and graft‐failure‐free survival rate (63.1%) of the RTS‐SLT group were worse than that of the WL‐DDLT group (79.3% and 79.3%; P < 0.05). The factors affecting graft survival rates were not definite. However, the factors affecting OS in the RTS‐SLT group were L‐MELD score >30 and DRWR ≤1.0. In the subgroup analysis, OS was not different between the 2 groups if the DRWR was >1.0, regardless of the L‐MELD score (P > 0.05). In conclusion, a sufficient volume of the graft estimated from DRWR‐matching could lead to better outcomes of adult SLTs with a RTS graft, even in patients with high L‐MELD scores.
Background
Tai chi, also called taiji or tai chi chuan, is a form of mind–body exercise that originated from China. It combines Chinese martial arts and meditative movements that promote balance and ...healing of the mind and body, involving a series of slowly performed, dance-like postures that flow into one another. As it comprises mental concentration, physical balance, muscle relaxation, and relaxed breathing, tai chi shows great potential for becoming widely integrated into the prevention and rehabilitation of a number of medical and psychological conditions.
Purpose
A growing body of clinical research has begun to evaluate the efficacy of tai chi as a therapy for a variety of health issues. A systematic review and meta-analysis were carried out on randomized controlled trials (RCTs) and quasi-experimental (Q-E) trials that studied the effects of tai chi on psychological well-being.
Method
Drawn from English and Chinese databases, 37 RCTs and 5 Q-E studies published up to May 31, 2013 were included in the systematic review. The methodological quality of the RCTs was evaluated based on the following criteria: adequate sequence generation, allocation concealment, blinding, completeness of outcome data, selective reporting, and other potential biases. Statistical analyses were performed using Review Manager version 5.0.
Results
The studies in this review demonstrated that tai chi interventions have beneficial effects for various populations on a range of psychological well-being measures, including depression, anxiety, general stress management, and exercise self-efficacy. Meta-analysis was performed on three RCTs that used depression as an outcome measure (ES = −5.97; 95 % CI −7.06 to −4.87), with
I
2
= 0 %.
Conclusion
In spite of the positive outcomes, the studies to date generally had significant methodological limitations. More RCTs with rigorous research design are needed to establish the efficacy of tai chi in improving psychological well-being and its potential to be used in interventions for populations with various clinical conditions.
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