It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced ‘metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

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BackgroundRenal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes.MethodsDapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue.ResultsAfter treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05).ConclusionDapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

Workplace bullying experienced by clinical nurses is associated with burnout, a factor that threatens the quality of nursing care and patient safety. This study examined the association of workplace bullying with burnout, professional quality of life, and turnover intention among clinical nurses. A descriptive cross-sectional study was conducted using a structured questionnaire. Data were collected from 324 nurses and were analyzed using t-test, one-way analysis of variance, and multiple regression. Controlling for the general characteristics of the participants, workplace bullying had a significant association with emotional exhaustion (B = 0.29, p < 0.01) and depersonalization (B = 0.15, p < 0.01) among the subdomains of burnout, compassion fatigue among the components of professional quality of life (B = 0.15, p < 0.01), and turnover intention (B = 0.05, p < 0.01). Thus, preventing workplace bullying is important to reduce clinical nurses’ burnout and turnover. The role of nursing leadership is crucial to develop interventions that reduce workplace bullying and successfully create a professional, nurturing, and supportive work culture.

While it is generally accepted that pedagogical content knowledge (PCK) is an essential knowledge base for science teachers, educational researchers are not clear on how it develops. Previous researchers have suggested that classroom practice may play a significant role. Therefore, it is important to look at beginning teachers' PCK and its development during the first years in the classroom. Using the pilot year data from a larger study, we developed and employed a rubric to help understand 24 beginning secondary science teachers ‘PCK, focusing on two categories: Knowledge of Student Learning and Knowledge of Instructional Strategies. The results of analysis did not show a statistically significant change between the groups, but when comparisons were made with all of the teachers, the category of Knowledge of Students Learning did significantly change. In this paper we report the results of the pilot year data, provide examples of how we employed the rubric to assess teachers’ PCK, and discuss how this study benefits understanding beginning teachers' PCK.

Background:The role of HDAC3 in allergic skin inflammation remains unknown. Results: HDAC3 interacts with Fc⑀RI and regulates expression of MCP1 through Sp1 and c-Jun to mediate allergic skin inflammation. Conclusion: HDAC3 mediates allergic skin inflammation in relation with angiogenesis by regulating MCP1. Significance: HDAC3 serves as a target for development of allergy therapeutics.

Recurrent ICHs and MBs are common after long-term follow-up of primary ICH. The number of MBs on baseline GRE may predict the recurrence of the ICH.

Highly accurate detection of the intracranial hemorrhage without delay is a critical clinical issue for the diagnostic decision and treatment in an emergency room. In the context of a study on diagnostic accuracy, there is a tradeoff between sensitivity and specificity. In order to improve sensitivity while preserving specificity, we propose a cascade deep learning model constructed using two convolutional neural networks (CNNs) and dual fully convolutional networks (FCNs). The cascade CNN model is built for identifying bleeding; hereafter the dual FCN is to detect five different subtypes of intracranial hemorrhage and to delineate their lesions. Using a total of 135,974 CT images including 33,391 images labeled as bleeding, each of CNN/FCN models was trained separately on image data preprocessed by two different settings of window level/width. One is a default window (50/100[level/width]) and the other is a stroke window setting (40/40). By combining them, we obtained a better outcome on both binary classification and segmentation of hemorrhagic lesions compared to a single CNN and FCN model. In determining whether it is bleeding or not, there was around 1% improvement in sensitivity (97.91% [± 0.47]) while retaining specificity (98.76% [± 0.10]). For delineation of bleeding lesions, we obtained overall segmentation performance at 80.19% in precision and 82.15% in recall which is 3.44% improvement compared to using a single FCN model.