Critical regulatory levels in tumor differentiation: Signaling pathways, epigenetics and non-coding transcripts.

Approaches to induce tumor differentiation often result in manageable and therapy-naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non-coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build-up.

The impact of nurses' perceptions of systems thinking on occurrence and reporting of adverse events: A cross-sectional study.

AIMS: To assess systems thinking level and its relationship with occurrence and reporting of adverse events in Iranian nurses. BACKGROUND: Systems thinking has recently emerged as an important element of patient safety and quality improvement in health care systems. It helps health care professionals to understand the different elements of health care systems, the interrelatedness and interdependencies of these elements in the health care systems. METHODS: This cross-sectional survey was carried out in 10 teaching hospitals in Tehran, Iran. A total of 511 nurses were selected using simple random sampling. Systems thinking was measured using the validated Systems Thinking Scale. Data analysis was performed by descriptive analyses, independent t test and logistic regression analysis. RESULTS: The average score for total systems thinking was a mean of 49.45 (SD = 12.10; range 0-80). In total, 67.5% of participants reported the experience of the occurrence of adverse events leading to harm to patients, and 65.2% of them responded as having appropriate adverse events reporting behaviours. Nurses who had higher scores in systems thinking were found to be more likely to report adverse events (odds ratio = 1.07; 95% CI = 1.05-1.09), whereas they were less prone to experience adverse events (odds ratio = 0.97; 95% CI = 0.95-0.98). CONCLUSION: Our results indicated that the nurses' systems thinking level was moderate. Systems thinking had a significant role in preventing the occurrence of adverse events as well as improving the reporting of adverse events. Therefore, it is recommended to enhance the competency of nurses' systems thinking to prevent the occurrence of adverse events and to improve the reporting of adverse events. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers need to focus on the systems thinking weaknesses and the occurrence and the reporting of adverse events in policymaking, practice and research. Also, systems thinking should be integrated with the health care system for preventing the occurrence of adverse events and improving reporting of adverse events. They should support, lead and allocate the essential pragmatic strategies and resources for the involvement of all health care members in policymaking.

A Wnt-mediated phenotype switch along the epithelial-mesenchymal axis defines resistance and invasion downstream of ionising radiation in oral squamous cell carcinoma.

BACKGROUND: Dynamic transitions of tumour cells along the epithelial-mesenchymal axis are important in tumorigenesis, metastasis and therapy resistance. METHODS: In this study, we have used cell lines, 3D spheroids and tumour samples in a variety of cell biological and transcriptome analyses to highlight the cellular and molecular dynamics of OSCC response to ionising radiation. RESULTS: Our study demonstrates a prominent hybrid epithelial-mesenchymal state in oral squamous cell carcinoma cells and tumour samples. We have further identified a key role for levels of E-cadherin in stratifying the hybrid cells to compartments with varying levels of radiation response and radiation-induced epithelial-mesenchymal transition. The response to radiation further entailed the generation of a new cell population with low expression levels of E-cadherin, and positive for Vimentin (ECADLow/Neg-VIMPos), a phenotypic signature that showed an enhanced capacity for radiation resistance and invasion. At the molecular level, transcriptome analysis of spheroids in response to radiation showed an initial burst of misregulation within the first 30 min that further declined, although still highlighting key alterations in gene signatures. Among others, pathway analysis showed an over-representation for the Wnt signalling pathway that was further confirmed to be functionally involved in the generation of ECADLow/Neg-VIMPos population, acting upstream of radiation resistance and tumour cell invasion. CONCLUSION: This study highlights the functional significance and complexity of tumour cell remodelling in response to ionising radiation with links to resistance and invasive capacity. An area of less focus in conventional radiotherapy, with the potential to improve treatment outcomes and relapse-free survival.

Generation of stable ARE- driven reporter system for monitoring oxidative stress.

BACKGROUND: NF-E2-related factor2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major defensive mechanism against oxidative stress and is up regulated by specific antioxidants and oxidants to comprise the chemoptotective response. Detection of ARE-activating compounds helps to develop new drugs and identify/quantify the tension range of the oxidants. Important reasons promoting this work are high throughput, rapid and inexpensive experiments relative to the in vitro studies for ARE-Nrf2 pathway monitoring of chemicals and environmental samples. METHODS: In this study hepatoma Huh7 reporter cell line was generated which contains a luciferase gene under the control of an ARE. This is the first example of ARE construct containing one copy of extended consensus response element. The cells were treated with hydroquinone (HQ) and p-benzoquinone (BQ) (oxidative stress inducers) and the antioxidant, curcumin. RESULTS: The luciferase activity was induced in a concentration-dependent manner in a concentration range of 1-2 µM for BQ and HQ. Curcumin was also validated as an ARE inducer in concentration above 10 µM. In addition, this reporter cell line provides a rapid detection as early as 4 h to respond to the ARE inducers. CONCLUSION: It is a powerful tool for the sensitive and selective screening of chemicals, drugs and environmental samples for their antioxidant and oxidant activities.

Dendrosomal curcumin inhibits metastatic potential of human SW480 colon cancer cells through Down-regulation of Claudin1, Zeb1 and Hef1-1 gene expression.

Colon cancer is one of the leading causes of cancer-associated death worldwide. The prognosis for advanced colorectal cancers remains dismal, mainly due to the propensity for metastatic progression. Accordingly, there is a need for effective anti-metastasis therapeutic agents. Since a great body of research has indicated anticancer effects for curcumin, we investigated the effects of dendrosomal curcumin (DNC) on cellular migration and adhesion of human SW480 cells and possible molecular mechanisms involved. Different methods were applied in this study including MTT, Scratch and adhesion assays as well as real-time PCR and transwell chamber assays. Based on the results obtained, DNC inhibits metastasis by decreasing Hef 1, Zeb 1 and Claudin 1 mRNA levels and can reduce SW480 cell proliferation with IC50values of 15.9, 11.6 and 7.64 µM at 24, 48 and 72 h post-treatment. Thus it might be considered as a safe formulation for therapeutic purpose in colorectal cancer cases.

How benzene and its metabolites affect human marrow derived mesenchymal stem cells.

Benzene is a known environmental pollutant with demonstrated leukemogenic activity. Marrow mesenchymal stem cells (MSCs), contribute to skeletal remodeling and repair. They also support haematopoiesis constructing important elements of haematopoietic niche. In the present study, the effects of a range of benzene concentrations along with those of its reactive metabolites, p-benzoquinone (BQ) and hydroquinone (HQ) on the viability of MSCs, apoptosis induction and caspase3/7 activity in these cells were analyzed. Our findings revealed that low concentrations of these chemicals (10µM of benzene, 5µM of either of BQ or HQ) significantly increase the number of chemically treated cells. Moreover, applied BQ/HQ concentrations were shown to be able to considerably inhibit caspase3/7 activity. While in benzene exposure experiments, the lowest concentration triggered the greatest increase in caspase3/7 activity during the initial hours of exposure. On the other hand, MSCs exposure to higher concentrations of benzene (100µM) and its metabolites, BQ/HQ (10µM and 50µM), can induce cell death after 24h of exposure mainly through apoptotic pathways. In addition, changes in the expression of six mRNAs due to being subjected to 10µM of BQ or HQ and 50µM of benzene were assessed. The genes under investigation were RUNX2, WNT5A, DKK1, JAG1, KITLG and CXCL12 which are expressed by MSCs playing roles in adipo-osteogenic differentiation of MSCs and the regulation of haematopoiesis. The analysis exhibited a great augmentation in RUNX2 expression associated with DKK1 and KITLG up-regulation. The results also indicated that treatment of cells with all three chemicals gives rise to down-regulation of JAG1 and treatment with both HQ and BQ triggers WNT5A over-expression. With regard to CXCL12, treatment with BQ caused slight up-regulation and treatment with HQ led to down-regulation. The alterations observed in the expression profile of genes could affect/modify the process of differentiation of MSCs into osteoblast. Other expected outcomes involve augmented canonical Wnt signaling activity in exposed cells with RUNX2 overexpression as the indicator which is probably forced to decrease to the normal level via DKK1 and WNT5A up-regulation. RUNX2 overexpression in MSCs can also be indicative of the RUNX2 up-regulation in myeloid progenitors thereby its involvement in AML development due to benzene exposure. Observed changes in the expression of WNT5A, DKK1, KITLG, CXCL12 and JAG1 can lead to the disturbance of HSC niche resulting in haematopoietic failure and leukemia development. It is obvious that increased viability together with caspase3/7 inhibition could aggravate the adverse effects of exposure to these chemicals.