Phenotype-independent DNA methylation changes in prostate cancer

BACKGROUND: Human prostate cancers display numerous DNA methylation changes compared to normal tissue samples. However, definitive identification of features related to the cells' malignant status has been compromised by the predominance of cells with luminal features in prostate cancers. METHODS: We generated genome-wide DNA methylation profiles of cell subpopulations with basal or luminal features isolated from matched prostate cancer and normal tissue samples. RESULTS: Many frequent DNA methylation changes previously attributed to prostate cancers are here identified as differences between luminal and basal cells in both normal and cancer samples. We also identified changes unique to each of the two cancer subpopulations. Those specific to cancer luminal cells were associated with regulation of metabolic processes, cell proliferation and epithelial development. Within the prostate cancer TCGA dataset, these changes were able to distinguish not only cancers from normal samples, but also organ-confined cancers from those with extraprostatic extensions. Using changes present in both basal and luminal cancer cells, we derived a new 17-CpG prostate cancer signature with high predictive power in the TCGA dataset. CONCLUSIONS: This study demonstrates the importance of comparing phenotypically matched prostate cell populations from normal and cancer tissues to unmask biologically and clinically relevant DNA methylation changes

Delivering better outcomes through customer-led project management: the case of the major project BT 21st Century Network in the UK

Traditional approaches of major project management take the strategy of selecting a supplier-led prime/systems integrator. Although this strategy pushes a significant amount of risk to the supplier, project performance may suffer due to lower engagement of the customer in the anticipation of potential issues involving a major project. Thus, this research investigates the implications of the customer, as opposed to a selected external supplier, assuming the role of systems/prime integrator, as a Problem Structuring Method (PSM) to better deal with the soft side and uncertainties of the project. A case study approach is conducted on the major project BT 21st Century Network (BT21CN) to demonstrate that customer-led systems integration projects may provide more balance in the relationship and distribution of risks between supplier and customer, having a positive impact on project performance, accelerating the development of BT’s organisational capabilities, and producing better project outcomes in the long term

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway

Adult hippocampal neurogenesis is decreased in rodent models for stress-related disorders at least partly through an elevated level of glucocorticoids. On the other hand, the mood stabilizer lithium (Li) commonly used for their treatment increases it. This effect is thought to be one of the therapeutic actions of Li, but the molecular mechanism has been poorly understood. Here we established the culture system of adult rat dentate gyrus-derived neural precursor cells (ADPs) and examined the effects of dexamethasone (DEX), an agonist of glucocorticoids receptor, and Li on ADP proliferation. It is possible for ADP to be a type 2a cell, which corresponds to the second stage in a model of four differentiation stages in adult hippocampal neural precursor cells. DEX decreased ADP proliferation, but Li did not have any effect on it. However, Li recovered ADP proliferation decreased by DEX. The recovery effect of Li was abolished by quercetin, an inhibitor of beta-catenin/TCF pathway. The intranuclear translocation of beta-catenin and expression of cyclin D1 are reciprocally regulated by DEX and Li in a way similar to proliferation. In addition, DEX increased the phosphorylation of Tyr(216), which renders glycogen synthase kinase-3beta (GSK-3beta) active on it. These results suggest that GSK-3beta and beta-catenin/TCF pathway might be important in the reciprocal effects between DEX and Li on ADP proliferation and are new targets of therapeutic agents for stress-related disorders

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

PURPOSE: To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). METHODS: The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. RESULTS: When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. RECOMMENDATIONS: Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients