Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin () gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin.

Ethical considerations in recruiting primary care patients to research studies.

Background: How patients are selected and subsequently invited to take part in research has important implications for gaining informed, voluntary consent.

Objective: This article identifies and discusses common ethical issues that are faced by researchers when recruiting patients from primary care settings.

Discussion: Recruiting primary care patients for research studies should be guided by the core ethical values of merit and integrity, respect, justice and beneficence.

Alcohol enquiry by GPs - Understanding patients' perspectives: A qualitative study.

Background: Patients' beliefs and attitudes toward receiving alcohol enquiry from general practitioners (GPs) are unclear. These need to be understood to implement pragmatic, early detection and brief intervention strategies.

Methods: We purposively sampled 23 participants from respondents of an earlier survey conducted in a general practice clinic in Sydney, Australia.

Consultation contexts and the acceptability of alcohol enquiry from general practitioners - a survey experiment.

Background: General practitioners have a crucial role in detecting risky drinking in patients. However, little is known about how the context of the consultation affect patient acceptability of these discussions.

Methods: During one week in May 2014, adult patients seen at a community general practice in Sydney were randomised to receive one of two postal questionnaires.

Let's listen to patients' and GPs' perspectives on alcohol-screening research.

Alcohol-screening questionnaires have been found to be effective in the early detection of risky drinking but are rarely used by clinicians in primary care. As research agenda tend not to seek the perspectives of patients and general practitioners (GPs), the best way to address the barriers to implementation is unclear. Contemporary research to explore patient beliefs and attitudes towards alcohol enquiry by GPs is needed.

Research ethics and approval process: A guide for new GP researchers.

Background: The underlying moral principles and values, and the virtues held as desirable for a researcher, should be reflected upon and embedded in the research. The foundation step is to download the National Health and Medical Research Council's (NHMRC's) National Statement on Ethical Conduct in Human Research and the NHMRC's Guidelines for Ethical Conduct in Aboriginal and Torres Strait Islander Health Research to use as references.

Objective: This paper draws on the experience of The Royal Australian College of General Practitioners' (RACGP's) National Research and Evaluation Ethics Committee to provide an eight-step approach to the research ethics process.

Australian general practitioner perceptions of the detection and screening of at-risk drinking, and the role of the AUDIT-C: a qualitative study.

Background: At-risk drinking is common in Australia. Validated screening tools such as the AUDIT-C have been promoted to general practitioners (GPs), but appear rarely used and detection of at-risk drinking in primary care remains low. We sought to describe Australian GP perceptions of the detection and screening of at-risk drinking; to understand their low uptake of alcohol screening questionnaires, and in particular, their attitude to the adoption of the AUDIT-C.

Available, intuitive and free! Building e-learning modules using web 2.0 services.

Background: E-learning is part of the mainstream in medical education and often provides the most efficient and effective means of engaging learners in a particular topic. However, translating design and content ideas into a useable product can be technically challenging, especially in the absence of information technology (IT) support. There is little published literature on the use of web 2.

Melatonin MT1 receptor-induced transcriptional up-regulation of p27(Kip1) in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-κB): potential implications on prostate cancer chemoprevention and therapy.

Our laboratory has recently demonstrated a melatonin MT1 receptor-mediated antiproliferative signaling mechanism in androgen receptor (AR)-positive prostate epithelial cells which involves up-regulation of p27(Kip1) through dual activation of Gα(s)/protein kinase A (PKA) and Gα(q)/protein kinase C (PKC) in parallel, and down-regulation of activated AR signaling via PKC stimulation. The aim of the present investigation was to identify the transcription factor that mediates melatonin's up-regulatory effect on p27(Kip1) in LNCaP and 22Rv1 prostate cancer cells. Deletion mapping and reporter assays of the p27(Kip1) promoter revealed that the putative melatonin-responsive transcription factor binds to a 116 base-pair region of the promoter sequence, which contains a potential nuclear factor kappa B (NF-κB) binding site.

Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: potential implications for therapeutic strategies against prostate cancer.

Recently, a novel melatonin MT(1) receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27(Kip1) due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Gα(s) and Gα(q) , has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT(1) receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT(1) /(Gα(s) ) PKA + (Gα(q) ) PKC/p27(Kip1) activated by melatonin in human prostate epithelial cells is AR dependent.

Signal transduction of receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gα(s) and Gα(q) proteins.

Melatonin has been shown to inhibit the proliferation of malignant and transformed human prostate epithelial cells by transcriptional up-regulation of p27(Kip1) expression via MTNR1A receptor-mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel. Given that melatonin MTNR1A receptor is a G protein-coupled receptor, this study was conducted to identify the specific G proteins that mediate the antiproliferative action of melatonin on human prostate epithelial cells. In 22Rv1 and RWPE-1 cells, knockdown of either Gα(s) or Gα(q) , but not Gα(i2) expression by RNA interference, abrogated the effects of melatonin on p27(Kip1) and cell proliferation.

The autocrine human secreted PDZ domain-containing protein 2 (sPDZD2) induces senescence or quiescence of prostate, breast and liver cancer cells via transcriptional activation of p53.

Tumor suppressive actions of the autocrine human secreted PDZ domain-containing protein 2 (sPDZD2) have been reported, but the mechanisms remain enigmatic. Here, we showed that sPDZD2 induced senescence of prostate cancer DU145 cells, quiescence of breast cancer MCF-7 and liver cancer Hep-G2 cells, via transcriptional activation of mutant or wild-type p53. Furthermore, sPDZD2 sensitized mutant p53-positive DU145 cells and wild-type p53-positive MCF-7 cells to apoptosis induction through genotoxic stress imposed by sub-lethal concentration of hydrogen peroxide.

Melatonin as a negative mitogenic hormonal regulator of human prostate epithelial cell growth: potential mechanisms and clinical significance.

Circannual variation in the human serum levels of prostate-specific antigen, a growth marker of the prostate gland, has been reported recently. The present study was conducted to investigate the role of the photoperiodic hormone melatonin (MLT) and its membrane receptors in the modulation of human prostate growth. Expression of MT(1) and MT(2) receptors was detected in benign human prostatic epithelial tissues and RWPE-1 cells.

Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention.

There is an unmet clinical demand for safe and effective pharmaceuticals/nutraceuticals for prostate cancer prevention and hormone-refractory prostate cancer treatment. Previous laboratory and human studies of our laboratory demonstrated an association between the antiproliferative action of melatonin and melatonin MT(1) receptor expression in prostate cancer. The aim of this study was to determine, using a pharmacological approach, the signaling mechanisms of melatonin in hormone-refractory 22Rv1 human prostate cancer cell antiproliferation.