Estrogen receptor β2 and β5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion

Estrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ERβ in the prostate epithelium. With the discovery of ERβ isoforms, data from previous studies that focused principally on the wild-type ERβ (ERβ1) may not be adequate in explaining the still controversial role of ERβ(s) in prostate carcinogenesis. In this study, using newly generated isoform-specific antibodies, immunohistochemistry (IHC) was performed on a tumor microarray comprised of 144 specimens. IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ERβ1, ERβ2, and ERβ5 in PCa. ERβ2 was commonly found in the cytoplasm and was the most abundant isoform followed by ERβ1 localized predominantly in the nucleus, and ERβ5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ERβ2 (nERβ2) is an independent prognostic marker for prostate specific antigen (PSA) failure and postoperative metastasis (POM). In a Kaplan–Meier analysis, the combined expression of both nERβ2 and cytoplasmic ERβ5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nERβ2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ERβ2 or ERβ5 enhanced PCa cell invasiveness but only PCa cells expressing ERβ5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ERβ2 and ERβ5 in PCa, and show that the two isoforms, singularly and conjointly, have prognostic values for PCa progression. These findings may aid future clinical management of PCa

Recycling in the management of solid waste : a study of the governance of Hong Kong's EcoPark

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial

Background: Research suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD). Aims: To compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive–behavioural therapy-based psychoeducation and usual care. Method: In total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels. Results: Linear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only. Conclusions: These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms

Type I and III Interferon Productions Are Impaired in X-Linked Agammaglobulinemia Patients Toward Poliovirus but Not Influenza Virus

BackgroundX-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by Bruton’s tyrosine kinase (BTK) mutation. Patients are susceptible to severe enterovirus infections. The underlying mechanism remains unknown. BTK is involved in toll-like receptors pathway, which initiates antiviral responses including interferon (IFN) productions.ObjectiveTo demonstrate type I and III IFN productions in dendritic cells of XLA patients is decreased in response to oral poliovirus vaccine (OPV) but not H1N1 virus.MethodsMonocyte-derived dendritic cells (MoDCs) were derived from nine XLA patients aged 22–32 years old and 23 buffy coats from Hong Kong Red Cross blood donors. LFM-A13 was used to inhibit BTK. OPV Sabin type 1 and H1N1 influenza virus were used to stimulate MoDCs with RPMI as mock stimulation. The antiviral cytokine productions and phenotypic maturation of MoDCs were determined 24 h post-stimulation. OPV RNA was determined at 0, 6, 12, and 24 h post-stimulation.ResultsUpon OPV stimulation, IFN-α2, IFN-β, and IFN-λ1 productions in MoDCs from XLA patients and BTK-inhibited MoDCs of healthy controls were significantly lower than that from healthy controls. Whereas upon H1N1 stimulation, the IFN-α2, IFN-β, and IFN-λ1 productions were similar in MoDCs from XLA patients, BTK-inhibited MoDCs of healthy controls and healthy controls. The mean fluorescent intensities (MFI) of CD83, CD86, and MHC-II in MoDCs from XLA patients in response to OPV was similar to that in response to mock stimulation, while the MFI of CD83, CD86, and MHC-II were significantly higher in response to H1N1 stimulation than that in response to mock stimulation. Whereas, the MFI of CD83, CD86, and MHC-II in MoDCs of healthy controls were significantly higher in response to both OPV and H1N1 stimulation compared to that in response to mock stimulation.ConclusionProduction of type I and III IFN in response to OPV was deficient in MoDCs from XLA patients, but was normal in response to H1N1 due to deficient BTK function. Moreover, phenotypic maturation of MoDCs from XLA patients was impaired in response to OPV but not to H1N1. These selective impairments may account for the unique susceptibility of XLA patients toward severe enterovirus infections

Dendritic and T Cell Response to Influenza is Normal in the Patients with X-Linked Agammaglobulinemia

Introduction Influenza virus is a potential cause of severe disease in the immunocompromised. X-linked agammaglobu-linemia (XLA) is a primary immunodeficiency characterized by the lack of immunoglobulin, B cells, and plasma cells, secondary to mutation in Bruton’s tyrosine kinase (Btk) gene

Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer of TRAMP Mice

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor which regulates the expression of many cytoprotective genes. In the present study, we found that the expression of Nrf2 was suppressed in prostate tumor of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice. Similarly, the expression of Nrf2 and the induction of NQO1 were also substantially suppressed in tumorigenic TRAMP C1 cells but not in non-tumorigenic TRAMP C3 cells. Examination of the promoter region of the mouse Nrf2 gene identified a CpG island, which was methylated at specific CpG sites in prostate TRAMP tumor and in TRAMP C1 cells but not in normal prostate or TRAMP C3 cells, as shown by bisulfite genomic sequencing. Reporter assays indicated that methylation of these CpG sites dramatically inhibited the transcriptional activity of the Nrf2 promoter. Chromatin immunopreceipitation (ChIP) assays revealed increased binding of the methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in the TRAMP C1 cells as compared to TRAMP C3 cells. In contrast, the binding of RNA Pol II and acetylated histone H3 to the Nrf2 promoter was decreased. Furthermore, treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) restored the expression of Nrf2 as well as the induction of NQO1 in TRAMP C1 cells. Taken together, these results indicate that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with MBD2 and histone modifications in the prostate tumor of TRAMP mice. Our present findings reveal a novel mechanism by which Nrf2 expression is suppressed in TRAMP prostate tumor, shed new light on the role of Nrf2 in carcinogenesis and provide potential new directions for the detection and prevention of prostate cancer

Successive influenza virus infection and Streptococcus pneumoniae stimulation alter human dendritic cell function

Background: Influenza virus is a major cause of respiratory disease worldwide and Streptococcus pneumoniae infection associated with influenza often leads to severe complications. Dendritic cells are key antigen presenting cells but its role in such co-infection is unclear.Methods: In this study, human monocyte derived-dentritic cells were either concurrently or successively challenged with the combination of live influenza virus and heat killed pneumococcus to mimic the viral pneumococcal infection. Dendritic cell viability, phenotypic maturation and cytokine production were then examined.Results: The challenge of influenza virus and pneumococcus altered dendritic cell functions dependent on the time interval between the successive challenge of influenza virus and pneumococcus, as well as the doses of pneumococcus. When dendritic cells were exposed to pneumococcus at 6 hr, but not 0 hr nor 24 hr after influenza virus infection, both virus and pneumococcus treated dendritic cells had greater cell apoptosis and expressed higher CD83 and CD86 than dendritic cells infected with influenza virus alone. Dendritic cells produced pro-inflammatory cytokines: TNF-α, IL-12 and IFN-γ synergistically to the successive viral and pneumococcal challenge. Whereas prior influenza virus infection suppressed the IL-10 response independent of the timing of the subsequent pneumococcal stimulation.Conclusions: Our results demonstrated that successive challenge of dendritic cells with influenza virus and pneumococcus resulted in synergistic up-regulation of pro-inflammatory cytokines with simultaneous down-regulation of anti-inflammatory cytokine, which may explain the immuno-pathogenesis of this important co-infection. © 2011 Wu et al; licensee BioMed Central Ltd.published_or_final_versio

Methods for monitoring and measurement of protein translation in time and space

Regulation of protein translation constitutes a crucial step in control of gene expression. In comparison to transcriptional regulation, however, translational control has remained a significantly under-studied layer of gene expression. This trend is now beginning to shift thanks to recent advances in nextgeneration sequencing, proteomics, and microscopy based methodologies which allow accurate monitoring of protein translation rates, from single target messenger RNA molecules to genome-wide scale studies. In this review, we summarize these recent advances, and discuss how they are enabling researchers to study translational regulation in a wide variety of in vitro and in vivo biological systems, with unprecedented depth and spatiotemporal resolution.The authors are funded by a Medical Research Council (MRC) Career Development Award to F. K. M. (MR/P009417/1)

Functionalization of artemisinin : new drugs for new purposes

Although artemisinin and its derivatives demonstrate promising screening results against malaria parasite, they still suffer from some drawbacks which render them far from ideal drugs. Cytotoxicity is one of the major problems. Furthermore, artemisinins are potential therapeutic agents against different pathogenic targets (e.g. cancer or tuberculosis). Tailored-made compounds for specific targeted pathogen are urgently needed. In this thesis, different novel derivatives are introduced. The initial idea, design and the screening are included. After the introduction in the first chapter, the second chapter starts to mention the synthesis of different glycosylated compounds which recognize the galectin receptors on cancer cells. The screening results of the N-glycosylated analogues are excellent. However, the compounds are not stable in acidic condition. Therefore, the C-glycosylated analogues were designed to overcome the problem. Two of the compounds were successfully made. The third chapter reveals the possibility of utilizing ‘Click reaction’ in artemisinin. Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry. Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) is the most popular example of click reaction which using cuprous ion to accreleration Huisgen 1,3-dipolar cycloaddition to give a single regioisomer.It was found that CuAAC was completely compatiable to artemisinin without reducing the peroxide bridge. Furthermore, both azide and alkynyl derivatives of artemisinin can be used as the scaffold. The fourth chapter discusses the use of novel co-factor model to design mechanism-based inhibitors of flavin cofactor. According to the model, artemisinin may perturb one of the important redox cycles, so as to exert oxidative stress on the parasite. Therefore, the inhibitors will bind tightly to the flavin cofactor of parasite after the artemisinin nucleus exert its function, causing malfunctioning of active site. These inhititors would be potential drugs for the pathogens which are vulnerable under oxidative condition like malaria parasites and mycobacterium. These derivatives were successfully made, and one candidate demonstrates an extraordinary activity against malaria at nanomolar scale. Chapter five involves the synthesis of artemisone homologues. Artemisone is a 10-amino-subsituted artemisinin derivative prepared by our group. Its Phase II data have already demonstrated that artemisone is curative when used in patients with non-severe malaria. The development of artemisone is continuing and the comparison between artesunate is going to be established for Phase II trials involving patients who do not respond to treatment with artesunate. But, artemisone is hydrolytic reactive under acidic condition and decompose at high temperature. These drawbacks prevent its usage in Africa where is humid and hot. Novel C-linked artemisone homologues were made. Surprisingly, the homologues was showed to have much lower activities compared to its parent compound which suggests the direct connection of C-10 and heteroatom is an important issue in potency. Last but not least, the last chapter reveals the design of new antibiotic as a mimic of platensimycin. Platensimycin is a novel class of antibiotic with unique mode of action by selectively inhibiting the β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) which are an essential component in fatty acid biosynthesis in Gram-positive bacteria. It was reported that the aromatic ring on platensimycin plays an important role in binding with protein on FabF/B so as to exert its effect. With the structural similarity between artemisinin and tetracyclic cage on platensimycin, the adduct of artemisinin and the aromatic ring which mimics the construction of platensimycin might be a useful compounds to target on FabF/B which is essential in bacterial growth. The antibiotic screening exhibited poor activities against different bacteria