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The non-native midge Eretmoptera murphyi is Antarctica's most persistent non-native insect and is known to impact the terrestrial ecosystems. It inhabits by considerably increasing litter turnover and availability of soil nutrients. The midge was introduced to Signy Island, South Orkney Islands, from its native South Georgia, and routes of dispersal to date have been aided by human activities, with little known about non-human-assisted methods of dispersal. This study is the first to determine the potential for dispersal of a terrestrial invertebrate species in Antarctica by combining physiological sea water tolerance data with quantitative assessments of ocean current journey times. Fourth instar larvae tolerated sea water submergence for up to 21 days, but submerged egg sacs had significantly reduced hatching success. Using near-surface drifter data, we conclude that ocean current dispersal from Signy Island would not present a risk of species transfer beyond the South Orkney Islands on the tested timescales. However, if E. murphyi were to be introduced to the South Shetlands Islands or Adelaide Island, which are located offshore of the Antarctic Peninsula, there would be a risk of successful oceanic dispersal to neighbouring islands and the Antarctic Peninsula mainland. This study emphasises the need for effective biosecurity measures and demonstrates the role that currently undocumented pathways may have in dispersing non-native species. [ABSTRACT FROM AUTHOR]

Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT). [ABSTRACT FROM AUTHOR]

Interferon regulatory factor-5 (IRF-5), a member of the mammalian IRF transcription factor family, is regulated by p53, type I interferon and virus infection. IRF-5 participates in virus-induced TLR-mediated innate immune responses and may play a role as a tumor suppressor. It was suppressed in various EBV-infected transformed cells, thus it is valuable to identify the suppression mechanism. We focused on a promoter CpG islands methylation, a kind of epigenetic regulation in EBV-associated Burkitt's lymphomas (BLs) and gastric carcinomas. IRF-5 is not detected in most of EBV-infected BL cell lines due to hypermethylation of IRF-5 distal promoter (promoter-A), which was restored by a demethylating agent, 5-aza-2′-deoxycytidine. Hypomethylation of CpG islands in promoter-A was observed only in EBV type III latent infected BL cell lines (LCL and Mutu III). Similarly, during EBV infection to Akata-4E3 cells, IRF-5 was observed at early time periods (2 days to 8 weeks), concomitant unmethylation of promoter-A, but suppressed in later infection periods as observed in latency I BL cell lines. Moreover, hypermethylation in IRF-5 promoter-A region was also observed in EBV-associated gastric carcinoma (EBVaGC) cell lines or primary gastric carcinoma tissues, which show type I latent infection. In summary, IRF-5 is suppressed by hypermethylation of its promoter-A in most of EBV-infected transformed cells, especially BLs and EBVaGC. EBV-induced carcinogenesis takes an advantage of proliferative effects of TLR signaling, while limiting IRF-5 mediated negative effects in the establishment of EBVaGCs. [ABSTRACT FROM AUTHOR]

Background:SOX2 is a member of SOX (SRY-related high mobility group box) family of transcription factors.Methods:In this study, we examined the expression of SOX2 in murine and human prostatic specimens by immunohistochemistry.Results:We found that SOX2 was expressed in murine prostates during budding morphogenesis and in neuroendocrine (NE) prostate cancer (PCa) murine models. Expression of SOX2 was also examined in human prostatic tissue. We found that SOX2 was expressed in 26 of the 30 BPH specimens. In these BPH samples, expression of SOX2 was limited to basal epithelial cells. In contrast, 24 of the 25 primary PCa specimens were negative for SOX2. The only positive primary PCa was the prostatic NE tumor, which also showed co-expression of synaptophysin. Additionally, the expression of SOX2 was detected in all prostatic NE tumor xenograft lines. Furthermore, we have examined the expression of SOX2 on a set of tissue microarrays consisting of metastatic PCa tissues. Expression of SOX2 was detected in at least one metastatic site in 15 of the 24 patients with metastatic castration-resistant PCa; and the expression of SOX2 was correlated with synaptophysin.Conclusions:SOX2 was expressed in developing prostates, basal cells of BPH, as well as prostatic NE tumors. [ABSTRACT FROM AUTHOR]

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The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers. [ABSTRACT FROM AUTHOR]

Background:Tumours are made up of a mixed population of different types of cells that include normal structures as well as ones associated with the malignancy, and there are multiple interactions between the malignant cells and the local microenvironment. These intercellular interactions, modulated by the microenvironment, effect tumour progression and represent a largely under-appreciated therapeutic target. We use observations of primary tumour biology from prostate cancer to extrapolate a mathematical model. Specifically, it has been observed that in prostate cancer three disparate cellular outcomes predominate: (i) the tumour remains well differentiated and clinically indolent - in this case the local stromal cells may act to restrain the growth of the cancer; (ii) early in its genesis the tumour acquires a highly malignant phenotype, growing rapidly and displacing the original stromal population (often referred to as small cell prostate cancer) - these less common aggressive tumours are relatively independent of the local microenvironment and (iii) the tumour co-opts the local stroma - taking on a classic stromagenic phenotype where interactions with the local microenvironment are critical to the cancer growth.Methods:We present an evolutionary game theoretical construct that models the influence of tumour-stroma interactions in driving these outcomes. We consider three characteristic and distinct cellular populations: stromal cells, tumour cells that are self-reliant in terms of microenvironmental factors and tumour cells that depend on the environment for resources, but can also co-opt stroma.Results:Using evolutionary game theory we explore a number of different scenarios that elucidate the impact of tumour-stromal interactions on the dynamics of prostate cancer growth and progression, and how different treatments in the metastatic setting can affect different types of tumours.Conclusion:The tumour microenvironment has a crucial role in selecting the traits of the tumour cells that will determine prostate cancer progression. Equally important treatments like hormone therapy affect the selection of these cancer phenotypes making it very important to understand how they impact prostate cancer's somatic evolution. [ABSTRACT FROM AUTHOR]

Elastic network models of biomolecules have proved to be relatively good at predicting global conformational changes particularly in large systems. Software that facilitates rapid and intuitive exploration of conformational change in elastic network models of large biomolecules in response to externally applied forces would therefore be of considerable use, particularly if the forces mimic those that arise in the interaction with a functional ligand. We have developed software that enables a user to apply forces to individual atoms of an elastic network model of a biomolecule through a haptic feedback device or a mouse. With a haptic feedback device the user feels the response to the applied force whilst seeing the biomolecule deform on the screen. Prior to the interactive session normal mode analysis is performed, or pre-calculated normal mode eigenvalues and eigenvectors are loaded. For large molecules this allows the memory and number of calculations to be reduced by employing the idea of the important subspace, a relatively small space of the first M lowest frequency normal mode eigenvectors within which a large proportion of the total fluctuation occurs. Using this approach it was possible to study GroEL on a standard PC as even though only 2.3% of the total number of eigenvectors could be used, they accounted for 50% of the total fluctuation. User testing has shown that the haptic version allows for much more rapid and intuitive exploration of the molecule than the mouse version. [ABSTRACT FROM AUTHOR]

The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-gamma (PPARγ) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPARγ in mice resulted in focal hyperplasia which developed into mouse prostatic intraepithelial neoplasia (mPIN). The grade of PIN became more severe with time. Electron microscopy (EM) showed accumulated secondary lysosomes containing cellular organelles and debris suggestive of autophagy. Consistent with this analysis the autophagy marker LC-3 was found to be upregulated in areas of PIN in PPARγ KO tissues. We selectively knocked down PPARγ2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically grafted tissues resembled the conditional PPARγ KO mouse prostates. EM studies of PPARγ- and PPARγ2-deficient epithelial cells in vitro were suggestive of autophagy, consistent with the prostatic tissue analysis. This was confirmed by examining expression of beclin-1 and LC-3. Gene expression profiling in PPARγ-/γ2-deficient cells indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. The putative autophagic phenotypes of PPARγ-deficient cells could be rescued by re-expression of either γ1 or γ2 isoform. We conclude that disruption of PPARγ signaling results in autophagy and oxidative stress during mPIN pathogenesis. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β is an important paracrine factor in tumorigenesis. Ligand binding of the type I and II TGF-β receptors initiate downstream signaling. The role of stromal TGF-β signaling in prostate cancer progression is unknown. In mice, the conditional stromal knockout of the TGF-β type II receptor expression (Tgfbr2fspKO) resulted in the development of prostatic intraepithelial neoplasia and progression to adenocarcinoma within 7 months. Clinically, we observed a loss of TGF-β receptor type II expression in 69% of human prostate cancer-associated stroma, compared to 15% of stroma associated with benign tissues (n=140, P-value <0.0001). To investigate the mechanism of paracrine TGF-β signaling in prostate cancer progression, we compared the effect of the prostatic stromal cells from Tgfbr2fspKO and floxed TGF-β type II receptor Tgfbr2floxE2/floxE2 mice on LNCaP human prostate cancer cells in vitro and tissue recombination xenografts. Induction of LNCaP cell proliferation and tumorigenesis was observed by Tgfbr2fspKO prostate stroma as a result of elevated Wnt3a expression. Neutralizing antibodies to Wnt3a reversed LNCaP tumorigenesis. The TGF-β inhibition of Wnt3a expression was in part through the suppression of Stat3 activity on the Wnt3a promoter. In conclusion, the frequent loss of stromal TGF-β type II receptor expression in human prostate cancer can relieve the paracrine suppression of Wnt3a expression.Oncogene (2008) 27, 7118–7130; doi:10.1038/onc.2008.293; published online 25 August 2008 [ABSTRACT FROM AUTHOR]

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH–Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO–S-nitrosylation–GAPDH–Siah1 cascade may represent an important molecular mechanism of cytotoxicity. [ABSTRACT FROM AUTHOR]

The Kapsosi’s sarcoma-associated herpesvirus, KSHV, is associated with cancers that have increased incidence in patients who are also HIV positive or who have undergone organ transplantation. It has recently been observed that β-catenin is overexpressed in two KSHV-associated cancers, Kaposi’s sarcoma and primary effusion lymphoma. Investigation of the underlying defect in β-catenin regulation revealed that the KSHV-encoded LANA protein stabilizes β-catenin by binding to the negative regulator GSK-3, causing a cell-cycle-dependent nuclear accumulation of GSK-3. Thus, redistribution of GSK-3 has been identified as yet another mechanism through which β-catenin can be dysregulated and contribute to human cancer. [ABSTRACT FROM AUTHOR]

The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that B-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated B-catenin accumulation; LANA itself upregulated expression of B-catenin in transfected cells. LANA stabilizes B-catenin by binding to the negative regulator GSK-3B, causing a cell cycle-dependent nuclear accumulation of GSK-3B. The LANA C terminus contains sequences similar to the GSK-3B-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3B or stabilize B-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3B can therefore be a source of B-catenin dysregulation in human cancers. [ABSTRACT FROM AUTHOR]

Calculations of the Rigid Unit Modes (RUMs) allowed in the nepheline structure are used to explain the diffuse scattering previously seen in electron diffraction experiments. The RUM calculations also show that the modulation wavelength for incommensurate nephelines is essentially determined by the framework topology. X-ray diffraction is used to measure the intensity of the diffuse scattering as a function of temperature. The diffuse intensity increases sharply at 308 K. This effect is interpreted as being due to the softening of a phonon mode, indicating a phase transition. Measurements of this phase transition below the transition temperature are made using hard mode infrared spectroscopy. [ABSTRACT FROM AUTHOR]

During bladder development, undifferentiated mesenchymal and epithelial cells undergo an orderly sequence of differentiation defined by the expression of smooth-muscle (α-actin, myosin, vinculin, desmin, vimentin, and laminin) and epithelial (cytokeratins 5, 7, 8, 14, 18 and 19) protein markers. This process requires mesenchymal-epithelial interactions with bladder epithelium (urothelium) necessary for the differentiation of bladder smooth muscle. Peptide growth factors such as keratinocyte growth factor (KGF) and transforming growth factors (TGF) α and β are likely candidates as mediators of these mesenchymal-epithelial interactions. Transcripts for KGF, TGF α, and TGF β are regulated during bladder development and during smooth-muscle hypertrophy secondary to bladder-outlet obstruction. Finally, two experimental bladder models - (1) partial outlet obstruction and (2) regeneration of bladder smooth muscle into an acellular tissue matrix - are described in the context of mesenchymal-epithelial interactions in the bladder. [ABSTRACT FROM AUTHOR]

The role of monitoring during endoscopy is not clearly defined. We have prospectively investigated continuous arterial oxygen saturation (SaO2) monitoring in 326 patients undergoing upper endoscopy (EGD) and 90 undergoing colonoscopy. Automated blood pressure recording was evaluated in 278 of these patients. SaO2 desaturation (less than 90%) occurred in 17.8% of patients undergoing EGD and 12.9% undergoing colonoscopy. Systolic blood pressure abnormalities (greater than 200 or less than 90 mmHg) occurred in 19.8% of EGD patients and 19.6% of colonoscopy patients. Treatment based on these abnormalities was required in 4.3% of patients during EGD and 8.8% during colonoscopy. A history of pulmonary or cardiac disease predicted increased risk during colonoscopy, while cardiac disease and age 60 years or above predicted desaturation during EGD. Pulse oximetry and automated blood pressure monitoring was especially valuable during endoscopy in the elderly and patients with cardiac or pulmonary disease. It may be used as a guide to therapeutic intervention and to avert major cardiopulmonary complications. [ABSTRACT FROM AUTHOR]

This report describes the development and characterization of an epithelial cell line (BPH-1) from human prostate tissue obtained by transurethral resection. Primary epithelial cell cultures were immortalized with SV40 large T antigen. One of the isolated clones was designated BPH-1. These cells have a cobblestone appearance in monolayer culture and are non-tumorigenic in nude mice following subcutaneous injection or subrenal capsule grafting. They express the SV40 large T antigen and exhibit increased levels of p53, as determined by immunocytochemistry. Cytogenetic analysis by G-banding demonstrated an aneuploid karyotype with a modal chromosome number of 76 (range 71 to 79, n=28) and 6 to 8 marker chromosomes. Some structurally rearranged chromosomes were observed, but the Y chromosome was normal. The expressed cytokeratin profile was consistent with a prostatic luminal epithelial cell. This profile was the same as that of primary prostatic epithelial cultures from which the BPH-1 cells were derived. In serum-free culture in plastic dishes epidermal growth factor (EGF), transforming growth factor (TGF)- α, fibroblast growth factor (FGF) 1 (aFGF), and FGF 7 (KGF) induced increased proliferation in these cells whereas FGF 2 (bFGF), TGF- β1, and TGF- β2 inhibited proliferative activity. Testosterone had no direct effect on the proliferative rate of BPH-1 cells. 5 α-Reductase, 3 α-hydroxysteroid oxidoreductase, and 17 β-hydroxy-steroid oxidoreductase activities were detected in BPH-1 cells. Expression of androgen receptors and the secretory markers, prostate specific antigen and prostatic acid phosphatase, were not detectable by immunocytochemistry, biochemical assay, or RT-PCR analysis. [ABSTRACT FROM AUTHOR]

Objective: To examine infant feeding practices up to 8 weeks postpartum in Hamilton-Wentworth., Methods: A cross-sectional survey of 227 women using a pre-discharge, self-administered questionnaire, medical record review and follow-up telephone interview., Results: Breastfeeding initiation rate was 85%. By 6-8 weeks postpartum, 30% of women had stopped breastfeeding; 55% had switched to formula within the first 14 days. Infants who did not receive supplementation in hospital were 2.49 times more likely than infants who received supplementation to breastfeed for at least 6 weeks. Although 54% of mothers who initiated breastfeeding reported receiving formula gift packs, no association was found., Conclusions: The breastfeeding initiation rate appears to have increased in Hamilton-Wentworth since 1995. However, this study reinforces the need to address early cessation and infant supplementation, and raises concern about violation of the WHO/UNICEF International Code of Marketing of Breastmilk Substitutes through mailing of formula coupons.

Health outcomes are becoming the currency of health care exchange, and a call for evidence dominates decision making at all levels. This discussion paper reviews methodological and sociopolitical barriers that impede the production and dissemination of outcome research in public health, with particular reference to nursing. Barriers to the production of high-quality research evidence include inaccessible graduate education and inadequate research funding. Also, randomized controlled trials (the ideal design for interventions studies) are uniquely difficult to implement for public health services. Practical and ethical difficulties arise in defining the intervention, implementing random allocation methods, selecting and measuring outcomes, and articulating adequate theoretical frameworks. When health care activity is defined as output, there is a tendency to exclude the ethical standing of preventive, supportive and communitarian functions. The production and interpretation of research results must remain part of a social, political and ethical debate, not a purely scientific one.

The purpose of this systematic overview was to summarize evidence about the effectiveness of adolescent suicide prevention curricula programs. A comprehensive search of published and unpublished literature resulted in retrieval of 11 relevant studies. The findings, of this overview indicate that there is currently insufficient evidence to support curriculum-based suicide prevention programs. The evidence suggests that there may be both beneficial and harmful effects of the programs on students. In most studies, knowledge related to suicide improved as a result of the programs. However, studies found both beneficial and harmful effects on attitudes related to suicide. One study found in increase in hopelessness and maladaptive coping for males following the intervention. The literature suggests that more broadly based comprehensive school health programs should be evaluated for their effectiveness in addressing the determinants of adolescent risk behaviour.

The purpose of this systematic overview was to assess the evidence for the effectiveness of public health nursing interventions when carried out by the strategy of home visiting. A search of published and unpublished literature resulted in retrieval of 108 articles; 77 articles were judged to be relevant. Validity criteria included method of allocation to the study groups, level of agreement to participate in the study, control for confounders, method of data collection (pretesting of data collection tools, blinding of data collectors to group allocation of study participants), quantitative measure of effect and percentage of participants available at follow-up. Using these criteria, 9 articles were judged to be strong, 5 moderate and 63 weak. There were no reported negative effects of home visiting in the 9 strong articles. Positive outcomes included improvement in children's mental development, mental health and physical growth; reduction in mother's anxiety, depression, and tobacco use; improvement in maternal employment, nutrition and other health habits; government cost saving; and reduced level of care required for the elderly.