A variant of the KLK4 gene is expressed as a cis sense-antisense chimeric transcript in prostate cancer cells

In humans, more than 30,000 chimeric transcripts originating from 23,686 genes have been identified. The mechanisms and association of chimeric transcripts arising from chromosomal rearrangements with cancer are well established, but much remains unknown regarding the biogenesis and importance of other chimeric transcripts that arise from nongenomic alterations. Recently, a SLC45A3–ELK4 chimera has been shown to be androgen-regulated, and is overexpressed in metastatic or high-grade prostate tumors relative to local prostate cancers. Here, we characterize the expression of a KLK4 cis sense–antisense chimeric transcript, and show other examples in prostate cancer. Using non-protein-coding microarray analyses, we initially identified an androgen-regulated antisense transcript within the 3′ untranslated region of the KLK4 gene in LNCaP cells. The KLK4 cis-NAT was validated by strand-specific linker-mediated RT-PCR and Northern blotting. Characterization of the KLK4 cis-NAT by 5′ and 3′ rapid amplification of cDNA ends (RACE) revealed that this transcript forms multiple fusions with the KLK4 sense transcript. Lack of KLK4 antisense promoter activity using reporter assays suggests that these transcripts are unlikely to arise from a trans-splicing mechanism. 5′ RACE and analyses of deep sequencing data from LNCaP cells treated ±androgens revealed six high-confidence sense–antisense chimeras of which three were supported by the cDNA databases. In this study, we have shown complex gene expression at the KLK4 locus that might be a hallmark of cis sense–antisense chimeric transcription.

Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma

We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.

Helping someone with problem drinking: Mental health first aid guidelines - a Delphi expert consensus study

Background Alcohol is a leading risk factor for avoidable disease burden. Research suggests that a drinker's social network can play an integral role in addressing hazardous (i.e., high-risk) or problem drinking. Often however, social networks do not have adequate mental health literacy (i.e., knowledge about mental health problems, like problem drinking, or how to treat them). This is a concern as the response that a drinker receives from their social network can have a substantial impact on their willingness to seek help. This paper describes the development of mental health first aid guidelines that inform community members on how to help someone who may have, or may be developing, a drinking problem (i.e., alcohol abuse or dependence). Methods A systematic review of the research and lay literature was conducted to develop a 285-item survey containing strategies on how to help someone who may have, or may be developing, a drinking problem. Two panels of experts (consumers/carers and clinicians) individually rated survey items, using a Delphi process. Surveys were completed online or via postal mail. Participants were 99 consumers, carers and clinicians with experience or expertise in problem drinking from Australia, Canada, Ireland, New Zealand, the United Kingdom, and the United States. Items that reached consensus on importance were retained and written into guidelines. Results The overall response rate across all three rounds was 68.7% (67.6% consumers/carers, 69.2% clinicians), with 184 first aid strategies rated as essential or important by ≥80% of panel members. The endorsed guidelines provide guidance on how to: recognize problem drinking; approach someone if there is concern about their drinking; support the person to change their drinking; respond if they are unwilling to change their drinking; facilitate professional help seeking and respond if professional help is refused; and manage an alcohol-related medical emergency. Conclusion The guidelines provide a consensus-based resource for community members seeking to help someone with a drinking problem. Improving community awareness and understanding of how to identify and support someone with a drinking problem may lead to earlier recognition of problem drinking and greater facilitation of professional help seeking.

Cloning and characterization of a novel human gene related to vascular endothelial growth factor

This paper describes the cloning and characterization of a new member of the vascular endothelial growth factor (VEGF) gene family, which we have designated VRF for VEGF-related-factor. Sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools indicate two alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted proteins differ at their carboxyl ends resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintains homology to VEGF at its carboxyl terminus and conserves all 16 cysteine residues of VEGF165. Similarity comparisons of this isoform revealed overall protein identity of 48% and conservative substitution of 69% with VEGF189. VRF is predicted to contain a signal peptide, suggesting that it may be a secreted factor. The VRF gene maps to the D11S750 locus at chromosome band 11q13, and the protein coding region, spanning approximately 5 kb, is comprised of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the two isoforms of VRF arise through alternate splicing of exon 6. VRF appears to be ubiquitously expressed as two transcripts of 2.0 and 5.5 kb; the level of expression is similar among normal and malignant tissues.

Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval

Loss of the short arm of chromosome 1 is frequently observed in many tumor types, including melanoma. We recently localized a third melanoma susceptibility locus to chromosome band 1p22. Critical recombinants in linked families localized the gene to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely we have performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. Eighty percent of familial melanomas exhibited loss of heterozygosity (LOH) within the region, with a smallest region of overlapping deletions (SRO) of 9 Mb between D1S207 and D1S435. This high frequency of LOH makes it very likely that the susceptibility locus is a tumor suppressor. In sporadic tumors, four SROs were defined. SRO1 and SRO2 map within the critical recombinant and familial tumor region, indicating that one or the other is likely to harbor the susceptibility gene. However, SRO3 may also be significant because it overlaps with the markers with the highest 2-point LOD score (D1S2776), part of the linkage recombinant region, and the critical region defined in mesothelioma. The candidate genes PRKCL2 and GTF2B, within SRO2, and TGFBR3, CDC7, and EVI5, in a broad region encompassing SRO3, were screened in 1p22-linked melanoma kindreds, but no coding mutations were detected. Allelic loss in melanoma cell lines was significantly less frequent than in fresh tumors, indicating that this gene may not be involved late in progression, such as in overriding cellular senescence, necessary for the propagation of melanoma cells in culture.

Do perceptions mirror reality? Student perceptions of learning versus grade outcomes

This research addresses whether educators should consider measuring if students have learned what was intended, as recommended by education researchers. Students in an Introductory Marketing subject were asked to complete a voluntary survey rating their own progress on the intended learning outcomes for the course. One hundred and one surveys were completed by students in the second-last teaching week of the semester. Student identification numbers were used to link student perceptions with their grade outcomes. Regression analysis was used to ascertain whether student perceptions of their progress on the intended learning outcomes for the course could be used to predict their grades. While the results were significant, student perceptions of their progress on learning outcomes were a poor predictor of grade outcomes. The results of this study suggest that student perceptions may not mirror the reality. These results are somewhat surprising and future research examining the degree of change in the learning outcomes perceived by students is warranted. This will further contribute to decisions surrounding whether educators should measure if students have learned what was intended.

Modeling perceived collision risk in port water navigation

An increase in the likelihood of navigational collisions in port waters has put focus on the collision avoidance process in port traffic safety. The most widely used on-board collision avoidance system is the automatic radar plotting aid which is a passive warning system that triggers an alert based on the pilot’s pre-defined indicators of distance and time proximities at the closest point of approaches in encounters with nearby vessels. To better help pilot in decision making in close quarter situations, collision risk should be considered as a continuous monotonic function of the proximities and risk perception should be considered probabilistically. This paper derives an ordered probit regression model to study perceived collision risks. To illustrate the procedure, the risks perceived by Singapore port pilots were obtained to calibrate the regression model. The results demonstrate that a framework based on the probabilistic risk assessment model can be used to give a better understanding of collision risk and to define a more appropriate level of evasive actions.

Hierarchical modeling of perceived collision risks in port fairways

Navigational collisions are one of the major safety concerns in many seaports. Despite the extent of recent works done on port navigational safety research, little is known about harbor pilot’s perception of collision risks in port fairways. This paper uses a hierarchical ordered probit model to investigate associations between perceived risks and the geometric and traffic characteristics of fairways and the pilot attributes. Perceived risk data, collected through a risk perception survey conducted among the Singapore port pilots, are used to calibrate the model. Intra-class correlation coefficient justifies use of the hierarchical model in comparison with an ordinary model. Results show higher perceived risks in fairways attached to anchorages, and in those featuring sharper bends and higher traffic operating speeds. Lesser risks are perceived in fairways attached to shoreline and confined waters, and in those with one-way traffic, traffic separation scheme, cardinal marks and isolated danger marks. Risk is also found to be perceived higher in night.

Developing a framework for planning healthy communities : the Logan Beaudesert health decision support system

In the last few decades, the focus on building healthy communities has grown significantly (Ashton, 2009). There is growing evidence that new approaches to planning are required to address the challenges faced by contemporary communities. These approaches need to be based on timely access to local information and collaborative planning processes (Murray, 2006; Scotch & Parmanto, 2006; Ashton, 2009; Kazda et al., 2009). However, there is little research to inform the methods that can support this type of responsive, local, collaborative and consultative health planning (Northridge et al., 2003). Some research justifies the use of decision support systems (DSS) as a tool to support planning for healthy communities. DSS have been found to increase collaboration between stakeholders and communities, improve the accuracy and quality of the decision-making process, and improve the availability of data and information for health decision-makers (Nobre et al., 1997; Cromley & McLafferty, 2002; Waring et al., 2005). Geographic information systems (GIS) have been suggested as an innovative method by which to implement DSS because they promote new ways of thinking about evidence and facilitate a broader understanding of communities. Furthermore, literature has indicated that online environments can have a positive impact on decision-making by enabling access to information by a broader audience (Kingston et al., 2001). However, only limited research has examined the implementation and impact of online DSS in the health planning field. Previous studies have emphasised the lack of effective information management systems and an absence of frameworks to guide the way in which information is used to promote informed decisions in health planning. It has become imperative to develop innovative approaches, frameworks and methods to support health planning. Thus, to address these identified gaps in the knowledge, this study aims to develop a conceptual planning framework for creating healthy communities and examine the impact of DSS in the Logan Beaudesert area. Specifically, the study aims to identify the key elements and domains of information that are needed to develop healthy communities, to develop a conceptual planning framework for creating healthy communities, to collaboratively develop and implement an online GIS-based Health DSS (i.e., HDSS), and to examine the impact of the HDSS on local decision-making processes. The study is based on a real-world case study of a community-based initiative that was established to improve public health outcomes and promote new ways of addressing chronic disease. The study involved the development of an online GIS-based health decision support system (HDSS), which was applied in the Logan Beaudesert region of Queensland, Australia. A planning framework was developed to account for the way in which information could be organised to contribute to a healthy community. The decision support system was developed within a unique settings-based initiative Logan Beaudesert Health Coalition (LBHC) designed to plan and improve the health capacity of Logan Beaudesert area in Queensland, Australia. This setting provided a suitable platform to apply a participatory research design to the development and implementation of the HDSS. Therefore, the HDSS was a pilot study examined the impact of this collaborative process, and the subsequent implementation of the HDSS on the way decision-making was perceived across the LBHC. As for the method, based on a systematic literature review, a comprehensive planning framework for creating healthy communities has been developed. This was followed by using a mixed method design, data were collected through both qualitative and quantitative methods. Specifically, data were collected by adopting a participatory action research (PAR) approach (i.e., PAR intervention) that informed the development and conceptualisation of the HDSS. A pre- and post-design was then used to determine the impact of the HDSS on decision-making. The findings of this study revealed a meaningful framework for organising information to guide planning for healthy communities. This conceptual framework provided a comprehensive system within which to organise existing data. The PAR process was useful in engaging stakeholders and decision-making in the development and implementation of the online GIS-based DSS. Through three PAR cycles, this study resulted in heightened awareness of online GIS-based DSS and openness to its implementation. It resulted in the development of a tailored system (i.e., HDSS) that addressed the local information and planning needs of the LBHC. In addition, the implementation of the DSS resulted in improved decision- making and greater satisfaction with decisions within the LBHC. For example, the study illustrated the culture in which decisions were made before and after the PAR intervention and what improvements have been observed after the application of the HDSS. In general, the findings indicated that decision-making processes are not merely informed (consequent of using the HDSS tool), but they also enhance the overall sense of ‗collaboration‘ in the health planning practice. For example, it was found that PAR intervention had a positive impact on the way decisions were made. The study revealed important features of the HDSS development and implementation process that will contribute to future research. Thus, the overall findings suggest that the HDSS is an effective tool, which would play an important role in the future for significantly improving the health planning practice.

Perceived collision risks in anchorages : a hierarchical ordered probit analysis

Navigational collisions are a major safety concern in many seaports. Despite the recent advances in port navigational safety research, little is known about harbor pilot’s perception of collision risks in anchorages. This study attempts to model such risks by employing a hierarchical ordered probit model, which is calibrated by using data collected through a risk perception survey conducted on Singapore port pilots. The hierarchical model is found to be useful to account for correlations in risks perceived by individual pilots. Results show higher perceived risks in anchorages attached to intersection, local and international fairway; becoming more critical at night. Lesser risks are perceived in anchorages featuring shoreline in boundary, higher water depth, lower density of stationary ships, cardinal marks and isolated danger marks. Pilotage experience shows a negative effect on perceived risks. This study indicates that hierarchical modeling would be useful for treating correlations in navigational safety data.

Whe' yu' from?

"Whe' yu' from?" The question was put to me as I wandered, camera in hand, in the old square of Spanish Town, Jamaica's former capital. The local man, lounging in the shade of one of the colonial Georgian buildings that enclose the square, was mildly curious about what he took to be a typical white tourish photgraphing the sights of the decayed historic town. At that time, my home was in Kingston where i lived with my wife and baby son. I was then working in the Jamaican Government Town Planning Department in a job that took me all over the island. Turning to my questioner, I replied, "Kingston". There was a brief pause, and then the man spoke again: "No Man! Whe' yu' really from?" I still have difficulties when asked this question. Where am I from? What does this question mean? Does it refer to where I was born, where I spent my previous life or where I live now? Does it have a broader meaning, an enquiry about my origins in terms of background and previous experience? The following chapters are my attempt to answer these questions for my own satisfaction and, I hope, for the amusement of others who may be interested in the life of an ordinary English boy whose dream to travel and see the world was realized in ways he could not possibly have imagined. Finding an appropriate title for this book was difficult. Thursday's Child, North and South and War and Peace all came to mind but, unfortunately for me, those titles had been appropriated by other writers. Thursdays's Child is quite a popular book title, presumably because people who were born on that day and, in the words of the nursery rhyme, had 'far to go', are especially likely to have travellers' tales to tell or life stories of the rags-to-riches variety. Born on a Thursday, I have travelled a lot and I suppose that I have gone far in life. Coming from a working class family, I 'got on' by 'getting a good education' and a 'good job'. I decided against adding to the list of Thursday's Children. North and South would have reflected my life in Britain, spent in both the North and South of England, and my later years, divided between the Northern and Southern Hemispheres of the globe, as well as in countries commonly referred to as the 'advanced' North and the 'underdeveloped' South. North and South has already been appropriated by Mrs Gaskell, something that did not deter one popular American writer from using the title for a book of his. My memories of World War Two and the years afterwards made War and Peace a possible candidate, but readers expectnig an epic tale of Tolstoyan proportions may have been disappointed. To my knowledge, no other book has the title "Whe' Yu' From?". I am grateful to the Jamaican man whose question lingered in my memory and provided the title of this memoir, written decades later. This book is a word picture. It is, in a sense, a self-portrait, and like all portraits, it captures something of the character, it attempts to tell the truth, but it is not the whole truth. This is because it is not my intention to write my entire life story; rather I wish to tell about some of the things in my experience of life that have seemed important or interesting to me. Unlike a painted portrait, the picture I have created is intended to suggest the passage of time. While, for most of us in Western society, time is linear and unidirectional, like the flight of an arrov or the trajectory of a bullet, memory rearranges things, calling up images of the past in no particular order, making connections that may link events in various patterns, circular, web-like, superimposed. The stream of consciousness is very unlike that of streams we encounter in the physical world. Connections are made in all directions; thoughts hop back and forth in time and space, from topic to topic. My book is a composition drawn from periods, events and thoughts as I remember them. Like life itself, it is made up of patches, some good, some bad, but in my experience, always fascinating. In recording my memories, I have been as accurate as possible. Little of what I have written is about spectacular sights and strange customs. Much of it focuses on my more modest explorations includng observations of everyday things that have attracted my attention. Reading through the chapters, I am struck by my childhood freedom to roam and engage in 'dangerous' activities like climbing trees and playing beside streams, things that many children today are no longer allowed to enjoy. Also noticeable is the survival of traditions and superstitions from the distant past. Obvious too, is my preoccupation with place names, both official ones that appear on maps and sign boards and those used by locals and children, names rarely seen in print. If there is any uniting theme to be found in what I have written, it must be my education in the fields, woods and streets of my English homeland, in the various other countries in which I have lived and travelled, as well as more formally from books and in classrooms. Much of my book is concerned with people and places. Many of the people I mention are among those who have been, and often have remained, important and close to me. Others I remember from only the briefest of encounters, but they remain in my memory because of some specific incident or circumstance that fixed a lasting image in my mind. Some of my closest friends and relatives, however, appear nowhere in these pages or they receive only the slightest mention. This is not because they played an unimportant roles in my life. It is because this book is not the whole story. Among those whe receive little or no mention are some who are especially close to me, with whom I have shared happy and sad times and who have shown me and my family much kindness, giving support when this was needed. Some I have known since childhood and have popped up at various times in my life, often in different parts of the world. Although years may pass without me seeing them, in an important sense they are always with me. These people know who they are. I hope that they know how much I love and appreciate them. When writing my memoir, I consulted a few of the people mentioned in this book, but in the main, I have relied on my own memory, asided by daiary and notebook entries and old correspondence. In the preparation of this manuscript, I benefited greatly from the expert advice and encouragement of Neil Marr of BeWrite Books. My wife Anne, inspiration for this book, also contributed in the valuable role of critic. She has my undying gratitude.

Effect of cumulative lightweight aggregate volume in concrete on its resistance to chloride-ion penetration

This paper presents an experimental study on the resistance of lightweight aggregate concretes to chloride-ion penetration in comparison to that of normal weight concrete of similar w/c. Salt ponding test (based on AASHTO T 259), rapid chloride permeability test (ASTM C 1202) and rapid migration test (NT Build 492) were carried out to evaluate the concrete resistance to the chloride-ion penetration. Results indicate that in general the resistance of the LWAC to the chloride-ion penetration was in the same order as that of NWAC of similar w/c. However, the increase in cumulative LWA volume and the incorporation of finer LWA particles led to higher charge passed, migration coefficient, and diffusion coefficient. Since the LWACs had lower 28-day compressive strength compared with that of the NWAC of similar w/c, the LWACs may have equal or better resistance to the chloride-ion penetration compared with the NWAC of equivalent strength. The trend of the resistance of concretes to chloride-ion penetration determined by the three test methods was reasonably consistent although there were some discrepancies due to different test methods.

Social capital and neighbourhood centres in Queensland : qualitative case studies of three neighbourhood centres

This research paper examines the potential of neighbourhood centres to generate and enhance social capital through their programs, activities, membership associations and community engagement. Social capital is a complex concept involving elements of norms, networks, and trust and is generally seen as enhancing community cohesion and the ability to attain common goals (outlined in more detail in Section 3). The aim of this research project is to describe the nature of social capital formation in terms of development and change in norms, networks and trust within the context of the operations of neighbourhood centres in three Queensland locations (i.e., Sherwood, Kingston/Slacks Creek, and Maleny). The study was prompted by surprisingly little research into how neighbourhood centres and their clients contribute to the development of social capital. Considering the large volume of research on the role of community organisations in building social capital, it is remarkable that perhaps the most obvious organisation with 'social capitalist' intentions has received so little attention (apart from Bullen and Onyx, 2005). Indeed, ostensibly, neighbourhood centres are all about social capital.

Letter to the editor

We read with interest the article entitled ‘Population spherical aberration: associations with ametropia, age, corneal curvature, and image quality’ by Amanda C Kingston and Ian G Cox (2013). The authors provided higher order aberrations data for a sample of 1124 eyes and performed correlation analyses to compare higher order aberrations with refraction and biometry data, such as spherical equivalent power and corneal curvature. Special attention was drawn to spherical aberration...