Kallikrein 14 is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

Effects of air pollution exposure on adult bicycle commuters : an investigation of respiratory health, motorised traffic proximity and the utility of commute re-routing

Bicycle commuting has the potential to be an effective contributing solution to address some of modern society’s biggest issues, including cardiovascular disease, anthropogenic climate change and urban traffic congestion. However, individuals shifting from a passive to an active commute mode may be increasing their potential for air pollution exposure and the associated health risk. This project, consisting of three studies, was designed to investigate the health effects of bicycle commuters in relation to air pollution exposure, in a major city in Australia (Brisbane). The aims of the three studies were to: 1) examine the relationship of in-commute air pollution exposure perception, symptoms and risk management; 2) assess the efficacy of commute re-routing as a risk management strategy by determining the exposure potential profile of ultrafine particles along commute route alternatives of low and high proximity to motorised traffic; and, 3) evaluate the feasibility of implementing commute re-routing as a risk management strategy by monitoring ultrafine particle exposure and consequential physiological response from using commute route alternatives based on real-world circumstances; 3) investigate the potential of reducing exposure to ultrafine particles (UFP; < 0.1 µm) during bicycle commuting by lowering proximity to motorised traffic with real-time air pollution and acute inflammatory measurements in healthy individuals using their typical, and an alternative to their typical, bicycle commute route. The methods of the three studies included: 1) a questionnaire-based investigation with regular bicycle commuters in Brisbane, Australia. Participants (n = 153; age = 41 ± 11 yr; 28% female) reported the characteristics of their typical bicycle commute, along with exposure perception and acute respiratory symptoms, and amenability for using a respirator or re-routing their commute as risk management strategies; 2) inhaled particle counts measured along popular pre-identified bicycle commute route alterations of low (LOW) and high (HIGH) motorised traffic to the same inner-city destination at peak commute traffic times. During commute, real-time particle number concentration (PNC; mostly in the UFP range) and particle diameter (PD), heart and respiratory rate, geographical location, and meteorological variables were measured. To determine inhaled particle counts, ventilation rate was calculated from heart-rate-ventilation associations, produced from periodic exercise testing; 3) thirty-five healthy adults (mean ± SD: age = 39 ± 11 yr; 29% female) completed two return trips of their typical route (HIGH) and a pre-determined altered route of lower proximity to motorised traffic (LOW; determined by the proportion of on-road cycle paths). Particle number concentration (PNC) and diameter (PD) were monitored in real-time in-commute. Acute inflammatory indices of respiratory symptom incidence, lung function and spontaneous sputum (for inflammatory cell analyses) were collected immediately pre-commute, and one and three hours post-commute. The main results of the three studies are that: 1) healthy individuals reported a higher incidence of specific acute respiratory symptoms in- and post- (compared to pre-) commute (p < 0.05). The incidence of specific acute respiratory symptoms was significantly higher for participants with respiratory disorder history compared to healthy participants (p < 0.05). The incidence of in-commute offensive odour detection, and the perception of in-commute air pollution exposure, was significantly lower for participants with smoking history compared to healthy participants (p < 0.05). Females reported significantly higher incidence of in-commute air pollution exposure perception and other specific acute respiratory symptoms, and were more amenable to commute re-routing, compared to males (p < 0.05). Healthy individuals have indicated a higher incidence of acute respiratory symptoms in- and post- (compared to pre-) bicycle commuting, with female gender and respiratory disorder history indicating a comparably-higher susceptibility; 2) total mean PNC of LOW (compared to HIGH) was reduced (1.56 x e4 ± 0.38 x e4 versus 3.06 x e4 ± 0.53 x e4 ppcc; p = 0.012). Total estimated ventilation rate did not vary significantly between LOW and HIGH (43 ± 5 versus 46 ± 9 L•min; p = 0.136); however, due to total mean PNC, accumulated inhaled particle counts were 48% lower in LOW, compared to HIGH (7.6 x e8 ± 1.5 x e8 versus 14.6 x e8 ± 1.8 x e8; p = 0.003); 3) LOW resulted in a significant reduction in mean PNC (1.91 x e4 ± 0.93 x e4 ppcc vs. 2.95 x e4 ± 1.50 x e4 ppcc; p ≤ 0.001). Commute distance and duration were not significantly different between LOW and HIGH (12.8 ± 7.1 vs. 12.0 ± 6.9 km and 44 ± 17 vs. 42 ± 17 mins, respectively). Besides incidence of in-commute offensive odour detection (42 vs. 56 %; p = 0.019), incidence of dust and soot observation (33 vs. 47 %; p = 0.038) and nasopharyngeal irritation (31 vs. 41 %; p = 0.007), acute inflammatory indices were not significantly associated to in-commute PNC, nor were these indices reduced with LOW compared to HIGH. The main conclusions of the three studies are that: 1) the perception of air pollution exposure levels and the amenability to adopt exposure risk management strategies where applicable will aid the general population in shifting from passive, motorised transport modes to bicycle commuting; 2) for bicycle commuting at peak morning commute times, inhaled particle counts and therefore cardiopulmonary health risk may be substantially reduced by decreasing exposure to motorised traffic, which should be considered by both bicycle commuters and urban planners; 3) exposure to PNC, and the incidence of offensive odour and nasopharyngeal irritation, can be significantly reduced when utilising a strategy of lowering proximity to motorised traffic whilst bicycle commuting, without significantly increasing commute distance or duration, which may bring important benefits for both healthy and susceptible individuals. In summary, the findings from this project suggests that bicycle commuters can significantly lower their exposure to ultrafine particle emissions by varying their commute route to reduce proximity to motorised traffic and associated combustion emissions without necessarily affecting their time of commute. While the health endpoints assessed with healthy individuals were not indicative of acute health detriment, individuals with pre-disposing physiological-susceptibility may benefit considerably from this risk management strategy – a necessary research focus with the contemporary increased popularity of both promotion and participation in bicycle commuting.

Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes

Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in individuals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 samples; and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10−11, OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools; this result has important implications for the design of future fine-mapping studies.

High levels of BACH2 associated with lower levels of BCL2 transcript abundance in t(14;18)(q21;q34) translocation positive non-Hodgkin’s lymphoma

The t(14;18)(q21;q34) BCL2 translocation is a common genetic alteration in follicular and diffuse large B-cell lymphoma. However, it is not invariably associated with BCL2 gene overexpression due to undefined mechanisms that regulate expression from the proximal immunoglobulin heavy-chain (IgH) promoter. The BACH2 transcriptional repressor is able to modulate activity of this promoter. Here we have shown that, in tumor samples with BCL2 translocation, those with high levels of BACH2 had significantly lower BCL2 transcript abundance compared to those with low levels of BACH2. This indicates that BACH2 may be partially responsible for regulation of BCL2 expression from the t(14;18)(q21;q34) translocation.

Patellar tendinopathy in junior basketball players : a controlled clinical and ultrasonographic study of 268 patellar tendons in players aged 14-18 years

Anterior knee pain is a common presenting complaint amongst adolescent athletes. We hypothesised that patellar tendinopathy may occur at a younger age than is generally recognised. Thus, we studied the patellar tendons in 134 elite 14- to 18-year-old female (n=64) and male (n=70) basketball players and 29 control swimmers (17 female, 12 male) clinically and with ultrasonography. We found that of 268 tendons, 19 (7%) had current patellar tendinopathy on clinical grounds (11% in males, 2% in females). Twenty-six percent of the basketball players' patellar tendons contained an ultrasonographic hypoechoic region. Ultrasonographic abnormality was more prevalent in the oldest tertile of players (17-18 years) than the youngest tertile (14-15.9 years). Of tendons categorised clinically as 'Never patellar tendinopathy', 22% had an ultrasonographic hypoechoic region nevertheless. This study indicates that patellar tendinopathy can occur in 14- to 18-year-old basketball players. Ultrasonographic tendon abnormality is 3 times as common as clinical symptoms

Reliability of a wellness inventory for use among adolescent females aged 12-14 years

Background The wellness construct has application in a number of fields including education, healthcare and counseling, particularly with regard to female adolescents. The effective measurement of wellness in adolescents can assist researchers and practitioners in determining lifestyle behaviors in which they are lacking. Behavior change interventions can then be designed which directly aid in the promotion of these areas. Methods The 5-Factor Wellness Inventory (designed to measure the Indivisible Self model of wellness) is a popular instrument for measuring the broad aspects of wellness amongst adolescents. The instrument comprises 97 items contributing to 17 subscales, five dimension scores, four context scores, total wellness score, and a life satisfaction index. This investigation evaluated the test-retest (intra-rater) reliability of the 5 F-Wel instrument in repeated assessments (seven days apart) among adolescent females aged 12-14 years. Percentages of exact agreement for individual items, and the number of respondents who scored within +/-5, +/-7.5 and +/-10 points for total wellness and the five summary dimension scores were calculated. Results Overall, 46 (95.8%) participants responded with complete data and were included in the analysis. Item agreement ranged from 47.8% to 100% across the 97 items (median 69.9%, interquartile range 60.9%-73.9%). The percentage of respondents who scored within +/-5, +/-7.5 and +/-10 points for total wellness at the re-assessment was 87.0%, 97.8% and 97.8% respectively. The percentage of respondents who scored within +/-5, +/-7.5 and +/-10 for the domain scores at the reassessment ranged between 54.3-76.1%, 78.3-95.7% and 89.1-95.7% respectively across the five dimensions. Conclusions These findings suggest there was considerable variation in agreement between the two assessments on some individual items. However, the total wellness score and the five dimension summary scores remained comparatively stable between assessments.

MMP-14 is expressed in preeclamptic placentas and mediates release of soluble endoglin

Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia.

Protein-energy malnutrition exists and is associated with negative outcomes in morbidly obese hospital patients

Prevalence of protein-energy malnutrition (PEM), food intake inadequacy and associated health-related outcomes in morbidly obese (Body Mass Index ≥ 40 kg/m2) acute care patients are unknown. This study reports findings in morbidly obese participants from the Australasian Nutrition Care Day Survey (ANCDS) conducted in 2010. The ANCDS was a cross-sectional survey involving acute care patients from 56 Australian and New Zealand hospitals. Hospital-based dietitians evaluated participants’ nutritional status (defined by Subjective Global Assessment, SGA) and 24-hour food intake (as 0%, 25%, 50%, 75%, and 100% of the offered food). Three months later, outcome data, including length of stay (LOS) and 90-day in-hospital mortality, were collected. Of the 3122 participants, 4% (n = 136) were morbidly obese (67% females, 55 ± 14 years, BMI: 48 ± 8 kg/m2). Eleven percent (n = 15) of the morbidly obese patients were malnourished, and most (n = 11/15, 73%)received standard hospital diets without additional nutritional support. Malnourished morbidly obese patients had significantly longer LOS and greater 90-day in-hospital mortality than well-nourished counterparts (23 days vs. 9 days, p = 0.036; 14% vs. 0% mortality, p = 0.011 respectively). Thirteen morbidly obese patients (10%) consumed only 25% of the offered meals with a significantly greater proportion of malnourished (n = 4, 27%) versus well-nourished (n = 9, 7%) (p = 0.018). These results provide new knowledge on the prevalence of PEM and poor food intake in morbidly obese patients in Australian and New Zealand hospitals. For the first time internationally, the study establishes that PEM is significantly associated with negative outcomes in morbidly obese patients and warrants timely nutritional support during hospitalisation.

Classification of echolocation calls from 14 species of bat by Support Vector Machines and Ensembles of Neural Networks

Calls from 14 species of bat were classified to genus and species using discriminant function analysis (DFA), support vector machines (SVM) and ensembles of neural networks (ENN). Both SVMs and ENNs outperformed DFA for every species while ENNs (mean identification rate – 97%) consistently outperformed SVMs (mean identification rate – 87%). Correct classification rates produced by the ENNs varied from 91% to 100%; calls from six species were correctly identified with 100% accuracy. Calls from the five species of Myotis, a genus whose species are considered difficult to distinguish acoustically, had correct identification rates that varied from 91 – 100%. Five parameters were most important for classifying calls correctly while seven others contributed little to classification performance.

Protecting World Heritage sites from the adverse impacts of climate change : obligations for States Parties to the World Heritage Convention

Through its mandate to protect and preserve places of ‘outstanding universal value’, the World Heritage Convention provides an unlikely yet effective tool in global efforts to mitigate climate change. The practical efficacy of the Strategy to Assist States Parties to Implement Appropriate Management Responses (‘the Strategy’), which represents the World Heritage Committee’s primary response to the threats posed by climate change to World Heritage sites, is undermined by its weak stance on mitigation. This paper argues that the World Heritage Convention imposes stronger obligations on States Parties than those contained in the Strategy, including a duty on States Parties to commit to ‘deep cuts’ in greenhouse gas emissions. In order to ensure the continuing success of the World Heritage Convention States Parties must engage in extensive mitigation strategies without delay.

An early feeding practices intervention for obesity prevention

Objective - Report long term outcomes of the NOURISH randomized controlled trial (RCT) that evaluated a universal intervention commencing in infancy to provide anticipatory guidance to first-time mothers on ‘protective’ complementary feeding practices which were hypothesized to reduce childhood obesity risk. Subjects and Methods - The NOURISH RCT enrolled 698 mothers (mean age 30.1 years, SD=5.3) with healthy term infants (51% female). Mothers were randomly allocated to usual care or to attend two 6-session, 12-week group education modules. Outcomes were assessed five times: baseline (infants 4.3 months); 6 months after module 1 (infants 14 months); 6 months after module 2 (infants 2 years) and at 3.5 and 5 years of age. Maternal feeding practices were self-reported using validated questionnaires. BMI Z-score was calculated from measured child height and weight. Linear Mixed Models evaluated intervention (group) effect across time. Results - Retention at 5 years of age was 61%. Across ages 2-5 years, intervention mothers reported less frequent use of non-responsive feeding practices on 6/9 scales. At 5 years they also reported more appropriate responses to food refusal on 7/12 items (Ps ≤.05). No statistically significant group effect was noted for anthropometric outcomes (BMI Z-score: P=.06), or the prevalence of overweight/obesity (control 13.3% vs. intervention 11.4%, P=.66). Conclusions - Anticipatory guidance on complementary feeding resulted in first-time mothers reporting increased use of protective feeding practices. These intervention effects were sustained up to five years of age and were paralleled by a non-significant trend for lower child BMI Z-scores at all post-intervention assessment points.

The relationship between number of fruits, vegetables, and noncore foods tried at age 14 months and food preferences, dietary intake patterns, fussy eating behavior, and weight status at age 3.7 years

Objective We examined whether exposure to a greater number of fruits, vegetables, and noncore foods (ie, nutrient poor and high in saturated fats, added sugars, or added salt) at age 14 months was related to children’s preference for and intake of these foods as well as maternal-reported food fussiness and measured child weight status at age 3.7 years. Methods This study reports secondary analyses of longitudinal data from mothers and children (n=340) participating in the NOURISH randomized controlled trial. Exposure was quantified as the number of food items (n=55) tried by a child from specified lists at age 14 months. At age 3.7 years, food preferences, intake patterns, and fussiness (also at age 14 months) were assessed using maternal-completed, established questionnaires. Child weight and length/height were measured by study staff at both age points. Multivariable linear regression models were tested to predict food preferences, intake patterns, fussy eating, and body mass index z score at age 3.7 years adjusting for a range of maternal and child covariates. Results Having tried a greater number of vegetables, fruits, and noncore foods at age 14 months predicted corresponding preferences and higher intakes at age 3.7 years but did not predict child body mass index z score. Adjusting for fussiness at age 14 months, having tried more vegetables at age 14 months was associated with lower fussiness at age 3.7 years. Conclusions These prospective analyses support the hypothesis that early taste and texture experiences influence subsequent food preferences and acceptance. These findings indicate introduction to a variety of fruits and vegetables and limited noncore food exposure from an early age are important strategies to improve later diet quality.

Group 14 element-based non-centrosymmetric quantum spin hall insulators with large bulk gap

To date, a number of two-dimensional (2D) topological insulators (TIs) have been realized in Group 14 elemental honeycomb lattices, but all are inversionsymmetric. Here, based on first-principles calculations, we predict a new family of 2D inversion-asymmetric TIs with sizeable bulk gaps from 105 meV to 284 meV, in X2–GeSn (X = H, F, Cl, Br, I) monolayers, making them in principle suitable for room-temperature applications. The nontrivial topological characteristics of inverted band orders are identified in pristine X2–GeSn with X = (F, Cl, Br, I), whereas H2–GeSn undergoes a nontrivial band inversion at 8% lattice expansion. Topologically protected edge states are identified in X2–GeSn with X = (F, Cl, Br, I), as well as in strained H2–GeSn. More importantly, the edges of these systems, which exhibit single-Dirac-cone characteristics located exactly in the middle of their bulk band gaps, are ideal for dissipationless transport. Thus, Group 14 elemental honeycomb lattices provide a fascinating playground for the manipulation of quantum states.

Bayesian refinement of association signals for 14 loci in 3 common diseases

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.