MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer

The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.

Risk of tuberculosis following HIV seroconversion in high-income countries

Background Few data exist on tuberculosis (TB) incidence according to time from HIV seroconversion in high-income countries and whether rates following initiation of a combination of antiretroviral treatments (cARTs) differ from those soon after seroconversion. Methods Data on individuals with well estimated dates of HIV seroconversion were used to analyse post-seroconversion TB rates, ending at the earliest of 1 January 1997, death or last clinic visit. TB rates were also estimated following cART initiation, ending at the earliest of death or last clinic visit. Poisson models were used to examine the effect of current and past level of immunosuppression on TB risk after cART initiation. Results Of 19 815 individuals at risk during 1982–1996, TB incidence increased from 5.89/1000 person-years (PY) (95% CI 3.77 to 8.76) in the first year after seroconversion to 10.56 (4.83 to 20.04, p=0.01) at 10 years. Among 11 178 TB-free individuals initiating cART, the TB rate in the first year after cART initiation was 4.23/1000 PY (3.07 to 5.71) and dropped thereafter, remaining constant from year 2 onwards averaging at 1.64/1000 PY (1.29 to 2.05). Current CD4 count was inversely associated with TB rates, while nadir CD4 count was not associated with TB rates after adjustment for current CD4 count, HIV-RNA at cART initiation. Conclusions TB risk increases with duration of HIV infection in the absence of cART. Following cART initiation, TB incidence rates were lower than levels immediately following seroconversion. Implementation of current recommendations to prevent TB in early HIV infection could be beneficial.

Variation in fat mobilization during early lactation differently affects feed intake, body condition, and lipid and glucose metabolism in high-yielding dairy cows.

Fat mobilization to meet energy requirements during early lactation is inevitable because of insufficient feed intake, but differs greatly among high-yielding dairy cows. Therefore, we studied milk production, feed intake, and body condition as well as metabolic and endocrine changes in high-yielding dairy cows to identify variable strategies in metabolic and endocrine adaptation to overcome postpartum metabolic load attributable to milk production. Cows used in this study varied in fat mobilization around calving, as classified by mean total liver fat concentrations (LFC) postpartum. German Holstein cows (n=27) were studied from dry off until d 63 postpartum in their third lactation. All cows were fed the same total mixed rations ad libitum during the dry period and lactation. Plasma concentrations of metabolites and hormones were measured in blood samples taken at d 56, 28, 15, and 5 before expected calving and at d 1 and once weekly up to d 63 postpartum. Liver biopsies were taken on d 56 and 15 before calving, and on d 1, 14, 28, and 49 postpartum to measure LFC and glycogen concentrations. Cows were grouped accordingly to mean total LFC on d 1, 14, and 28 in high, medium, and low fat-mobilizing cows. Mean LFC (±SEM) differed among groups and were 351±14, 250±10, and 159±9 mg/g of dry matter for high, medium, and low fat-mobilizing cows, respectively, whereas hepatic glycogen concentrations postpartum were the highest in low fat-mobilizing cows. Cows in the low group showed the highest dry matter intake and the least negative energy balance postpartum, but energy-corrected milk yield was similar among groups. The decrease in body weight postpartum was greatest in high fat-mobilizing cows, but the decrease in backfat thickness was greatest in medium fat-mobilizing cows. Plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate were highest around calving in high fat-mobilizing cows. Plasma triglycerides were highest in the medium group and plasma cholesterol concentrations were lowest in the high group at calving. During early lactation, the decrease in plasma glucose concentrations was greatest in the high group, and plasma insulin concentrations postpartum were highest in the low group. The revised quantitative insulin sensitivity check index values decreased during the transition period and postpartum, and were highest in the medium group. Plasma cortisol concentrations during the transition period and postpartum period and plasma leptin concentrations were highest in the medium group. In conclusion, cows adapted differently to the metabolic load and used variable strategies for homeorhetic regulation of milk production. Differences in fat mobilization were part of these strategies and contributed to the individual adaptation of energy metabolism to milk production.

Personality factors in elementary school children: Contributions to academic performance over and above executive functions?

Unique contributions of Big Five personality factors to academic performance in young elementary school children were explored. Extraversion and Openness (labeled “Culture” in our study) uniquely contributed to academic performance, over and above the contribution of executive functions in first and second grade children (N = 446). Well established associations between Conscientiousness and academic performance, however, could only be replicated with regard to zero-order correlations. Executive functions (inhibition, updating, and shifting), for their part, proved to be powerful predictors of academic performance. Results were to some extent dependent on the criterion with which academic performance was measured: Both personality factors had stronger effects on grades than on standardized achievement tests, whereas the opposite was true for executive functions. Finally, analyses on gender differences revealed that Extraversion and Openness/Culture played a more dominant role in girls than in boys, but only regarding grades.

Pressure-temperature estimates of the lizardite/antigorite transition in high pressure serpentinites

Serpentine minerals in natural samples are dominated by lizardite and antigorite. In spite of numerous laboratory experiments, the stability fields of these species remain poorly constrained. This paper presents petrological observations and the Raman spectroscopy and XRD analyses of natural serpentinites from the Alpine paleo-accretionary wedge. Serpentine varieties were identified from a range of metamorphic pressure and temperature conditions from sub-greenschist (P < 4 kbar, T ~ 200–300 °C) to eclogite facies conditions (P > 20 kbar, T > 460 °C) along a subduction geothermal gradient. We use the observed mineral assemblage in natural serpentinite along with the Tmax estimated by Raman spectroscopy of the carbonaceous matter in associated metasediments to constrain the temperature of the lizardite to antigorite transition at high pressures. We show that below 300 °C, lizardite and locally chrysotile are the dominant species in the mesh texture. Between 320 and 390 °C, lizardite is progressively replaced by antigorite at the grain boundaries through dissolution–precipitation processes in the presence of SiO2 enriched fluids and in the cores of the lizardite mesh. Above 390 °C, under high-grade blueschist to eclogite facies conditions, antigorite is the sole stable serpentine mineral until the onset of secondary olivine crystallization at 460 °C.

Neotethys closure history of Anatolia: insights from 40Ar–39Ar geochronology and P–T estimation in high pressure metasedimentary rocks

The multiple high-pressure (HP), low-temperature (LT) metamorphic units of Western and Central Anatolia offer a great opportunity to investigate the subduction- and continental accretion-related evolution of the eastern limb of the long-lived Aegean subduction system. Recent reports of the HP–LT index mineral Fe-Mg-carpholite in three metasedimentary units of the Gondwana-derived Anatolide–Tauride continental block (namely the Afyon Zone, the Ören Unit and the southern Menderes Massif) suggest a more complicated scenario than the single-continental accretion model generally put forward in previous studies. This study presents the first isotopic dates (white mica 40Ar–39Ar geochronology), and where possible are combined with P–T estimates (chlorite thermometry, phengite barometry, multi-equilibrium thermobarometry), on carpholite-bearing rocks from these three HP–LT metasedimentary units. It is shown that, in the Afyon Zone, carpholite-bearing assemblages were retrogressed through greenschist-facies conditions at c. 67–62 Ma. Early retrograde stages in the Ören Unit are dated to 63–59 Ma. In the Kurudere–Nebiler Unit (HP Mesozoic cover of the southern Menderes Massif), HP retrograde stages are dated to c. 45 Ma, and post-collisional cooling to c. 26 Ma. These new results support that the Ören Unit represents the westernmost continuation of the Afyon Zone, whereas the Kurudere–Nebiler Unit correlates with the Cycladic Blueschist Unit of the Aegean Domain. In Western Anatolia, three successive HP–LT metamorphic belts thus formed: the northernmost Tavşanlı Zone (c. 88–82 Ma), the Ören–Afyon Zone (between 70 and 65 Ma), and the Kurudere–Nebiler Unit (c. 52–45 Ma). The southward younging trend of the HP–LT metamorphism from the upper and internal to the deeper and more external structural units, as in the Aegean Domain, points to the persistence of subduction in Western Anatolia between 93–90 and c. 35 Ma. After the accretion of the Menderes–Tauride terrane, in Eocene times, subduction stopped, leading to continental collision and associated Barrovian-type metamorphism. Because, by contrast, the Aegean subduction did remain active due to slab roll-back and trench migration, the eastern limb (below Southwestern Anatolia) of the Hellenic slab was dramatically curved and consequently teared. It therefore is suggested that the possibility for subduction to continue after the accretion of buoyant (e.g. continental) terranes probably depends much on palaeogeography.

The Role of Acidic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor 4 in High Grade Serous Carcinoma

Background: High grade serous carcinoma whether ovarian, tubal or primary peritoneal, continues to be the most lethal gynecologic malignancy in the USA. Although combination chemotherapy and aggressive surgical resection has improved survival in the past decade the majority of patients still succumb to chemo-resistant disease recurrence. It has recently been reported that amplification of 5q31-5q35.3 is associated with poor prognosis in patients with high grade serous ovarian carcinoma. Although the amplicon contains over 50 genes, it is notable for the presence of several members of the fibroblast growth factor signaling axis. In particular acidic fibroblast growth factor (FGF1) has been demonstrated to be one of the driving genes in mediating the observed prognostic effect of the amplicon in ovarian cancer patients. This study seeks to further validate the prognostic value of fibroblast growth receptor 4 (FGFR4), another candidate gene of the FGF/FGFR axis located in the same amplicon. The emphasis will be delineating the role the FGF1/FGFR4 signaling axis plays in high grade serous ovarian carcinoma; and test the feasibility of targeting the FGF1/FGFR4 axis therapeutically. Materials and Methods: Spearman and Pearson correlation studies on data generated from array CGH and transcriptome profiling analyses on 51 microdissected tumor samples were used to identify genes located on chromosome 5q31-35.3 that showed significant correlation between DNA and mRNA copy numbers. Significant correlation between FGF1 and FGFR4 DNA copy numbers was further validated by qPCR analysis on DNA isolated from 51 microdissected tumor samples. Immunolocalization and quantification of FGFR4 expression were performed on paraffin embedded tissue samples from 183 cases of high-grade serous ovarian carcinoma. The expression was then correlated with clinical data to assess impact on survival. The expression of FGF1 and FGFR4 in vitro was quantified by real-time PCR and western blotting in six high-grade serous ovarian carcinoma cell lines and compared to those in human ovarian surface epithelial cells to identify overexpression. The effect of FGF1 on these cell lines after serum starvation was quantified for in vitro cellular proliferation, migration/invasion, chemoresistance and survival utilizing a combination of commercially available colorimetric, fluorometric and electrical impedance assays. FGFR4 expression was then transiently silenced via siRNA transfection and the effects on response to FGF1, cellular proliferation, and migration were quantified. To identify relevant cellular pathways involved, responsive cell lines were transduced with different transcription response elements using the Cignal-Lenti reporter system and treated with FGF1 with and without transient FGFR4 knock down. This was followed by western blot confirmation for the relevant phosphoproteins. Anti-FGF1 antibodies and FGFR trap proteins were used to attempt inhibition of FGF mediated phenotypic changes and relevant signaling in vitro. Orthotopic intraperitoneal tumors were established in nude mice using serous cell lines that have been previously transfected with luciferase expressing constructs. The mice were then treated with FGFR trap protein. Tumor progression was then followed via bioluminescent imaging. The FGFR4 gene from 52 clinical samples was sequenced to screen for mutations. Results: FGFR4 DNA and mRNA copy numbers were significantly correlated and FGFR4 DNA copy number was significantly correlated with that of FGF1. Survival of patients with high FGFR4 expressing tumors was significantly shorter that those with low expression(median survival 28 vs 55 month p< 0.001) In a multivariate cox regression model FGFR expression significantly increased risk of death (HR 2.1, p<0.001). FGFR4 expression was significantly higher in all cell lines tested compared to HOSE, OVCA432 cell line in particular had very high expression suggesting amplification. FGF1 was also particularly overexpressed in OVCA432. FGF1 significantly increased cell survival after serum deprivation in all cell lines. Transient knock down of FGFR4 caused significant reduction in cell migration and proliferation in vitro and significantly decreased the proliferative effects of FGF1 in vitro. FGFR1, FGFR4 traps and anti-FGF1 antibodies did not show activity in vitro. OVCA432 transfected with the cignal lenti reporter system revealed significant activation of MAPK, NFkB and WNT pathways, western blotting confirmed the results. Reverse phase protein array (RPPA) analysis also showed activation of MAPK, AKT, WNT pathways and down regulation of E Cadherin. FGFR trap protein significantly reduced tumor growth in vivo in an orthotopic mouse model. Conclusions: Overexpression and amplification of several members of the FGF signaling axis present on the amplicon 5q31-35.3 is a negative prognostic indicator in high grade serous ovarian carcinoma and may drive poor survival associated with that amplicon. Activation of The FGF signaling pathway leads to downstream activation of MAPK, AKT, WNT and NFkB pathways leading to a more aggressive cancer phenotype with increased tumor growth, evasion of apoptosis and increased migration and invasion. Inhibition of FGF pathway in vivo via FGFR trap protein leads to significantly decreased tumor growth in an orthotopic mouse model.

Radiometric Method for Emissivity Retrieval in High Reflective Materials

High reflective materials in the microwave region play a very important role in the realization of antenna reflectors for a broad range of applications, including radiometry. These reflectors have a characteristic emissivity which needs to be characterized accurately in order to perform a correct radiometric calibration of the instrument. Such a characterization can be performed by using open resonators, waveguide cavities or by radiometric measurements. The latter consists of comparative radiometric observations of absorbers, reference mirrors and the sample under test, or using the cold sky radiation as a direct reference source. While the first two mentioned techniques are suitable for the characterization of metal plates and mirrors, the latter has the advantages to be also applicable to soft materials. This paper describes how, through this radiometric techniques, it is possible to characterize the emissivity of the sample relative to a reference mirror and how to characterize the absolute emissivity of the latter by performing measurements at different incident angles. The results presented in this paper are based on our investigations on emissivity of a multilayer insulation material (MLI) for space mission, at the frequencies of 22 and 90 GHz.

Cognitive performance in high-altitude climbers: a comparative study of saccadic eye movements and neuropsychological tests

Impairment of cognitive performance during and after high-altitude climbing has been described in numerous studies and has mostly been attributed to cerebral hypoxia and resulting functional and structural cerebral alterations. To investigate the hypothesis that high-altitude climbing leads to cognitive impairment, we used of neuropsychological tests and measurements of eye movement (EM) performance during different stimulus conditions. The study was conducted in 32 mountaineers participating in an expedition to Muztagh Ata (7,546 m). Neuropsychological tests comprised figural fluency, line bisection, letter and number cancellation, and a modified pegboard task. Saccadic performance was evaluated under three stimulus conditions with varying degrees of cortical involvement: visually guided pro- and anti-saccades, and visuo-visual interaction. Typical saccade parameters (latency, mean sequence, post-saccadic stability, and error rate) were computed off-line. Measurements were taken at a baseline level of 440 m and at altitudes of 4,497, 5,533, 6,265, and again at 440 m. All subjects reached 5,533 m, and 28 reached 6,265 m. The neuropsychological test results did not reveal any cognitive impairment. Complete eye movement recordings for all stimulus conditions were obtained in 24 subjects at baseline and at least two altitudes and in 10 subjects at baseline and all altitudes. Measurements of saccade performances showed no dependence on any altitude-related parameter and were well within normal limits. Our data indicates that acclimatized climbers do not seem to suffer from significant cognitive deficits during or after climbs to altitudes above 7,500 m. We demonstrated that investigation of EMs is feasible during high-altitude expeditions.

Impacts of a word-picture training on literacy skills in elementary school children and youths with intellectual disabilities

Objective: There is convincing evidence that phonological, orthographic and semantic processes influence children’s ability to learn to read and spell words. So far only a few studies investigated the influence of implicit learning in literacy skills. Children are sensitive to the statistics of their learning environment. By frequent reading they acquire implicit knowledge about the frequency of letter patterns in written words, and they use this knowledge during reading and spelling. Additionally, semantic connections facilitate to storing of words in memory. Thus, the aim of the intervention study was to implement a word-picture training which is based on statistical and semantic learning. Furthermore, we aimed at examining the training effects in reading and spelling in comparison to an auditory-visual matching training and a working memory training program. Participants and Methods: One hundred and thirty-two children aged between 8 and 11 years participated in training in three weekly session of 12 minutes over 8 weeks, and completed other assessments of reading, spelling, working memory and intelligence before and after training. Results: Results revealed in general that the word-picture training and the auditory-visual matching training led to substantial gains in reading and spelling performance in comparison to the working-memory training. Although both children with and without learning difficulties profited in their reading and spelling after the word-picture training, the training program led to differential effects for the two groups. After the word-picture training on the one hand, children with learning difficulties profited more in spelling as children without learning difficulties, on the other hand, children without learning difficulties benefit more in word comprehension. Conclusions: These findings highlight the need for frequent reading trainings with semantic connections in order to support the acquisition of literacy skills.

Executive functioning, metacognition, and self-perceived competence in elementary school children: An explorative study on their interrelations and their role for school achievement

In the present study, associations between executive functioning, metacognition, and self-perceived competence in the context of early academic outcomes were examined. A total of 209 children attending first grade were initially assessed in terms of their executive functioning and academic self-concept. One year later, children’s executive functioning, academic self-concept, metacognitive monitoring and control, as well as their achievement in mathematics and literacy were evaluated. Structural equation modeling revealed that executive functioning was significantly related to metacognitive control, both cross-sectionally and longitudinally, and that self-concept was substantially associated with metacognitive monitoring, both cross-sectionally and longitudinally. Individual differences in executive functioning and metacognitive control were significantly related to academic outcomes, with metacognitive control appearing to yield a more circumscribed influence on academic outcomes (only literacy) compared to executive functioning (literacy and mathematics).

Search for Quantum Black Hole Production in High-Invariant-Mass Lepton plus Jet Final States Using pp Collisions at root s=8 TeV and the ATLAS Detector

This Letter presents a search for quantum black-hole production using 20.3 fb(-1) of data collected with the ATLAS detector in pp collisions at the LHC at root s = 8 TeV. The quantum black holes are assumed to decay into a final state characterized by a lepton (electron or muon) and a jet. In either channel, no event with a lepton-jet invariant mass of 3.5 TeV or more is observed, consistent with the expected background. Limits are set on the product of cross sections and branching fractions for the lepton + jet final states of quantum black holes produced in a search region for invariant masses above 1 TeV. The combined 95% confidence level upper limit on this product for quantum black holes with threshold mass above 3.5 TeV is 0.18 fb. This limit constrains the threshold quantum black-hole mass to be above 5.3 TeV in the model considered.

Immigrant students’ psychological adjustment in the school context: A meta-synthesis of qualitative research on acculturation

This contribution focuses on the characteristics of the school context and their impact on immigrant students’ acculturation and adjustment at school. Research suggests that the ways immigrants acculturate is related to their well being (e.g. Phinney, et al., 2001; Ward & Rana-Deuba, 1999), although findings have been contradictory across methods and studies (e.g. Rogler, 1991; Escobar & Vega, 2001). Debates in acculturation research currently center on issues of acculturation measurement (e.g. Berry, 2009; Rudmin, 2009), as most research is conducted in the quantitative tradition. In addition, some have suggested (Birman, 2011) that research on acculturation in the tradition of cross-cultural psychology adopts an overly individualistic perspective, and lacks attention to the specific contexts of acculturation. Alternatively, the contextual approach proposes that the relationship between acculturation and adjustment is shaped by the surrounding context (Birman & Simon, 2013). For immigrant children, schools are the setting where the process of acculturation unfolds, and an important context in which to study their adjustment and well being (Birman, et al., 2007; Makarova & Herzog, 2011). Though rarely used in this tradition of acculturation research (Chirkov, 2009), qualitative methods are uniquely suited to gain insight to facilitate theory development, as well as appreciate the contextual nature of the acculturation process. Yet we are not aware of efforts to synthesize the empirical qualitative literature on this topic. Applying the methodology of meta-synthesis for qualitatieve research (Walsh & Downe, 2005) our contribution attempts to integrate results from qualitative studies on impact of acculturation on immigrant students’ psychological adjustment in the school context. For this purpose 84 articles which matched the inclusion criteria were selected. Overall, the results of our study show that within the school context a number of structural as well as process characteristics can be identified as crucial for immigrant youth psychological adjustment. Moreover, our findings indicate that immigrant youths’ psychological adjustment is related to other individual outcomes of acculturation in the school context such as behavioral adjustment, peer-relationships, academic achievement and identity development of immigrant youth.