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Ultrasound imaging of the lung and associated tissues may play an important role in the management of patients with COVID-19-associated lung injury. Compared with other monitoring modalities, such as auscultation or radiographic imaging, we argue lung ultrasound has high diagnostic accuracy, is ergonomically favourable and has fewer infection control implications. By informing the initiation, escalation, titration and weaning of respiratory support, lung ultrasound can be integrated into COVID-19 care pathways for patients with respiratory failure. Given the unprecedented pressure on healthcare services currently, supporting and educating clinicians is a key enabler of the wider implementation of lung ultrasound. This narrative review provides a summary of evidence and clinical guidance for the use and interpretation of lung ultrasound for patients with moderate, severe and critical COVID-19-associated lung injury. Mechanisms by which the potential lung ultrasound workforce can be deployed are explored, including a pragmatic approach to training, governance, imaging, interpretation of images and implementation of lung ultrasound into routine clinical practice. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes infections have been described in patients with diverse types of malignancy, especially leukemia. We report the case of a 65-year-old man with previously untreated hairy cell leukemia characterized by CD5 positivity and trisomy 12 (3% of blood lymphocytes) who developed bacteremia due to L. monocytogenes serotype 1/2b. We summarize clinical features and treatment of this patient and five previously reported patients with hairy cell leukemia who also had L. monocytogenes infections. All six patients were men. Their mean age at infection diagnosis was 70 y. Three men had undergone splenectomy 4–11 y before they developed L. monocytogenes infection. The central nervous system was the primary site of infection in four men. Bacteremia alone occurred in two other men. At diagnosis of infection, one man was receiving antileukemia chemotherapy and another man was receiving treatment for Kaposi’s sarcoma. Two other patients had other comorbid conditions. All six men recovered from their infections. [ABSTRACT FROM AUTHOR]

14 C analysis of flue gas by accelerator mass spectrometry (AMS) and liquid scintillation counting (LSC) were used to determine the biomass fraction of mixed waste at an operational energy-from-waste (EfW) plant. Results were converted to bioenergy (% total) using mathematical algorithms and assessed against existing industry methodologies which involve manual sorting and selective dissolution (SD) of feedstock. Simultaneous determinations using flue gas showed excellent agreement: 44.8 ± 2.7% for AMS and 44.6 ± 12.3% for LSC. Comparable bioenergy results were obtained using a feedstock manual sort procedure (41.4%), whilst a procedure based on selective dissolution of representative waste material is reported as 75.5% (no errors quoted). 14 C techniques present significant advantages in data acquisition, precision and reliability for both electricity generator and industry regulator. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cellular protein kinases are anti-herpesvirus drug targets. [•] Herpesvirus protein kinases are anti-herpesvirus drug targets. [•] Future directions for the exploitation of protein kinases are presented. [Copyright &y& Elsevier]

Furan has been found to form in foods during thermal processing. These findings, a classification of furan as a possibly carcinogenic to humans, and a limited amount of data on the concentration of furan in products on the Canadian market prompted the authors to conduct a survey of canned and jarred food products. Methyl analogues of furan, 2-methylfuran and 3-methylfuran, were analysed concurrently with furan via a newly developed isotope dilution method, as these analogues were detected in foods in the authors' earlier work and are likely to undergo a similar metabolic fate as furan itself. The paper reports data on 176 samples, including 17 samples of baby food. The vast majority of samples were packaged in cans or jars. Furan was detected above 1 ng g−1 in all non-baby food samples with a median of 28 ng g−1 and concentrations ranging from 1.1 to 1230 ng g−1. Also, 96% of these samples were found to contain 2-methylfuran above 1 ng g−1 with a median of 12.8 ng g−1 and a maximum concentration of 152 ng g−1, while 81% of samples were found to contain 3-methylfuran above 1 ng g−1 with a median of 6 ng g−1 and a maximum concentration of 151 ng g−1. Similarly, furan was detected above 1 ng g−1 in all baby food samples with a median of 66.2 ng g−1 and concentrations ranging from 8.5 to 331 ng g−1. Also, 100% of these samples were found to contain 2-methylfuran above 1 ng g−1 with a median of 8.7 ng g−1 and a maximum concentration of 50.2 ng g−1, while 65% of samples were found to contain 3-methylfuran above 1 ng g−1 with a median of 1.6 ng g−1 and a maximum concentration of 22.9 ng g−1. Additionally, three coffee samples were analysed 'as is', without brewing, and were found to have high levels of furans, especially 2-methylfuran, at a maximum of 8680 ng g−1. Using this data set, dietary exposures to furan and total furans were calculated. Average furan and total furan intakes by adults (≥20 years) were estimated at approximately 0.37 and 0.71 µg kg−1 of body weight day−1 respectively. [ABSTRACT FROM AUTHOR]

Insects are highly successful animals inhabiting marine, freshwater and terrestrial habitats from the equator to the poles. As a group, insects have limited ability to regulate their body temperature and have thus required a range of strategies to support life in thermally stressful environments, including behavioural avoidance through migration and seasonal changes in cold tolerance. With respect to overwintering strategies, insects have traditionally been divided into two main groups: freeze tolerant and freeze avoiding, although this simple classification is underpinned by a complex of interacting processes, i.e. synthesis of ice nucleating agents, cryoprotectants, antifreeze proteins and changes in membrane lipid composition. Also, in temperate and colder climates, the overwintering ability of many species is closely linked to the diapause state, which often increases cold tolerance ahead of temperature-induced seasonal acclimatisation. Importantly, even though most species can invoke one or both of these responses, the majority of insects die from the effects of cold rather than freezing. Most studies on the effects of a changing climate on insects have focused on processes that occur predominantly in summer (development, reproduction) and on changes in distributions rather than winter survival per Se. For species that routinely experience cold stress, a general hypothesis would be that predicted temperature increases of 1°C to 5°C over the next 50-100 years would increase winter survival in some climatic zones. However, this is unlikely to be a universal effect. Negative impacts may occur if climate warming leads to a reduction or loss of winter snow cover in polar and sub-polar areas, resulting in exposure to more severe air temperatures, increasing frequency of freeze-thaw cycles and risks of ice encasement. Likewise, whilst the dominant diapause-inducing cue (photoperiod) will be unaffected by global climate change, higher temperatures may modify normal rates of development, leading to a de-coupling of synchrony between diapause-sensitive life-cycle stages and critical photoperiods for diapause induction. In terms of climate warming and potential heat stress, the most recent predictions of summer temperatures in Europe of 40°C or higher in 50-75 years, are close to the current upper lethal limit of some insects. Long-term data sets on insect distributions and the timing of annual migrations provide strong evidence for 'positive' responses to higher winter temperatures over timescales of the past 20-50 years in North America, Europe and Asia. [ABSTRACT FROM AUTHOR]

We thank Drs Sikachi and Agrawal [1] for their response to our article [2] and wholeheartedly agree that point-of-care ultrasound imaging has a valuable role to play across a range of organ systems and disease presentations [3], including those of relevance in COVID-19 disease. In identifying a narrow remit and application of ultrasound imaging in COVID-19 disease, our publication empowers the deployment of workforces to address one of the principal organs compromised by COVID-19 disease. Within all of the above we strongly encourage point-of-care scanning clinicians to work in partnership with ultrasound imaging specialists (such as radiologists, career sonographers, vascular technologists, etc) to elevate the standard of imaging across the board [5]. [Extracted from the article]

The Notch signaling pathway influences cell fate decisions, proliferation versus differentiation and cell survival. Viruses both utilize and manipulate the differentiation state of infected cells, promote or block cell cycling and employ a variety of mechanisms to evade innate cellular anti-viral responses and promote cell survival. In light of these commonalities, it is perhaps not surprising that several viruses have tapped into the Notch pathway to advance their own life cycles. This first became apparent from studies showing targeting of Epstein-Barr virus proteins to the nuclear effector of Notch signaling CSL (CBF1/RBPJk). More recently the Kaposi’s sarcoma-associated herpesvirus RTA protein has been found to bind CSL. Notch pathway interactions have also been described for adenovirus SV40 and human papilloma virus. This review focuses on the herpesvirus protein interactions with the Notch pathway and the insights that these interactions have provided. [Copyright &y& Elsevier]

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 latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in all KSHV-associated malignancies. LANA is essential for replication and maintenance of the viral episomes during latent infection. However, LANA also has a transcriptional regulatory role and can affect gene expression both positively and negatively. A previously performed yeast two-hybrid screen identified glycogen synthase kinase 3 (GSK-3) as a LANA-interacting protein. Interaction with both GSK-3α and GSK-3β was confirmed in transfected cells with coprecipitation assays. GSK-3β also interacted with the herpesvirus saimiri homolog ORF73. GSK-3β is an intermediate in the Wnt signaling pathway and a negative regulator of β-catenin. In transfected cells, LANA was shown to overcome GSK-3β-mediated degradation of β-catenin. Examination of primary effusion lymphoma (PEL) cells found increased levels of β-catenin relative to KSHVnegative B cells, and this translated into increased activity of a β-catenin-responsive reporter containing Tcf/Lef binding sites. In tetradecanoyl phorbol acetate-treated PEL cells, loss of LANA expression correlated temporally with loss of detectable β-catenin. LANA was found to alter the intracellular distribution of GSK-3β so that nuclear GSK-3β was more readily detectable in the presence of LANA. Mapping experiments with coimmunoprecipitation assays revealed that both N-terminal and C-terminal LANA sequences were required for efficient GSK-3β interaction. LANA mutants that were defective for GSK-3β interaction were unable to mediate GSK-3β relocalization or activate a β-catenin-responsive Tcf-luciferase reporter. This study identified manipulation of GSK-3β activity as a mechanism by which LANA may modify transcriptional activity and contribute to the phenotype of primary effusion lymphoma. [ABSTRACT FROM AUTHOR]

Abstract. The thermal preferences of Alaskozetes antarcticus (Acari, Cryptostigmata) and Cryptopygus antarcticus (Collembola, Isotomidae) were investigated over 6 h within a temperature gradient (-3 to +13 °C), under 100% relative humidity (RH) conditions. After 10 days of acclimation at -2 or +11 °C, individual supercooling points (SCP) and thermopreferences were assessed, and compared with animals maintained for 10 days under fluctuating field conditions (-6 to +7 °C). Acclimation at -2 °C lowered the mean SCP of both A. antarcticus (-24.2 ± 9.1) and C. antarcticus (-14.7 ± 7.7) compared to field samples (-19.0 ± 9.0 and -10.7 ± 5.2, respectively). Acclimation at +11 °C increased A. antarcticus mean SCP values (-13.0 ± 8.5) relative to field samples, whereas those of C. antarcticus again decreased (-16.7 ± 9.1). Mites acclimated under field conditions or at +11 °C selected temperatures between -3 and +1 °C. After acclimation at -2 °C, both species preferred +1 to +5 °C. Cryptopygus antarcticus maintained under field conditions preferred +5 to +9 °C, whereas individuals acclimated at +11 °C selected +9 to +13 °C. For A. antarcticus , thermopreference was not influenced by its cold hardened state. The distribution of field specimens was further assessed within two combined temperature and humidity gradient systems: (i) 0–3 °C/12% RH, 3–6 °C/33% RH, 6–9 °C/75% RH and 9–12 °C/100% RH and (ii) 0–3 °C/100% RH, 3–6 °C/75% RH, 6–9 °C/33% RH and 9–12 °C/12% RH. In gradient (i), C. antarcticus distributed homogeneously, but, in gradient (ii), C. antarcticus preferred 0–3 °C/100% RH. Alaskozetes antarcticus selected temperatures between 0 and +6 °C regardless of RH conditions. Cryptopygus antarcticus appears better able than A. antarcticus to opportunistically utilize... [ABSTRACT FROM AUTHOR]

The reactions of monoterpenes and related C10 compounds with H3O+ in a proton transfer reaction-mass spectrometer (PTR-MS) were studied, with a view to better understanding the signal produced by this instrument when detecting these compounds. The monoterpenes α- and β-pinene, 3-carene and limonene produced fragment ions of masses 67, 81 and 95 as well as a protonated molecular ion of mass 137, while p-cymene (C10H14) produced ions of masses 41, 91, 93 and 119 in addition to mass 135. The fragmentation patterns were observed to vary as E/N was varied. Camphor (C10H16O) did not fragment within the E/N range 80–120 Td. The proton transfer reaction rate coefficients for these monoterpene species with H3O+ were found to be 2.2×10−9 to 2.5×10−9 cm3 s−1. For camphor the rate coefficient was 4.4×10−9 cm3 s−1. Water vapour pressure in the inlet air affected the fragmentation pattern for p-cymene, limonene and 3-carene. The uncertainties associated with the PTR-MS measurement of these compounds are discussed. [Copyright &y& Elsevier]

Examines the characteristics and applications of a proton transfer reaction-mass spectrometer (PTR-MS) for measuring volatile organic compounds in ambient air. Demonstration on linearity of the response of PTR-MS; Validation of ratios predicted by the PTR-MS; Components of instrument output.

SummaryThe hygropreference of adult Onychiurus arcticus (Tullberg) was investigated over 2 h at 0, 10 and 20°C, along humidity gradients (12–98% RH) established using different salt solutions. At all temperatures O. arcticus preferred the highest humidity (98% RH). At 0 and 20°C, saturated conditions were preferred to 98% RH. The hygropreference of the mite Lauroppia translamellata (Willmann) was also assessed at 20°C, and no clear RH preference was observed. This species survived the loss of 24.9 ± 2.1% of its initial water content when held for 24 h at 20°C and 12% RH. A range of assays designed to eliminate the influence of thigmotactic behaviour and population clumping permit exclusion of these factors as being responsible for the observed results. The mean initial water content of O. arcticus samples (71.7 ± 10.9, 73.4 ± 4.0 and 73.8 ± 23.5% at 0, 10 and 20°C, respectively) did not differ significantly between temperatures, indicating that the results were not influenced by differences in initial hydrated state. The percentage water loss of individuals within the gradient increased with temperature, and differed significantly between regimes. The ecological significance of the observed humidity preferences are discussed. [ABSTRACT FROM AUTHOR]

Background: Migrants in high-income countries (HICs) may have been disproportionately affected by the COVID-19 pandemic, yet the extent to which they are impacted, and their predisposing risk factors, are not clearly understood. We did a systematic review to assess clinical outcomes, indirect health and social impacts, and key risk factors in migrants. Methods: Our systematic review following PRISMA guidelines (PROSPERO CRD42020222135) identified peer-reviewed and grey literature relating to migrants (foreign-born) and COVID-19 in 82 HICs. Primary outcomes were cases, hospitalisations and deaths from COVID-19 involving migrants; secondary outcomes were indirect health and social impacts and risk factors. Results: 3016 data sources were screened with 158 from 15 countries included in the analysis. We found migrants are at increased risk of SARS-CoV-2 infection and are over-represented among cases (e.g. constituting 42% of cases in Norway [to 27/4/2020], 26% in Denmark [to 7/9/2020], and 32% in Sweden [to 7/5/ 2020]); some datasets from Europe show migrants may be over-represented in deaths with increased all-cause mortality in migrants in some countries in 2020. Undocumented migrants, migrant health and care workers, and migrants housed in camps have been especially affected, with certain nationality groups disproportionately impacted. Migrants experience a range of risk factors for COVID-19, including high-risk occupations, overcrowded accommodation, and barriers to healthcare including inadequate information, language barriers, and reduced entitlement. Conclusions: Migrants in HICs are at high risk of COVID-19, with a range of specific risk factors that have not been well-considered in the public health response to date. These data are of immediate relevance to the policy response to the pandemic, with strategies urgently needed to reduce transmission. Migrant populations must also be better considered in national plans for COVID-19 vaccination roll-out. On behalf of ESGITM Key messages: • Migrants in high-income countries may be disproportionately represented in COVID-19 infections and deaths, with higher levels of many vulnerabilities and risk factors. • Migrants must be better included in all aspects of the pandemic response, including vaccination roll-out. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) and mental illnesses are highly prevalent globally and often co-exist. Whilst poor mental health is known to modulate immune function, whether mental disorders causally increase TB incidence is unknown. This systematic review examines the association between mental health and TB disease risk to inform clinical and public health measures. Methods: We carried out a systematic review following PRISMA guidelines (PROSPERO CRD42019158071). We searched MEDLINE, PsycINFO and PsycEXTRA databases alongside reference list and citation searching. Inclusion criteria were original research studies published 01/01/1970-11/05/2020 reporting data on the relationship between mental health and risk of TB disease. CASP and AXIS checklists were used to critically appraise included studies. Results: We screened 1546 records published over 50 years, resulting in data synthesised from 607,184 individuals. Settings include Asia, South America, and Africa, and both mood (e.g. depression) and psychotic (e.g. schizophrenia) disorders are investigated. Robust evidence from cohort studies in Asia shows that depression and schizophrenia can increase risk of TB disease, with effect estimates ranging from HR = 1.15 [95% CI 1.03-1.28] to HR = 2.63 [95% CI 1.74-3.96] for depression and HR = 1.52 [95% CI 1.29-1.79] to RR = 3.04 for schizophrenia, and a dose-response relationship reported in one study. These data are consistent with data from cross-sectional studies, such as a large survey across low- and middle-income countries (n = 242,952) reporting OR = 3.36 [95% CI 3.01- 4.50] for a depressive episode in those with TB versus those without. Conclusions: Individuals with mental illnesses including depression and schizophrenia experience increased TB incidence and represent a high-risk population to target for screening and treatment. Integrated care for mental health and TB is needed, and interventions tackling mental illnesses and underlying drivers may help reduce TB incidence globally. Key messages: • This systematic review examines data from 607,184 individuals and finds evidence that mental health is a risk factor for TB disease. • Those suffering from depression and schizophrenia are an at-risk population that could be identified and targeted for TB screening and treatment. [ABSTRACT FROM AUTHOR]

Studies the masking effect of the Epstein-Barr virus nuclear antigen 2 (EBNA2) on transcriptional repression. Co-localization of EBNA2 and transcriptional repression domains; Mutation the C promoter binding factor 1 (CPBF1); Action of EBNA2.

A letter to the editor is presented in response to the article "Who knows how many anaesthetists we need?" by N. Redfern and W. Harrop-Griffiths published in a 2013 issue of the journal.

Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth. We investigated the effects of clofoctol on an EBV-positive Burkitt lymphoma cell line and confirmed the upregulation of all three branches of the UPR and activation of EBV lytic gene expression. While immediate early, early, and late EBV RNAs were all upregulated, immediate early and early viral proteins but not late viral proteins were expressed. Furthermore, infectious virions were not produced. The use of clofoctol in combination with a protein kinase R-like endoplasmic reticulum kinase inhibitor led to expression of late viral proteins. The effects of clofoctol on EBV lytic protein upregulation were not limited to lymphoid tumor cell lines but also occurred in naturally infected epithelial gastric cancer and nasopharyngeal cancer cell lines. An agent that upregulates lytic viral protein expression but that does not lead to the production of infectious virions may have particular value for lytic induction strategies in the clinical setting. [ABSTRACT FROM AUTHOR]

Forty samples of commercially brewed coffee samples from 3 national chains and 48 samples of non-brewed coffee samples were collected from retail outlets located in a single Canadian city and analyzed for furan, 2-methylfuran and 3-methylfuran by headspace gas chromatography–mass spectrometry. Non-brewed samples were analyzed “as is” and some were also analyzed after brewing in the laboratory using several preparation techniques. The three analytes were detected in all samples. The rank order of concentrations for all samples was 2-methylfuran >furan > 3-methylfuran. Ground coffee types sampled included regular ground, decaffeinated and cartridge type coffee; mean furan concentrations for these coffee types were 2200, 2450 and 2360 ng/g; 9470, 10400 and 10700 ng/g for 2-methylfuran; and 447, 463 and 508 ng/g for 3-methylfuran respectively. Mean levels for both regular and decaffeinated instant coffee powders were lower with mean furan concentrations of 233 and 327 ng/g; 1600 and 1800 ng/g for 2-methylfuran and 72.9 and 75.2 ng/g for 3-methylfuran respectively. Commercially brewed coffee types sampled included regular ground, decaffeinated and espresso coffee; mean furan concentrations for these coffee types were 38.7, 53.1 and 157 ng/g; 172, 184 and 583 ng/g for 2-methylfuran; and 6.4, 6.7 and 19 ng/g for 3-methylfuran respectively. Brewing coffee samples in laboratory as per manufacturers’ instructions resulted in 27–85% loss of furans—as compared to not brewed samples, loss of methyl furans exceeded that of furan by 10–15%. Brewed coffee stored/standing for up to 30 min resulted in further losses of furans, from 3 to 47%. Degree of loss was not analyte dependent but was highly influenced by storage conditions. [ABSTRACT FROM AUTHOR]

British sheep farmers were invited to complete a questionnaire about the impact of Schmallenberg virus (SBV) on animal health, welfare and their own emotional wellbeing during the 2011-2012 lambing season, through Defra and Farming Industry websites, letters to farmers who had requested SBV laboratory tests and advertisement at Sheep 2012. The 494 responders included SBV confirmed (positive by RT-PCR) (n=76), SBV suspected by farmer (n=140) or SBV not suspected (n=278). Percentage of barren ewes was similar across SBV groups, however, lamb and ewe losses were higher on responder farms where SBV was confirmed or suspected. The median percentages of all lambs born (and lambs born deformed ) that died within one week of birth was 10.4 per cent (5.5 per cent), 7.0 per cent (2.9 per cent) and 5.3 per cent (0 per cent), respectively, on SBV confirmed, suspected and not suspected farms (P<0.001). Eight to 16 per cent of SBV confirmed or suspected farms reported lamb mortality of ⩾40 per cent. Farmer perceived impact was greater where SBV was confirmed or suspected (P<0.001): 25 per cent reported a high impact on emotional wellbeing (4 per cent of SBV not suspected), 13 per cent reported a high impact on flock welfare and financial performance and 6 per cent were less likely to farm sheep next year because of SBV (<2 per cent in SBV not suspected). Overall, SBV impact has been large relative to reported sheep loss. [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 concentration of acrylamide was measured in selected varieties of five brands of potato chips and breakfast cereals over a 5-year period. Most of the products were purchased in one locality in Canada. Samples were analysed by an isotope dilution (13C3) acrylamide method. They were extracted with water, partitioned with dichloromethane, filtered through a 5 kDa centrifuge filter, cleaned-up on HLB Oasis polymeric and Accucat mixed mode anion and cation exchange SPE columns, and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The acrylamide concentration in potato chips varied from 106 to 4630 ng g−1, while values in cereals varied from 50 to 347 ng g−1. Wide variations were observed between brands, within brands over time, and between lots of the same brand. A subset of potato chip samples was analysed for in vitro antioxidant activity. No relationship was found between antioxidative capacity of potato chips and their acrylamide content. [ABSTRACT FROM AUTHOR]

Abstract: Intermittently closed and open lakes and lagoons (ICOLLs) are shallow barrier lakes which are intermittently connected to the sea and experience saline intrusions. Many ICOLLs are mechanically opened to prevent flooding of surrounding agricultural and urban land and to flush water of poor quality. In this study, the effects of modified opening regimes (frequency and duration of barrier openings and closures) on water quality and phytoplankton in two New Zealand ICOLLs were investigated over a number of opening/closure cycles. Water quality in Lake Ellesmere (Te Waihora) responded weakly to both opening and closing events, indicating that sea–ICOLL exchange did not markedly improve water quality. Conversely, water quality in Waituna Lagoon responded rapidly to barrier openings; water level decreased to near sea level within days of opening and subsequent seawater exchange resulted in rapid decreases in nitrate and chlorophyll a concentrations. The closure of Waituna Lagoon resulted in rapid rise in water level and a pulse of nitrate and phosphorus in the water column and phytoplankton chlorophyll a concentrations increased with increasing closed-period duration. Based on data on the underwater light climate and nutrient dynamics, phytoplankton in Lake Ellesmere was probably light-limited, whereas phytoplankton in Waituna Lagoon was rarely light-limited, and appeared to be predominately P-limited. The marked differences in responses of Lake Ellesmere and Waituna Lagoon to barrier openings and closures reflected differences in ICOLL water levels and morphological characteristics, which dictated the degree of tidal flushing when the barriers were open. The inter-ICOLL differences observed in this study indicate that unless the effects of ICOLL openings/closures on phytoplankton and nutrient dynamics are understood, changes to ICOLL opening regimes may have unintended consequences for the water quality and ecology of these systems. [Copyright &y& Elsevier]

Low-frequency synthetic aperture radar (SAR) systems are of interest primarily because of their ability to see through foliage for a variety of purposes. Unfortunately, the very high frequency/ultra-high frequency bands are used by a large number of services such as television, radio and communications. The authors describe a number of different radio frequency interference suppression techniques that have been investigated and that were tested on wide bandwidth low-frequency SAR data collected on board a helicopter using the Airborne Data Acquisition System (ADAS) low-frequency radar. The least-mean-square (LMS) filter and the Wiener filter are both investigated in detail. The adaptive Wiener filter is found to have superior suppression and sidelobe performance and is also computationally much faster than the LMS filter when applied to the ADAS data. [ABSTRACT FROM AUTHOR]

Emission fluxes for a range of C[sub 8]-C[sub 15] volatile organic compounds (VOCs) were determined from the seaweed Fucus spiralis (spiral wrack) and an adjacent sand surface during low tide on the coastline of Mace Head, Ireland. These two surface types, assessed using dynamic flux chamber systems, are typical of the Mace Head inter-tidal zone. A range of nalkanes and oxygenates were routinely identified in the measurement of chamber air. Examination of the odd/even nalkane ratios and use of the carbon preference index (CPI) suggested a biogenic source for these compounds (CPIs > 2 in for all samples). Fluxes of n-pentadecane, the most predominant n-alkane, ranged from 0.2 to 5.1 µg m[sup -2] h[sup -1] (0.924 nmol m[sup -]2 h[sup -1]), while oxygenates such as nonanal and decanal had fluxes ranging from <0.1 to 4.4 µg m[sup -2] h[sup -1] (<0.1-31 nmol m[sup -2h[sup -1]) and <0.1 to 4.6 µg m[sup -2]h[sup -1] (<0.1 30 nmol m[sup -2]h[sup -1]), respectively. Seaweed emission rates for n-pentadecane were correlated with photosynthetically active radiation (PAR) (r[sub s] = 0.94) while emissions from sand showed correlation with temperature (r[sub s] = 0.85). This suggests a possible biochemical route controlling the release of npentadecane from spiral wrack, and temperature-driven volatilisation from sand. Volatilisation from residual seawater trapped in the sand may explain the comparable flux of both n-alkanes and oxygenates from this surface. Unlike the nalkanes, oxygenate fluxes from sand correlate with PAR, suggesting a photo-dependent production from organic carbon residues present in seawater. Comparison with previous flux estimates from coastal seawater indicates that the two source types (Fucus spiralis and bare sand) are significant but not dominant sources of these VOCs. [ABSTRACT FROM AUTHOR]

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]

The Kaposi's sarcoma associated herpesvirus (KSHV) encoded LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. In a previous study, we have identified LANA interacting proteins using a protein array screen. Here, we explore the effect of LANA on the stability and activity of RLIM (RING-finger LIM-domain-interacting protein, encoded by the RNF12 gene) a novel LANA interacting protein identified in that protein screen. RLIM is an E3 ubiquitin ligase that leads to the ubiquitination and degradation of several transcription regulators, such as LMO2, LMO4, LHX2, LHX3, LDB1 and the telomeric protein TRF1. Expression of LANA leads to down-regulation of RLIM protein levels. This LANA-mediated RLIM degradation is blocked in the presence of the proteasome inhibitor, MG132. Therefore, the interaction between LANA and RLIM could be detected in co-immunoprecipitation assay only in the presence of MG132 to prevent RLIM degradation. A RING finger mutant RLIM (HH 590, 593 EE) is resistant to LANA mediated degradation, suggesting that LANA promotes RLIM auto-ubiquitination. Interestingly, we found that LANA enhanced the degradation of some RLIM substrates, such as LDB1 and LMO2, and prevented RLIM mediated degradation of others such as LHX3 and TRF1. We also show that transcription regulation by RLIM substrates is modulated by LANA. RLIM substrates are assembled into multi-protein transcription regulator complexes that regulate the expression of many cellular genes. Therefore, our study identified another way KSHV can modulate cellular gene expression. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib. IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is etiologically linked to infectious mononucleosis and several human cancers. EBV encodes a conserved protein kinase BGLF4 that plays a key role in the viral life cycle. To provide new insight into the host proteins regulated by BGLF4, we utilized stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare site-specific phosphorylation in BGLF4-expressing Akata B cells. Our analysis revealed BGLF4-mediated hyperphosphorylation of 3,046 unique sites corresponding to 1,328 proteins. Frequency analysis of these phosphosites revealed a proline-rich motif signature downstream of BGLF4, indicating a broader substrate recognition for BGLF4 than its cellular ortholog cyclin-dependent kinase 1 (CDK1). Further, motif analysis of the hyperphosphorylated sites revealed enrichment in ATM, ATR and Aurora kinase substrates while functional analyses revealed significant enrichment of pathways related to the DNA damage response (DDR), mitosis and cell cycle. Phosphorylation of proteins associated with the mitotic spindle assembly checkpoint (SAC) indicated checkpoint activation, an event that inactivates the anaphase promoting complex/cyclosome, APC/C. Furthermore, we demonstrated that BGLF4 binds to and directly phosphorylates the key cellular proteins PP1, MPS1 and CDC20 that lie upstream of SAC activation and APC/C inhibition. Consistent with APC/C inactivation, we found that BGLF4 stabilizes the expression of many known APC/C substrates. We also noted hyperphosphorylation of 22 proteins associated the nuclear pore complex, which may contribute to nuclear pore disassembly and SAC activation. A drug that inhibits mitotic checkpoint activation also suppressed the accumulation of extracellular EBV virus. Taken together, our data reveal that, in addition to the DDR, manipulation of mitotic kinase signaling and SAC activation are mechanisms associated with lytic EBV replication. All MS data have been deposited in the ProteomeXchange with identifier PXD002411 (). [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]

Background: The ECDC has called for innovative strategies to deliver multidisease screening (TB, LTBI, HIV, hepatitis B/C, Chagas, Strongyloidiasis and schistosomiasis) and catch-up vaccination (MMR, DTP) to adult migrants within the primary care context. We did a UK i qualitative study to explore current practice and seek views on a novel integrated digital tool to support delivery of screening recommendations for migrants https://emishealth.vids.io/videos/a49ad1bb1a18e4c72c/healthcatch- up-with-requested-edits-mp4). Methods: Phase 1 was conducted via telephone with clinical primary care practitioners (PCPs) (phase 1) and informed data collection and analysis for phase 2 with administrative staff. Data were analysed iteratively, informed by thematic analysis (Ethics no.20/HRA/1674). Results: 64 participants were recruited in Phase 1 (25 general practitioners [GPs], 15 nurses, 7 healthcare assistants, 1 pharmacist); Phase 2 comprised administrative staff (11 Practice-Managers, 5 receptionists). There was lack of consistency in delivery of screening and vaccination. Most GP practices adopted a practice-specific approach, or had no system in place; screening only for HIV and hepatitis B/C. Barriers to screening were perceived lack of knowledge/training and limited financial resources. Facilitators included having an infectious disease/migrant-health champion, incentivisation, and clear protocols. Participants responded positively to the integrated Health Catch-UP! tool, confirming that it would increase screening and vaccination, reduce missed opportunities for preventative healthcare, and raise awareness of migrant health. Conclusions: Infectious disease screening and catch-up vaccination is not currently delivered well in primary care in high-migrant receiving European countries. Innovative digital tools like Health Catch-UP! could aid clinical decision-making and facilitating improved health outcomes for migrants. Further work is needed to evaluate this intervention [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]

Protein phosphorylation is a dynamic and reversible event that greatly influences cellular function. Identifying the key regulatory elements that determine cellular phenotypes during development and oncogenesis requires the ability to dynamically monitor proteome-wide events. Here, we report the development of a new strategy to monitor dynamic changes of protein phosphorylation in cells and tissues using functional protein microarrays as the readout. To demonstrate this technology's ability to identify condition-dependent phosphorylation events, human protein microarrays were incubated with lysates from cells or tissues under activation or inhibition of c-Met, a receptor tyrosine kinase involved in tissue morphogenesis and malignancy. By comparing the differences between the protein phosphorylation profiles obtained using the protein microarrays, we were able to recover many of the proteins that are known to be specifically activated (i.e., phosphorylated) upon c-Met activation by the hepatocyte growth factor (HGF). Most importantly, we discovered many proteins that were differentially phosphorylated by lysates from cells or tissues when the c-Met pathway was active. Using phosphorylation-specific antibodies, we were able to validate several candidate proteins as new downstream components of the c-Met signaling pathway in cells. We envision that this new approach, like its DNA microarray counterpart, can be further extended toward profiling dynamics of global protein phosphorylation under many different physiological conditions both in cellulo and in vivo in a high-throughput and cost-effective fashion. [ABSTRACT FROM AUTHOR]

The Kaposi sarcoma associated herpesvirus (KSHV) latency associated nuclear antigen (LANA) is expressed in all KSHV associated malignancies and is essential for maintenance of KSHV genomes in infected cells. To identify kinases that are potentially capable of modifying LANA, in vitro phosphorylation assays were performed using an Epstein Barr virus plus LANA protein microarray and 268 human kinases purified in active form from yeast. Interestingly, of the Epstein-Barr virus proteins on the array, the EBNA1 protein had the most similar kinase profile to LANA. We focused on nuclear kinases and on the N-terminus of LANA (amino acids 1-329) that contains the LANA chromatin binding domain. Sixty-three nuclear kinases phosphorylated the LANA N-terminus. Twenty-four nuclear kinases phosphorylated a peptide covering the LANA chromatin binding domain (amino acids 3-21). Alanine mutations of serine 10 and threonine 14 abolish or severely diminish chromatin and histone binding by LANA. However, conversion of these residues to the phosphomimetic glutamic acid restored histone binding suggesting that phosphorylation of serine 10 and threonine 14 may modulate LANA function. Serine 10 and threonine 14 were validated as substrates of casein kinase 1, PIM1, GSK-3 and RSK3 kinases. Short-term treatment of transfected cells with inhibitors of these kinases found that only RSK inhibition reduced LANA interaction with endogenous histone H2B. Extended treatment of PEL cell cultures with RSK inhibitor caused a decrease in LANA protein levels associated with p21 induction and a loss of PEL cell viability. The data indicate that RSK phosphorylation affects both LANA accumulation and function. [ABSTRACT FROM AUTHOR]

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]

Background. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, and Kaposi's sarcoma-associated herpesvirus (KSHV) has a restricted seroprevalence. Both viruses are associated with malignancies that have an increased frequency in individuals who are coinfected with human immunodeficiency virus type 1 (HIV-1). Methods. To obtain an overview of humoral immune responses to these viruses, we generated a protein array that displayed 174 EBV and KSHV polypeptides purified from yeast. Antibody responses to EBV and KSHV were examined in plasma from healthy volunteers and patients with B cell lymphoma or with AIDS-related Kaposi's sarcoma or lymphoma. Results. In addition to the commonly studied antigens, IgG responses were frequently detected to the tegument proteins KSHV ORF38 and EBV BBRF and BGLF2 and BNRF1 and to the EBV early lytic proteins BRRF1 and BORF2. The EBV vIL-10 protein was particularly well recognized by plasma IgA. The most intense IgG responses to EBV antigens occurred in HIV-1-positive patients. No clear correlation was observed between viral DNA load in plasma and antibody profile. Conclusions. The protein array provided a sensitive platform for global screening; identified new, frequently recognized viral antigens; and revealed a broader humoral response to EBV compared with KSHV in the same patients. [ABSTRACT FROM AUTHOR]

Chicken eggs categorised as conventional, omega-3 enriched, free range and organic were collected at grading stations in three regions of Canada between 2005 and 2006. Free run eggs, which were only available for collection from two regions, were also sampled during this time frame. Egg yolks from each of these egg types (n = 162) were analysed to determine brominated flame retardant levels, specifically polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD). PBDEs were detected in 100% of the 162 samples tested, while HBCD was observed in 85% of the egg yolks. Total PBDE concentrations in egg yolks ranged from 0.018 to 20.9 ng g−1 lipid (median = 3.03 ng g−1 lipid), with PBDE 209 identified as being the major contributor to ΣPBDE concentrations. In addition to PBDE 209, PBDE 99, 47, 100, 183 and 153 were important contributors to ΣPBDE concentrations. Total HBCD concentrations ranged from below the limit of detection to a maximum concentration of 71.9 ng g−1 lipid (median = 0.053 ng g−1 lipid). The α-isomer was the dominant contributor to ΣHBCD levels in Canadian egg yolks and was the most frequently detected HBCD isomer. ΣPBDE levels exhibited large differences in variability between combinations of region and type. ΣHBCD concentrations were not significantly different among regions, although differences were observed between the different types of egg yolks analysed in the present study. [ABSTRACT FROM AUTHOR]

DNA methylation and histone modifications play an important role in transcription regulation. In cancer cells, many promoters become aberrantly methylated through the activity of the de novo DNA methyltransferases DNMT3a and DNMT3b and acquire repressive chromatin marks. NEDD8 is a ubiquitin-like protein modifier that is conjugated to target proteins, such as cullins, to regulate their activity, and cullin 4A (CUL4A) in its NEDD8-modified form is essential for repressive chromatin formation. We found that DNMT3b associates with NEDD8-modified proteins. Whereas DNMT3b interacts directly in vitro with NEDD8, conjugation of NEDD8 to target proteins enhances this interaction in vivo. DNMT3b immunoprecipitated two major bands of endogenously NEDDylated proteins at the size of NEDDylated cullins, and indeed DNMT3b interacted with CUL1, CUL2, CUL3, CUL4A, and CUL5. Moreover, DNMT3b preferentially immunoprecipitated the NEDDylated form of endogenous CUL4A. NEDD8 enhanced DNMT3b-dependent DNA methylation. Chromatin immunoprecipitation assays suggest that DNMT3b recruits CUL4A and NEDD8 to chromatin, whereas deletion of Dnmt3b reduces the association of CUL4A and NEDD8 at a repressed promoter in a cancer cell line. [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]

In order to manage risk of ochratoxin A (OTA) in foods, we re-evaluated the tolerable daily intake (TDI), derived the negligible cancer risk intake (NCRI), and conducted a probabilistic risk assessment. A new approach was developed to derive 'usual' probabilistic exposure in the presence of highly variable occurrence data, such as encountered with low levels of OTA. Canadian occurrence data were used for various raw food commodities or finished foods and were combined with US Department of Agriculture (USDA) food consumption data, which included data on infants and young children. Both variability and uncertainty in input data were considered in the resulting exposure estimates for various age/sex strata. Most people were exposed to OTA on a daily basis. Mean adjusted exposures for all age–sex groups were generally below the NCRI of 4 ng OTA kg bw−1, except for 1–4-year-olds as a result of their lower body weight. For children, the major contributors of OTA were wheat-based foods followed by oats, rice, and raisins. Beer, coffee, and wine also contributed to total OTA exposure in older individuals. Predicted exposure to OTA decreased when European Commission maximum limits were applied to the occurrence data. The impact on risk for regular eaters of specific commodities was also examined. [ABSTRACT FROM AUTHOR]