STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Global justice and the opportunity costs of conservation.

Opportunity costs can represent a significant portion of the costs associated with conservation projects and frequently outstrip other kinds of cost. They are typically understood to refer to the benefits someone would have obtained if conservation projects had not required them to give up current activities, such as farming or hunting or if the land had been available for uses other than conservation. This familiar way of identifying opportunity costs is flawed, however, because it threatens to condone, or take advantage of, the injustices that many people face that affect their opportunities. I integrated ideas from the political theory of global justice to examine how the analysis of opportunity costs illustrates the importance of considering conservation and issues of global justice together, rather than thinking about them in isolation. I distinguish four baselines for defining opportunity costs. A status quo baseline defines opportunity costs by asking what people would have earned had a conservation project not happened. A willingness to accept baseline defines them by asking people what it would take to make them indifferent to whether a conservation project takes place or not. An antipoverty baseline suggests that opportunity costs have been met when people affected by a project are not left in poverty. An egalitarian baseline suggests opportunity costs have been met when people are not left in relative disadvantage, with worse than average opportunities. I argue that the egalitarian baseline is the most acceptable from the point of view of justice. Such a baseline would suggest that, in practice, many of the world's poor are being unjustly treated, or even exploited, as a result of conservation activities.

Los costos de oportunidad pueden representar una porción significativa de los costos asociados con los proyectos de conservación y con frecuencia superan otros tipos de costos. Comúnmente se entiende que estos costos se refieren a los beneficios que alguien habría obtenido si los proyectos de conservación no los hubieran requerido para renunciar a ciertas actividades, como la agricultura o la cacería, o si la tierra hubiera estado disponible para otros usos además de la conservación. Sin embargo, esta manera familiar de identificar los costos de oportunidad es defectuosa ya que amenaza con perdonar, o aprovechar, las injusticias que muchas personas enfrentan y que afectan sus oportunidades. Integré ideas de la teoría política de la justicia global para examinar cómo el análisis de los costos de oportunidad ilustra la importancia de considerar en conjunto la conservación y los temas de justicia global, en lugar de considerarlos de manera aislada. Distingo cuatro líneas base para definir los costos de oportunidad. Una línea base de orden establecido define los costos de oportunidad al preguntar a las personas lo que habrían obtenido de no haberse realizado un proyecto de conservación. Una línea base de la voluntad de aceptación las define al preguntar a las personas qué necesitarían para volverse indiferentes a si se realiza o no un proyecto de conservación. Una línea base de antipobreza sugiere que los costos de oportunidad se han cumplido cuando las personas afectadas por un proyecto no quedan en la pobreza. Una línea base igualitaria sugiere que los costos de oportunidad se han cumplido cuando las personas no quedan en una desventaja relativa, con peores oportunidades al promedio. Argumento que la línea base igualitaria es la más aceptable desde el punto de vista de la justicia. Dicha línea base sugeriría que, en la práctica, muchas de las personas que viven en pobreza son tratadas injustamente, o incluso explotadas, como resultado de las actividades de conservación.

Multimillijoule coherent terahertz bursts from picosecond laser-irradiated metal foils.

Ultrahigh-power terahertz (THz) radiation sources are essential for many applications, for example, THz-wave-based compact accelerators and THz control over matter. However, to date none of the THz sources reported, whether based upon large-scale accelerators or high-power lasers, have produced THz pulses with energies above the millijoule (mJ) level. Here, we report a substantial increase in THz pulse energy, as high as tens of mJ, generated by a high-intensity, picosecond laser pulse irradiating a metal foil. A further up-scaling of THz energy by a factor of ∼4 is observed when introducing preplasmas at the target-rear side. Experimental measurements and theoretical models identify the dominant THz generation mechanism to be coherent transition radiation, induced by the laser-accelerated energetic electron bunch escaping the target. Observation of THz-field-induced carrier multiplication in high-resistivity silicon is presented as a proof-of-concept application demonstration. Such an extremely high THz energy not only triggers various nonlinear dynamics in matter, but also opens up the research era of relativistic THz optics.

Sharing conservation burdens fairly.

We examined how, from the point of view of justice, the burdens of paying for conservation should be shared. I resisted simple answers to the question of who should pay for conservation that lean on a single moral principle. I identified 3 relevant principles that relate to who causes conservation challenges, who has greater capacity to carry burdens, and who stands to benefit from conservation. I argue for a distinctive pluralist framework for allocating conservation burdens that grants a proper role to all 3 principles. A multistep process can be used to put the framework into practice. First, identify cases in which conservation is necessary. Second, consider whether people knew or could have been expected to anticipate the consequences of their activities and whether they had reasonable alternatives to acting the way they did. Third, turn to facts about benefits; when no culprit for conservation challenges can be found, ask who benefits from acts of conservation. In the second and third stages, consideration must also be given to ability to pay.

Reparto Equitativo de las Responsabilidades de Conservación Resumen Examinamos cómo, desde el punto de vista de la justicia, se deberían repartir las responsabilidades del pago por conservación. Me resistí a las respuestas para la pregunta de quién debería pagar por la conservación que fueron simples y que se inclinaban por un solo principio moral. Identifiqué tres principios relevantes que se relacionan con quién genera obstáculos para la conservación, quién tiene una mayor capacidad para cargar con las responsabilidades, y quién se beneficiará con la conservación. Abogo por un marco de trabajo distintivo y pluralista para la asignación de responsabilidades de la conservación que otorgue un papel adecuado para los tres principios. Un proceso con múltiples pasos puede usarse para poner en práctica el marco de trabajo. Primero, se deben identificar los casos en los cuales la conservación es necesaria. Segundo, se debe considerar si las personas conocían o podrían haber esperado las consecuencias de sus acciones y si tenían alternativas razonables a las acciones que realizaron. Tercero, ver hacia los hechos sobre los beneficios; cuando no se puede hallar a un culpable de los retos para la conservación, se debe preguntar quién se beneficia con los actos de conservación. En los pasos dos y tres también se debe considerar la habilidad para pagar.

Individual strategies and release site features determine the extent of deviation in clock-shifted pigeons at familiar sites.

When homing from familiar areas, homing pigeons are able to exploit previously acquired topographical information, but the mechanisms behind this ability are still poorly understood. One possibility is that they recall the familiar release site topographical features in association with the home direction (site-specific compass orientation strategy), another that the spatial relationships among landmarks guide their route home (piloting strategy), without relying on the compass mechanism. The two strategies can be put in conflict by releasing clock-shifted birds at familiar locations, in order to highlight which is preferred. We analysed GPS tracks of clock-shifted pigeons, with familiarity controlled at each of three different release sites, and we observed that pigeons can display individual preferences for one of the two orientation strategies and that some characteristic features of the release site have an important role in determining the level of landmark-based homeward orientation.

Landscape complexity influences route-memory formation in navigating pigeons.

Observations of the flight paths of pigeons navigating from familiar locations have shown that these birds are able to learn and subsequently follow habitual routes home. It has been suggested that navigation along these routes is based on the recognition of memorized visual landmarks. Previous research has identified the effect of landmarks on flight path structure, and thus the locations of potentially salient sites. Pigeons have also been observed to be particularly attracted to strong linear features in the landscape, such as roads and rivers. However, a more general understanding of the specific characteristics of the landscape that facilitate route learning has remained out of reach. In this study, we identify landscape complexity as a key predictor of the fidelity to the habitual route, and thus conclude that pigeons form route memories most strongly in regions where the landscape complexity is neither too great nor too low. Our results imply that pigeons process their visual environment on a characteristic spatial scale while navigating and can explain the different degrees of success in reproducing route learning in different geographical locations.

Nucleosome reorganisation in breast cancer tissues.

BACKGROUND: Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. RESULTS: We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. CONCLUSIONS: Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring.

Bioinformatics tools developed to support BioCompute Objects.

Developments in high-throughput sequencing (HTS) result in an exponential increase in the amount of data generated by sequencing experiments, an increase in the complexity of bioinformatics analysis reporting and an increase in the types of data generated. These increases in volume, diversity and complexity of the data generated and their analysis expose the necessity of a structured and standardized reporting template. BioCompute Objects (BCOs) provide the requisite support for communication of HTS data analysis that includes support for workflow, as well as data, curation, accessibility and reproducibility of communication. BCOs standardize how researchers report provenance and the established verification and validation protocols used in workflows while also being robust enough to convey content integration or curation in knowledge bases. BCOs that encapsulate tools, platforms, datasets and workflows are FAIR (findable, accessible, interoperable and reusable) compliant. Providing operational workflow and data information facilitates interoperability between platforms and incorporation of future dataset within an HTS analysis for use within industrial, academic and regulatory settings. Cloud-based platforms, including High-performance Integrated Virtual Environment (HIVE), Cancer Genomics Cloud (CGC) and Galaxy, support BCO generation for users. Given the 100K+ userbase between these platforms, BioCompute can be leveraged for workflow documentation. In this paper, we report the availability of platform-dependent and platform-independent BCO tools: HIVE BCO App, CGC BCO App, Galaxy BCO API Extension and BCO Portal. Community engagement was utilized to evaluate tool efficacy. We demonstrate that these tools further advance BCO creation from text editing approaches used in earlier releases of the standard. Moreover, we demonstrate that integrating BCO generation within existing analysis platforms greatly streamlines BCO creation while capturing granular workflow details. We also demonstrate that the BCO tools described in the paper provide an approach to solve the long-standing challenge of standardizing workflow descriptions that are both human and machine readable while accommodating manual and automated curation with evidence tagging. Database URL:  https://www.biocomputeobject.org/resources.

Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma.

Functional impairment of the tumour suppressor PTEN is common in primary prostate cancer and has been linked to relapse post-radiotherapy (post-RT). Pre-clinical modelling supports elevated CXC chemokine signalling as a critical mediator of PTEN-depleted disease progression and therapeutic resistance. We assessed the correlation of PTEN deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a PTEN LOW/CXCR1HIGH/CXCR2HIGH cluster of tumours that associates with earlier time to biochemical recurrence [hazard ratio (HR) 5.87 and 2.65, respectively] and development of systemic metastasis (HR 3.51). In vitro, CXCL signalling was further amplified following exposure of PTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in PTEN-depleted cell-based models increased IR sensitivity. In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to PTEN-deficient xenografts attenuated tumour growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL signalling and anti-apoptotic protein expression. Interventions targeting CXC chemokine signalling may provide an effective strategy to combine with RT in locally advanced prostate cancer patients with known presence of PTEN-deficient foci.

Protocols for Studies on Genetically Engineered Mouse Models in Prostate Cancer.

Cancer studies have entered an era that is heavily focused on the contribution of the tumor microenvironment. For this reason, in vivo experimentation in an immunodeficient model system is no longer fit for purpose. As a consequence, numerous genetically engineered mouse models (GEMMs) which self-develop tumors have been developed to allow experiments to be performed in a fully immunocompetent setting. One of the most commonly used technologies is Cre-loxP recombination due to its unique ability to control target gene expression in a specified tissue type. However, the major limitation of these models remains the inability to generate sufficient numbers of age-matched mice for a synchronized experimental start date. For this reason, the derivation of cell lines from genetically modified murine prostate tissue is desirable and allows for the generation of syngeneic models via subcutaneous or orthotopic injection.

Novel contaminants identified in fish kills in the Red River watershed, 2011-2013.

Provisional molecular weights and chemical formulas were assigned to 4 significant previously unidentified contaminants present during active fish kills in the Red River region of Oklahoma. The provisional identifications of these contaminants were determined using high-resolution liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS), LC-Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICRMS), and LC-ion trap mass spectrometry (LC-ITMS). Environmental water samples were extracted using a solid-phase extraction (SPE) method, and sediment samples were extracted using a modified sonication liquid extraction method. During screening of the samples, 2 major unknown chromatographic peaks were detected at m/z 624.3 and m/z 639.3. The peak at m/z 639.3 was firmly identified, through the use of an authentic standard, as a porphyrin, specifically chlorin-e6-trimethyl ester, with m/z 639.31735 (M + H)+ and molecular formula C37 H43 N4 O6 . The other major peak, at m/z 624.3 (M + H)+ , was identified as an amide-containing porphyrin. It was discovered that the amide compound was an artifact created during the SPE process by reaction of ammonium hydroxide at 1 of 3 potential reaction sites on chlorin-e6-trimethyl ester. Other unique nontargeted chemicals were also detected and the importance of their identification is discussed. Environ Toxicol Chem 2018;37:336-344. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists.

Expression of tumor necrosis factor-α (TNFα) in the serum of prostate cancer patients is associated with poorer outcome and progression to castrate-resistant (CRPC) disease. TNFα promotes the activity of NFκB, which regulates a number of anti-apoptotic and proinflammatory genes, including those encoding the inhibitor of apoptosis proteins (IAPs); however, in the presence of IAP antagonists, TNFα can induce cell death. In the presence of recombinant or macrophage-derived TNFα, we found that IAP antagonists triggered degradation of cIAP1 and induced formation of Complex-IIb, consisting of caspase-8, FADD and RIPK1 in CRPC models; however, no, or modest levels of apoptosis were induced. This resistance was found to be mediated by both the long (L) and short (S) splice forms of the caspase-8 inhibitor, FLIP, another NFκB-regulated protein frequently overexpressed in CRPC. By decreasing FLIP expression at the post-transcriptional level in PC3 and DU145 cells (but not VCaP), the Class-I histone deacetylase (HDAC) inhibitor Entinostat promoted IAP antagonist-induced cell death in these models in a manner dependent on RIPK1, FADD and Caspase-8. Of note, Entinostat primarily targeted the nuclear rather than cytoplasmic pool of FLIP(L). While the cytoplasmic pool of FLIP(L) was highly stable, the nuclear pool was more labile and regulated by the Class-I HDAC target Ku70, which we have previously shown regulates FLIP stability. The efficacy of IAP antagonist (TL32711) and Entinostat combination and their effects on cIAP1 and FLIP respectively were confirmed in vivo, highlighting the therapeutic potential for targeting IAPs and FLIP in proinflammatory CRPC.

Contemporary diagnosis and management of hypercholesterolemia in elderly acute myocardial infarction patients: a population-based study.

There are limited data regarding the diagnosis and treatment of hypercholesterolemia in elderly patients with acute myocardial infarction (AMI). The authors describe the in-hospital and discharge prescription patterns of lipid-lowering agents in patients hospitalized with an AMI, and identify factors associated with low rates of utilization of these therapies. The authors analyzed the Minnesota Heart Survey, a population-based surveillance project that retrospectively abstracted the medical records of patients hospitalized with AMI in 2001-2002 from 21 hospitals in the Minneapolis-St Paul metropolitan area. They identified 2773 patients 30 years and older with an AMI. The mean total cholesterol was 175+/-45 mg/dL, the mean low-density lipoprotein cholesterol was 104+/-38 mg/dL, and the mean high-density lipoprotein cholesterol was 44+/-14 mg/dL. Statins were prescribed at discharge to 74.6%, 63.2%, and 38.5% of patients younger than 65, 65-74, and 75 years and older, respectively (P<.0001). The utilization of statins was highly correlated with the administration of other standard AMI therapies-aspirin, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and reperfusion therapy-and was more prevalent among patients undergoing percutaneous coronary intervention than among those undergoing coronary artery bypass surgery. Elderly patients remain less likely to receive lipid-lowering therapy following an AMI. Greater attention is required to ensure that elderly AMI patients without contraindications are appropriately treated with lipid-lowering therapy.

Use of nonprescription medications for perceived cardiovascular health.

BACKGROUND: Nonprescription products (over-the-counter drugs; vitamins/minerals; and nonvitamin, nonmineral supplements) are promoted or advertised for cardiovascular health. The extent of nonprescription products used specifically for perceived cardiovascular health (NONRX-CVH) is unknown. This study aimed to (1) determine prevalence and types of nonprescription medications used for NONRX-CVH, (2) compare the demographics of NONRX-CVH users to persons using nonprescription medications in general, and (3) determine the prevalence of use of NONRX-CVH among those taking a prescription medication for a cardiovascular reason. METHODS: A cross-sectional survey comprised the probability sample of 3128 adults in the Minneapolis-St. Paul area in the 2000-2002 Minnesota Heart Survey. Trained interviewers collected medication information from participants using a structured medication inventory approach. RESULTS: Analysis in 2005 shows that 10% of participants (n=315) self-reported taking one or more nonprescription medications in the past 2 weeks for a perceived cardiovascular health purpose. Among these individuals, prevalence of use of vitamin/mineral supplements, nonvitamin/nonmineral supplements, and over-the-counter products for a cardiovascular purpose was 37.5%, 21.3%, and 54.6%, respectively. Popular NONRX-CVHs were aspirin (52.1%), vitamin E (24.4%), garlic (9.8%), and omega-3/fish oils/fatty acids (3.8%). NONRX-CVH users were older than general nonprescription users (p<0.001). Of 613 people using a prescription drug for cardiovascular reasons, 135 (22%) reported using one or more NONRX-CVH medications. CONCLUSIONS: Use of NONRX-CVHs, especially aspirin, vitamin E, and herbals, is common, and older patients may use aspirin or dietary supplements for this purpose. Physicians having patients with cardiovascular disease should ask about nonprescription medication usage, as some NONRX-CVHs may be inappropriate.

Population trends in leisure-time physical activity: Minnesota Heart Survey, 1980-2000.

PURPOSE: Twenty-year trends in lifestyle (leisure, household, and transportation related) physical activity and leisure-time physical activity (LTPA) were evaluated in the Minnesota Heart Survey (MHS), a population-based surveillance study to monitor trends in cardiovascular risk factor levels among residents of the Minneapolis-St. Paul metropolitan area. METHODS: The Minnesota LTPA questionnaire was administered to adult participants in one of five cross-sectional MHS surveys conducted in 1980 (N = 1626), 1985 (N = 2292), 1990 (N = 2552), 1995 (N = 2432), and 2000 (N = 3089). Occupational activity was queried in 1980, 1995, and 2000. Age-adjusted, gender-specific geometric means of lifestyle physical activity and LTPA and of light-, moderate-, and vigorous-intensity activities were calculated for each survey. The proportion of adults participating in regular physical activity for 30 and 60 min x d(-1) was reported. RESULTS: Male gender, younger age, higher educational status, and employment were characteristic of greater participation in physical activity. Daily energy expenditure from lifestyle physical activity and LTPA increased between 1980 and 2000 in both genders, and workplace activity decreased. Using direct questions, the prevalence of men and women participating in 30 or more minutes of physical activity at least five times per week ranged from 8 to 12%, with no time trend. Only 1% of participants participated 60 min daily. Overall, BMI was 1-2 kg x m(-2) lower among individuals who participated regularly in physical activity. CONCLUSIONS: Although energy expenditure was lower than national recommendations, greater physical activity was associated with lower body mass. Public health strategies are needed to facilitate participation in physical activity, especially for women, elderly, and less educated individuals.

PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy.

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.

Evaluating laser-driven Bremsstrahlung radiation sources for imaging and analysis of nuclear waste packages.

A small scale sample nuclear waste package, consisting of a 28mm diameter uranium penny encased in grout, was imaged by absorption contrast radiography using a single pulse exposure from an X-ray source driven by a high-power laser. The Vulcan laser was used to deliver a focused pulse of photons to a tantalum foil, in order to generate a bright burst of highly penetrating X-rays (with energy >500keV), with a source size of <0.5mm. BAS-TR and BAS-SR image plates were used for image capture, alongside a newly developed Thalium doped Caesium Iodide scintillator-based detector coupled to CCD chips. The uranium penny was clearly resolved to sub-mm accuracy over a 30cm(2) scan area from a single shot acquisition. In addition, neutron generation was demonstrated in situ with the X-ray beam, with a single shot, thus demonstrating the potential for multi-modal criticality testing of waste materials. This feasibility study successfully demonstrated non-destructive radiography of encapsulated, high density, nuclear material. With recent developments of high-power laser systems, to 10Hz operation, a laser-driven multi-modal beamline for waste monitoring applications is envisioned.

Phosphorylation of the regulatory subunit of smooth muscle protein phosphatase 1M at Thr850 induces its dissociation from myosin.

Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited.

In-situ and invasive carcinoma within a phyllodes tumor associated with lymph node metastases.

BACKGROUND: Phyllodes tumors (cystosarcoma phyllodes) are uncommon lesions in the female breast. Rarely, the occurrence of carcinoma within a phyllodes tumor has been reported in the literature, but has never been associated with lymph node metastases. CASE PRESENTATION: A 26-year-old woman presented with a firm, mobile, non-tender mass in the left breast and palpable lymph nodes in the left axilla. The excised lesion appeared well circumscribed and lobulated, with variable fleshy and firm areas. Microscopic examination showed a circumscribed fibroepithelial lesion with a well developed leaf-like architecture, in keeping with a benign phyllodes tumor. The epithelial component showed extensive high grade ductal carcinoma in-situ (DCIS) and invasive carcinoma of no special type, located entirely within the phyllodes tumor. Subsequent axillary lymph node dissection revealed metastatic carcinoma in four lymph nodes. CONCLUSIONS: Although rare, phyllodes tumors may harbor DCIS and invasive carcinoma, with potential for lymph node metastasis.