Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: implications for TRAIL-based therapy in humans?

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, as it can induce apoptosis specifically in tumor cells but not in normal cells. Although earlier mouse tumor studies revealed a strong tissue dependency of TRAIL and its death receptor in suppressing primary tumorigenesis or experimental metastases, we recently found that TRAIL-R inhibits lymph node metastases without affecting primary tumor formation in a mouse model of multistage skin tumorigenesis. This finding uncouples the role of TRAIL in primary tumorigenesis from metastasis formation, likely by sensitization of previously TRAIL-resistant tumor cells upon detachment, an early step required for metastasis formation. Therefore, TRAIL-R is a novel metastasis suppressor, suggesting that TRAIL-related tumor therapy might be most effective in primary tumors and early metastatic cancers, before selection for TRAIL resistance occurs

Lithostratigraphy, sedimentation and evolution of the Volta Basin in Ghana

We present a revised lithostratigraphy for the Voltaian Supergroup of Ghana, based on a review of existing literature, interpretations of remotely sensed data and reconnaissance field survey of the Volta Basin. These strata thicken eastwards, to a maximum of between 5 and 6 km adjacent to the Pan-African Dahomeyide orogen. They began to accumulate some time after about 1000 Ma, along the margin of an epicontinental sea. Initial sedimentation, comprising the age-equivalent Kwahu and Bombouaka Groups, shows a cyclical mode of deposition controlled by eustatic changes in sea-level that produced a range of nearshore marine, littoral and terrestrial environments. A major erosional interval was followed by deposition of the 3–4 km thick Oti-Pendjari Group. Basal tillites and associated sandy diamictons are correlated with the Marinoan (end-Cryogenian) glaciation, indicating a maximum depositional age of about 635 Ma. The overlying cap carbonates and tuffs were deposited within a shallow epeiric sea bordered by a volcanically active rift system. The main part of the group records the transition from a rifted passive margin to a fully developed foreland basin receiving marine flysch in the form of argillaceous strata interbedded with highly immature wacke-type sandstones and conglomerates. Maximum accommodation space was developed within a foredeep adjacent to the Dahomeyide belt. Towards the end of the orogenic phase, the foredeep succession became partially inverted and then was buried under coarse terrestrial, red-bed molasse of the Obosum Group

A Labor Lawyer\u27s Guide to the Americans with Disabilities Act of 1990*

On July 26, 1990, in a joyous ceremony on the south lawn of the White House, President George Bush signed the Americans with Disabilities Act of 1990 lx into la

Thermally modulated biliary excretion of taurocholate in rainbow trout

Biliary excretion of taurocholate in thermally acclimated rainbow trout was stimulated at higher environmental temperature (18 vs. 14 or 10° C)e Acute 4° C shifts in body temperature produced more pronounced changes in biliary excretion. Thermally modulated biliary excretion was negatively correlated with plasma half live of taurocholate. Absorption of intraperitoneally injected taurocholate into plasma or tissue distribution were both independent of temperature. Hepatic blood flow as measured by laser doppler velocimetry was also stimulated at 18° C. The correlation coefficient between hepatic blood flow and biliary excretion rate was 0.73 for 7 different thermal treatments, The activities of liver plasma membrane ATPases as analysed by Michaelis-Menton kinetics and temperature responses did not appear to be affected by acclimation to 10 or 18° C. Thermal modulation of hepatic blood flow provides a sound explanation for the observed temperature dependence of the plasma half life and biliary excretion rate of taurocholate in rainbow trout

Childhood- versus Adolescent-Onset Antisocial Youth with Conduct Disorder: Psychiatric Illness, Neuropsychological and Psychosocial Function

The present study investigates whether youths with childhood-onset antisocial behavior have higher rates of psychiatric illness, neuropsychological and psychosocial dysfunction than youths who engage in antisocial behavior for the first time in adolescence. Prior studies have generally focused on single domains of function in heterogeneous samples. The present study also examined the extent to which adolescent-onset antisocial behavior can be considered normative, an assumption of Moffitt's dual taxonomy model.Forty-three subjects (34 males, 9 females, mean age = 15.31, age range 12-21) with a diagnosis of conduct disorder (CD) were recruited through Headspace Services and the Juvenile Justice Community Centre. We compared childhood-onset antisocial youths (n = 23) with adolescent-onset antisocial youths (n = 20) with a conduct disorder, across a battery of psychiatric, neuropsychological and psychosocial measures. Neuropsychological function of both groups was also compared with normative scores from control samples.The childhood-onset group displayed deficits in verbal learning and memory, higher rates of psychosis, childhood maltreatment and more serious violent behavior, all effects associated with a large effect size. Both groups had impaired executive function, falling within the extremely low range (severely impaired).Childhood-onset CD displayed greater cognitive impairment, more psychiatric symptoms and committed more serious violent offences. The finding of severe executive impairment in both childhood- and adolescent-onset groupings challenges the assumption that adolescent-onset antisocial behavior is a normative process

Risk and Performance Analyses Supporting Closure of WMA C at the Hanford Site in Southeast Washington

The Office of River Protection under the U.S. Department of Energy (DOE) is pursuing closure of the Single-Shell Tank (SST) Waste Management Area 0NMA) C as stipulated by the Hanford Federal Facility Agreement and Consent Order (HFFACO) under federalrequirements and work tasks will be done under the State-approved closure plans and permits. An initial step in meeting the regulatory requirements is to develop a baseline risk assessment representing current conditions based on available characterization data and information collected at the WMA C location. The baseline risk assessment will be supporting a Resource Conservation and Recovery Act of 1976 (RCRA) Field Investigation (RFI)/Corrective Measures Study (CMS) for WMA closure and RCRA corrective action. Complying with the HFFACO conditions also involves developing a long-term closure Performance Assessment (PA) that evaluates human health and environmental impacts resulting from radionuclide inventories in residual wastes remaining in WMA C tanks and ancillary equipment. This PAis being developed to meet the requirements necessary for closure authorization under DOE Order 435.1 and Washington State Hazardous Waste Management Act. To meet the HFFACO conditions, the long-term closure risk analysis will include an evaluation of human health and environmental impacts from hazardous chemical inventories along with other performance Comprehensive Environmental Response, Compensation, and Liability Act Appropriate and Applicable Requirements (CERCLA ARARs) in residualwastes left in WMA C facilities after retrieval and removal. This closure risk analysis is needed to needed to comply with the requirements for permitted closure. Progress to date in developing a baseline risk assessment of WMA C has involved aspects of an evaluation of soil characterization and groundwater monitoring data collected as a part of the RFI/CMS and RCRA monitoring. Developing the long-term performance assessment aspects has involved the construction of detailed numericalmodels of WMA C using the Subsurface Transport Over Multiple Phases (STOMP(C)) computer code, the development of a technical approach for abstraction of a range of representative STOMP(C) simulations into a system-level modelbased on the GoldSim0 system-levelmodelsoftware. The STOMP(C)-based models will be used to evaluate local-scale impacts and closed facility performance over a sufficient range of simulations to allow for development of the system-level model of the WMA C. The GoldSim0-based system-level model will be used to evaluate overall sensitivity of modeled parameters and the estimate the uncertainty in potentialfuture impacts from a closed WMA C facility

A case series of Acceptance and Commitment Therapy (ACT) for reducing symptom interference in functional neurological disorders

There is limited high-quality evidence supporting psychological treatments for functional neurological disorders (FNDs), and what evidence exists suggests that the impact of such treatments could be improved. One way to increase effectiveness is to utilize approaches that can have impact across heterogeneous FND presentations. Acceptance and Commitment Therapy (ACT) targets a transdiagnostic process called psychological flexibility and is used effectively to integrate multidisciplinary treatments in other clinical contexts. Here, we present a consecutive case series (N = 8) of a relatively brief (6 to 10 sessions) ACT intervention, delivered face to face by a clinical psychologist in an outpatient neuropsychology service. Treatment aimed to reduce symptom interference and improve mood via improvements in psychological flexibility. Service users presented with a range of FND symptoms (e.g., syncope, limb paralysis, and paraesthesia). Following treatment, 5 participants showed reliable improvements in symptom interference (Work and Social Adjustment Scale), 2 to the extent of clinical significance; 4 had reliable improvements in mood (Clinical Outcomes in Routine Evaluation—10), and 2 within the range of clinical significance. There were no reliable deteriorations in symptom interference or mood. Marked variation was apparent on the measure of psychological flexibility (Acceptance and Action Questionnaire II), with 4 reliable improvements, 3 within the range of clinical significance, and also 2 reliable deteriorations. These promising results suggest that further investigation of an ACT approach to FND is warranted. Future studies should include measures of psychological flexibility with greater comprehensibility

Tumor suppression by p53 in the absence of Atm.

Oncogenes can induce p53 through a signaling pathway involving p19/Arf. It was recently proposed that oncogenes can also induce DNA damage, and this can induce p53 through the Atm DNA damage pathway. To assess the relative roles of Atm, Arf, and p53 in the suppression of Ras-driven tumors, we examined susceptibility to skin carcinogenesis in 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Atm- and p53-deficient mice and compared these results to previous studies on Arf-deficient mice. Mice with epidermal-specific deletion of p53 showed increased papilloma number and progression to malignant invasive carcinomas compared with wild-type littermates. In contrast, Atm-deficient mice showed no increase in papilloma number, growth, or malignant progression. gamma-H2AX and p53 levels were increased in both Atm(+/+) and Atm(-/-) papillomas, whereas Arf(-/-) papillomas showed much lower p53 expression. Thus, although there is evidence of DNA damage, signaling through Arf seems to regulate p53 in these Ras-driven tumors. In spontaneous and radiation-induced lymphoma models, tumor latency was accelerated in Atm(-/-)p53(-/-) compound mutant mice compared with the single mutant Atm(-/-) or p53(-/-) mice, indicating cooperation between loss of Atm and loss of p53. Although p53-mediated apoptosis was impaired in irradiated Atm(-/-) lymphocytes, p53 loss was still selected for during lymphomagenesis in Atm(-/-) mice. In conclusion, in these models of oncogene- or DNA damage-induced tumors, p53 retains tumor suppressor activity in the absence of Atm

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD