The dual specificity phosphatase 2 gene is hypermethylated in human cancer and regulated by epigenetic mechanisms

Background: Dual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway. Downregulation of the dual specificity phosphatase 2 (DUSP2) has been reported in cancer. Epigenetic silencing of tumor suppressor genes by abnormal promoter methylation is a frequent mechanism in oncogenesis. It has been shown that the epigenetic factor CTCF is involved in the regulation of tumor suppressor genes. Methods: We analyzed the promoter hypermethylation of DUSP2 in human cancer, including primary Merkel cell carcinoma by bisulfite restriction analysis and pyrosequencing. Moreover we analyzed the impact of a DNA methyltransferase inhibitor (5-Aza-dC) and CTCF on the epigenetic regulation of DUSP2 by qRT-PCR, promoter assay, chromatin immuno-precipitation and methylation analysis. Results: Here we report a significant tumor-specific hypermethylation of DUSP2 in primary Merkel cell carcinoma (p=0.05). An increase in methylation of DUSP2 was also found in 17 out of 24 (71 %) cancer cell lines, including skin and lung cancer. Treatment of cancer cells with 5-Aza-dC induced DUSP2 expression by its promoter demethylation, Additionally we observed that CTCF induces DUSP2 expression in cell lines that exhibit silencing of DUSP2. This reactivation was accompanied by increased CTCF binding and demethylation of the DUSP2 promoter. Conclusions: Our data show that aberrant epigenetic inactivation of DUSP2 occurs in carcinogenesis and that CTCF is involved in the epigenetic regulation of DUSP2 expression

RASSF1A Is Part of a Complex Similar to the Drosophila Hippo/Salvador/Lats Tumor-Suppressor Network

SummaryThe Ras Association Domain Family 1A (RASSF1A) gene is one of the most frequently silenced genes in human cancer. RASSF1A has been shown to interact with the proapoptotic kinase MST1. Recent work in Drosophila has led to the discovery of a new tumor-suppressor pathway involving the Drosophila MST1 and MST2 ortholog, Hippo, as well as the Lats/Warts serine/threonine kinase and a protein named Salvador (Sav). Little is known about this pathway in mammalian cells. We report that complexes consisting of RASSF1A, MST2, WW45 (the human ortholog of Sav), and LATS1 exist in human cells. MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins. Components of this complex are localized at centrosomes and spindle poles from interphase to telophase and at the midbody during cytokinesis. Both RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation. Mitosis is delayed in Rassf1a−/− mouse embryo fibroblasts and frequently results in cytokinesis failure, similar to what has been observed for LATS1-deficient cells. RASSF1A, MST2, or WW45 can rescue this defect. The complex of RASSF1A, MST2, WW45, and LATS1 consists of several tumor suppressors, is conserved in mammalian cells, and appears to be involved in controlling mitotic exit

Resuscitation Endpoints in Traumatic Shock: A Focused Review with Emphasis on Point-of-Care Approaches

Trauma resuscitation is a blend of art and science, with the traumatologist at the helm of a large, multidisciplinary team, making split-second decisions and overseeing various parallel processes. Despite tremendous progress over the past few decades, the “art” component continues to play a large part in the overall trauma resuscitation process, with the “science” part slowly but steadily increasing its footprint as a determinant of processes and decisions. Thus, it becomes critical for all clinicians to be able to recognize the evidence-based factors which can be most valuable in guiding trauma resuscitations. This chapter serves as an overview of the current clinical findings, resuscitative endpoints, imaging techniques, and physiologic indices that are most helpful in order to promptly recognize and treat traumatic shock as well as projecting forward to look at novel techniques and biomarkers. Though a single universal marker that accurately and consistently identifies traumatic shock has yet to be discovered, certain factors discussed, such as lactate and base deficit, have been proven to be much more reliable than others

Angle resolved photoelectron spectroscopy of two-color XUV-NIR ionization with polarization control

Electron emission caused by extreme ultraviolet (XUV) radiation in the presence of a strong near infrared (NIR) field leads to multiphoton interactions that depend on several parameters. Here, a comprehensive study of the influence of the angle between the polarization directions of the NIR and XUV fields on the two-color angle-resolved photoelectron spectra of He and Ne is presented. The resulting photoelectron angular distribution strongly depends on the orientation of the NIR polarization plane with respect to that of the XUV field. The prevailing influence of the intense NIR field over the angular emission characteristics for He(1s) and Ne(2p) ionization lines is shown. The underlying processes are modeled in the frame of the strong field approximation (SFA) which shows very consistent agreement with the experiment reaffirming the power of the SFA for multicolor-multiphoton ionization in this regime

The Dynamic Exponent of the Two-Dimensional Ising Model and Monte Carlo Computation of the Sub-Dominant Eigenvalue of the Stochastic Matrix

We introduce a novel variance-reducing Monte Carlo algorithm for accurate determination of autocorrelation times. We apply this method to two-dimensional Ising systems with sizes up to $15 \times 15$, using single-spin flip dynamics, random site selection and transition probabilities according to the heat-bath method. From a finite-size scaling analysis of these autocorrelation times, the dynamical critical exponent $z$ is determined as $z=2.1665$ (12)

Operative Hemostasis in Trauma and Acute Care Surgery: The Role of Biosurgical Agents

Trauma and acute care surgery (TACS) constitutes the foundation of emergency surgical services in the United States. Blunt and penetrating traumatic injuries are a leading cause of death worldwide. Non-trauma general surgical emergencies are also a major source of morbidity and mortality. Operative interventions performed within the scope of TACS often revolve around the core principles of contamination control, hemostasis, surgical repair, and subsequent functional restoration. Hemorrhage control is an integral part of emergent operative interventions, and while most instances of surgical bleeding require direct suture ligation or some other form of direct tissue intervention, some circumstances call for the use of adjunctive means of hemostasis. This is especially applicable to situations and settings where direct applications of surgical energy, suture ligation, or direct compression are not possible. Difficult-to-control bleeding can be highly lethal and operative control can be very challenging when confounded by the lethal triad of acidosis, coagulopathy and hypothermia. Topical biosurgical materials (BSM) are of great value in such scenarios, and their use across a variety of settings, from pre-hospital trauma application to emergency general surgery operations, represents an important adjunct to improve patient outcomes. Here we present the different BSMs, discuss their various uses, and provide insight on future applications and developments in this important area

Heuristic derivation of continuum kinetic equations from microscopic dynamics

We present an approximate and heuristic scheme for the derivation of continuum kinetic equations from microscopic dynamics for stochastic, interacting systems. The method consists of a mean-field type, decoupled approximation of the master equation followed by the `naive' continuum limit. The Ising model and driven diffusive systems are used as illustrations. The equations derived are in agreement with other approaches, and consequences of the microscopic dependences of coarse-grained parameters compare favorably with exact or high-temperature expansions. The method is valuable when more systematic and rigorous approaches fail, and when microscopic inputs in the continuum theory are desirable.Comment: 7 pages, RevTeX, two-column, 4 PS figures include

Implicit learning of affective responses in dementia patients: a face-emotion-association paradigm

The aim of the present study was to develop and evaluate an ecologically valid approach to assess implicit learning of affective responses in dementia patients. We designed a Face-Emotion-Association paradigm (FEA) that allows to quantify the influence of stimuli with positive and negative valence on affective responses. Two pictures of neutral male faces are rated on the dimensions of valence and arousal before and after aversive versus pleasant fictitious biographical information is paired with each of the pictures. At the second measurement time point, memory for pictures and biographical content is tested. The FEA was tested in 21 patients with dementia and 13 healthy controls. Despite severely impaired explicit memory, patients changed valence and arousal ratings according to the biographical content and did not differ in their ratings from the control group. The results demonstrate that our FEA paradigm is a valid instrument to investigate learning of affective responses in dementia patients

Nonequilibrium relaxation of the two-dimensional Ising model: Series-expansion and Monte Carlo studies

We study the critical relaxation of the two-dimensional Ising model from a fully ordered configuration by series expansion in time t and by Monte Carlo simulation. Both the magnetization (m) and energy series are obtained up to 12-th order. An accurate estimate from series analysis for the dynamical critical exponent z is difficult but compatible with 2.2. We also use Monte Carlo simulation to determine an effective exponent, z_eff(t) = - {1/8} d ln t /d ln m, directly from a ratio of three-spin correlation to m. Extrapolation to t = infinity leads to an estimate z = 2.169 +/- 0.003.Comment: 9 pages including 2 figure

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury