Liposomal phosphatidylserine inhibits tumor cytotoxicity of liver macrophages induced by muramyl dipeptide and lipopolysaccharide

Liposomes can very efficiently deliver immunomodulators to macrophages so as to induce tumor cytotoxicity. Liposomes most widely used for that purpose contain negatively charged lipids, in particular phosphatidylserine (PS), to enhance liposome uptake by the macrophages. We investigated the effect of three negatively charged liposomal lipids on the in vitro activation of liver macrophages to tumor cytotoxicity by muramyl dipeptide (MDP) and lipopolysaccharide (LPS). Both MDP- and LPS-induced tumor cytotoxicity towards murine colon adenocarcinoma cells were strongly inhibited by PS-containing liposomes. Under comparable conditions phosphatidylglycerol (DPPG)-containing or dicetyl phosphate (DCP)-containing liposomes did not inhibit or only marginally inhibited the induction of tumor cytotoxicity. We did not observe PS-mediated inhibition of tumor cell toxicity when the exposure of the macrophages to PS-liposomes was limited to the 4-h activation period prior to addition of the tumor target cells, suggesting that the inhibitory effect is accomplished at the level of the later stages of the activation process. Previously, we showed that macrophages which are activated to tumor cytotoxicity during a 24-h incubation with MDP become refractory to a second activation with MDP. Now we observed that simultaneous incubation with PS-containing liposomes partially prevents this refractoriness, which is also compatible with an interfering action of PS at a relatively late stage in the activation process. We conclude that PS, despite its reported stimulatory effect on liposome uptake by macrophages, can seriously antagonize the effectiveness of immunomodulating, agents acting on macrophages. This bears relevance to the use of PS-containing liposomes as a vehicle for such agents. The results are discussed in perspective of earlier reported pharmacological effects of PS and its metabolites.</p

Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation.

BACKGROUND: Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha(1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney. METHODS AND RESULTS: Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal I/R in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of renal caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-alpha expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion. CONCLUSIONS: We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatmen

Detecting time-fragmented cache attacks against AES using Performance Monitoring Counters

Cache timing attacks use shared caches in multi-core processors as side channels to extract information from victim processes. These attacks are particularly dangerous in cloud infrastructures, in which the deployed countermeasures cause collateral effects in terms of performance loss and increase in energy consumption. We propose to monitor the victim process using an independent monitoring (detector) process, that continuously measures selected Performance Monitoring Counters (PMC) to detect the presence of an attack. Ad-hoc countermeasures can be applied only when such a risky situation arises. In our case, the victim process is the AES encryption algorithm and the attack is performed by means of random encryption requests. We demonstrate that PMCs are a feasible tool to detect the attack and that sampling PMCs at high frequencies is worse than sampling at lower frequencies in terms of detection capabilities, particularly when the attack is fragmented in time to try to be hidden from detection

Anharmonicity of flux lattices and thermal fluctuations in layered superconductors

We study elasticity of a perpendicular flux lattice in a layered superconductor with Josephson coupling between layers. We find that the energy contains ln(flux displacement) terms, so that elastic constants cannot be strictly defined. Instead we define effective elastic constants by a thermal average. The tilt modulus has terms with ln(T) which for weak fields, i.e. Josephson length smaller than the flux line spacing, lead to displacement square average proportional to T/ln(T). The expansion parameter indicates that the dominant low temperature phase transition is either layer decoupling at high fields or melting at low fields.Comment: 15 pages, 2 eps figures, Revtex, submitted to Phys. Rev. B. Sunj-class: superconductivit

Disorder Induced Transitions in Layered Coulomb Gases and Superconductors

A 3D layered system of charges with logarithmic interaction parallel to the layers and random dipoles is studied via a novel variational method and an energy rationale which reproduce the known phase diagram for a single layer. Increasing interlayer coupling leads to successive transitions in which charge rods correlated in N>1 neighboring layers are nucleated by weaker disorder. For layered superconductors in the limit of only magnetic interlayer coupling, the method predicts and locates a disorder-induced defect-unbinding transition in the flux lattice. While N=1 charges dominate there, N>1 disorder induced defect rods are predicted for multi-layer superconductors.Comment: 4 pages, 2 figures, RevTe

Immunologic aspect of ovarian cancer and p53 as tumor antigen

Ovarian cancer represents the fifth leading cause of death from all cancers for women. During the last decades overall survival has improved due to the use of new chemotherapy schedules. Still, the majority of patients die of this disease. Research reveals that ovarian cancer patients exhibit significant immune responses against their tumor. In this review the knowledge obtained thus far on the interaction of ovarian cancer tumor cells and the immune system is discussed. Furthermore the role of p53 as tumor antigen and its potential role as target antigen in ovarian cancer is summarized. Based on the increased knowledge on the role of the immune system in ovarian cancer major improvements are to be expected of immunotherapy based treatment of this disease

Josephson Plasma Resonance in Bi2Sr2CaCu2O8+yBi_2 Sr_2 Ca Cu_2 O_{8+y} with Spatially Dependent Interlayer-Phase Coherence

We study the Josephson plasma resonance (JPR) in Bi$_2$Sr$_2$CaCu$_2$O$_{8+y}$ (BSCCO) with spatially dependent interlayer-phase coherence (IPC). The half-irradiated BSCCO (HI-BSCCO), in which columnar defects are introduced only in a half of the sample, shows several resonance peaks, which are not simple superposition of the peaks in irradiated- and pristine-parts. JPR in HI-BSCCO changes its character from irradiated- to pristine-type at a crossover frequency ($\omega_{cr}$). We demonstrate that the one-dimensional \LSGE, which takes into account the spatial dependence of IPC, can reproduce most of the experimental findings including the presence of $\omega_{cr}$.Comment: 4 figure

Quantum-noise--randomized data-encryption for WDM fiber-optic networks

We demonstrate high-rate randomized data-encryption through optical fibers using the inherent quantum-measurement noise of coherent states of light. Specifically, we demonstrate 650Mbps data encryption through a 10Gbps data-bearing, in-line amplified 200km-long line. In our protocol, legitimate users (who share a short secret-key) communicate using an M-ry signal set while an attacker (who does not share the secret key) is forced to contend with the fundamental and irreducible quantum-measurement noise of coherent states. Implementations of our protocol using both polarization-encoded signal sets as well as polarization-insensitive phase-keyed signal sets are experimentally and theoretically evaluated. Different from the performance criteria for the cryptographic objective of key generation (quantum key-generation), one possible set of performance criteria for the cryptographic objective of data encryption is established and carefully considered.Comment: Version 2: Some errors have been corrected and arguments refined. To appear in Physical Review A. Version 3: Minor corrections to version

Josephson Plasma Resonance as a Structural Probe of Vortex Liquid

Recent developments of the Josephson plasma resonance and transport c-axis measurements in layered high T$_{c}$ superconductors allow to probe Josephson coupling in a wide range of the vortex phase diagram. We derive a relation between the field dependent Josephson coupling energy and the density correlation function of the vortex liquid. This relation provides a unique opportunity to extract the density correlation function of pancake vortices from the dependence of the plasma resonance on the $ab$-component of the magnetic field at a fixed $c$-axis component.Comment: 4 pages, 1 fugure, accepted to Phys. Rev. Let

Immunological and Clinical Effects of Vaccines Targeting p53-Overexpressing Malignancies

Approximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53-specific cytotoxic T-lymphocytes (CTL) and CD4+ T-helper cells eradicates p53-overexpressing tumors in mice. Furthermore, p53 antibodies and p53-specific CTLs can be detected in cancer patients, indicating that p53 is immunogenic. Based on these results, clinical trials were initiated. In this paper, we review immunological and clinical responses observed in cancer patients vaccinated with p53 targeting vaccines. In most trials, p53-specific vaccine-induced immunological responses were observed. Unfortunately, no clinical responses with significant reduction of tumor-burden have occurred. We will elaborate on possible explanations for this lack of clinical effectiveness. In the second part of this paper, we summarize several immunopotentiating combination strategies suitable for clinical use. In our opinion, future p53-vaccine studies should focus on addition of these immunopotentiating regimens to achieve clinically effective therapeutic vaccination strategies for cancer patients