Liposomes in chemo- and immunotherapy of cancer

In this paper, we report on the in vivo behavior of liposomes as a function of their size and composition. It is emphasized that by varying these parameters we can influence not only the rate of blood elimination but also the intrahepatic destination of the liposomes. Thus, we show that small liposomes with diameters well below 100 nm can reach and be internalized by the parenchymal cells of the liver, i.e. the hepatocytes. The rate and the extent at which this occurs depends on the liposomal composition. With respect to the application of liposomes as a drug carrier system in anticancer therapy, we put emphasis on the liver macrophage, i.e. the Kupffer cell, as a target cell. Large liposomes with diameters well over 100 nm exclusively are taken up by these cells as far as hepatic uptake is concerned. By encapsulation within liposomes, a drug may be delivered specifically to these macrophages; this will prevent its rapid excretion from the body and/or undesired accumulation in other cell types. Two examples of the way in which this condition may be exploited are presented. First, we demonstrate the formation of intracellular depots in the macrophages of the cytostatic drug 5-fluorodeoxyuridine (FUdR), thus preventing the rapid metabolism of the drug by the hepatocytes and allowing its sustained release from the macrophages and subsequent uptake by adjacent metastatic tumor cells. Second, we show that the liposome-encapsulated immunomodulator muramyl dipeptide is capable of activating liver macrophages both in vitro and in vivo to a tumor-specific cytotoxic state, and this can result in substantial reduction of metastatic growth in the livers of mice inoculated in the spleen with colon adenocarcinoma cells.     

Computational aspects of the expected differential probability of 4-round AES and AES-like ciphers

In this paper we study the security of the Advanced Encryption Standard (AES) and AES-like block ciphers against differential cryptanalysis. Differential cryptanalysis is one of the most powerful methods for analyzing the security of block ciphers. Even though no formal proofs for the security of AES against differential cryptanalysis have been provided to date, some attempts to compute the maximum expected differential probability (MEDP) for two and four rounds of AES have been presented recently. In this paper, we will improve upon existing approaches in order to derive better bounds on the EDP for two and four rounds of AES based on a slightly simplified S-box. More precisely, we are able to provide the complete distribution of the EDP for two rounds of this AES variant with five active S-boxes and methods to improve the estimates for the EDP in the case of six active S-boxes.     

Corrosion susceptibility of potential rock bolts in aerated multi-ionic simulated concentrated water

Rock bolts used for the reinforcement of underground mines, tunnels and nuclear waste repositories are made up of low and medium carbon steels, and high strength low alloy steels. Typical rock bolt systems used for rock reinforcement are mechanically anchored bolts, grout anchored, frictional rock stabilizers and strand anchors. For nuclear waste repository sites such as Yucca Mountain (YM) as well as for mines and tunnels, in addition to mechanical properties, corrosion properties are also important due to potential seepage of water through the fractures or pores in the rock. During temporary rock support period of 50-100 years, the temperature of the tunnel at YM should be maintained at ambient conditions. For any reason if the rock bolts are exposed to YM waters and high temperatures in the tunnel then there is a chance of corrosion of steel rock bolts. In this study an attempt was made to study the corrosion properties of various potential rock bolts for YM tunnel support via the aid of electrochemical corrosion testing. At ambient temperature (25 °C) all the rock bolts that were studied showed good corrosion resistance in these waters. At higher temperatures, 60 °C and 90 °C, corrosion resistance of rock bolts decreased, but due to special stress relief heat treatment of one of the frictional rock stabilizers (Swellex Mn 24) the corrosion rates were lower than all other tested rock bolts. Note: Swellex, Split set and Williams are the proprietary names of Atlas Copco, International Roll Forms, Inc. and Williams Form Engineering Corp, respectively.     

Motor denervation induces altered muscle fibre type densities and atrophy in a rat model of neuropathic pain

Loose ligation of a sciatic nerve in rats (chronic constriction injury; CCI) provokes sensory, autonomic, and motor disturbances like those observed in humans with partial peripheral nerve injury. So far, it is unknown whether these motor disturbances result from (mechanical) allodynia or from damage to the motor neuron. These considerations prompted us to assess, in CCI rats, the density of motor axons in both the ligated sciatic nerve and the ipsilateral femoral nerve. To this end, we determined the number of cholinesterase positive fibres. It has been demonstrated previously that muscle fibre type density may be used as a measure of motor denervation and/or hypokinesia. Therefore, the myofibrillar ATPase reaction was employed to assess fibre type density in biopsies obtained from the lateral gastrocnemius muscle (innervated by sciatic nerve) and rectus femoris muscle (innervated by femoral nerve). We observed axonal degeneration of motor fibres within the loosely ligated sciatic nerve, both at an intermediate (day 21) and at a late stage (day 90) after nerve injury. The reduction in the number of motor nerve fibres was more pronounced distal to the site of the ligatures than proximal. A (less pronounced) reduction of motor fibres was observed in the ipsilateral (non-ligated) femoral nerve. In line with these findings, we observed altered fibre type densities in muscle tissue innervated by the ligated sciatic nerve as well as the non-ligated femoral nerve indicative of motor denervation rather than hypokinesia. The findings of this study suggest that the motor disorder induced by partial nerve injury involves degeneration of motor nerve fibres not only within the primarily affected nerve but also within adjacent large peripheral nerves. This spread outside the territory of the primarily affected nerve suggests degeneration of motor neurons at the level of the central nervous system.     

Partial peripheral neuropathy and denervation induced adrenoceptor supersensitivity. Functional studies in an experimental model

OBJECTIVE: To determine the influence of iron dextran intraperitoneal administration on the function and histology of the peritoneum in rats undergoing chronic peritoneal dialysis. DESIGN: Prospective, randomized experimental study. MATERIALS: Fifty-four Sprague-Dawley rats were divided into five groups: 3 study groups--high dose group (H), n = 12; intermediate dose (M), n = 12; and low dose group (L), n = 12--a dialysis control group (D), n = 12; and a tissue control (C), n = 7. INTERVENTIONS: The study groups were given Dianeal containing iron dextran in a concentration of 0.5, 0.25, and 0.125 mg/L (groups H, M, and L respectively). Group D was given standard Dianeal. Group C was never dialyzed. MAIN OUTCOME MEASURES: A 2-hour peritoneal equilibrium test (PET) was performed on the eighth day, at 3 months, and at 6 months. After the final PET, the animals were sacrificed and the peritoneal membrane was evaluated by gross inspection and light microscopy (silver, prussian blue, and trichrome staining). RESULTS: Peritoneal transport of small solutes followed the same pattern in all groups, increasing over time. The peritonitis index was similar in the groups. No iron deposits or morphologic differences were seen in the gross inspection of the peritoneal cavity. No peritoneal iron deposition was detected in the histological analysis with prussian blue staining. No differences were noted in the light microscopic analysis of the mesothelial cell layer (silver staining), nor did the morphometric analysis of the submesothelial space show any differences in thickness between the groups. CONCLUSION: These findings suggest the absence of toxic effects of iron dextran on the peritoneal cavity of rats in the concentrations studied. Further studies should be performed to evaluate the effectiveness of these dosages delivered intraperitoneally to maintain iron homeostasis.     

Inhibition of angiotensin I-converting enzyme by wheat gliadin hydrolysates

A tryptic gliadin hydrolysate was fractionated into peptide fractions, which were assigned to either the central domain (CD) or terminal domains (TD) of gliadins. The domains were expected to contain amino acid (AA) sequences which, when released from the parent protein, inhibit the angiotensin I-converting enzyme (ACE), which plays a key role in regulating blood pressure. A proline (Pro) poor TD related fraction, containing the smallest peptides, showed the highest ACE inhibitory activity (IC₅₀ = 0.33 mg/ml). Additional peptidases were selected based on their in silico predicted ability to release ACE inhibitory peptides. Further hydrolysis of the tryptic hydrolysate fractions with thermolysin, Clarex, Alcalase and Esperase increased ACE inhibitory activities. Immobilised Ni²⁺-ion affinity chromatography (IMAC) purification of a TD related peptide fraction obtained by sequential hydrolysis with trypsin and thermolysin yielded a fraction with an IC₅₀ value of 0.02 mg/ml. This IMAC fraction was enriched in histidine and hydrophobic AA (Pro, Val, Ile, Leu and Phe).     

An experimental study on creep of welded tuff

This paper presents results of five creep tests conducted in uniaxial compression at room temperature. The test specimens were from the welded Topopah Spring tuff formation at Yucca Mountain, Nevada. The specimens exhibited brittle failure. Multiple stress levels were applied in steps to each specimen. Each stress level was maintained for 3 days or longer. The transient creep for all the stress levels can be well described by power functions. The transient creep is caused by an elastic aftereffect. The tuff does not show real steady-state creep. The so-called steady-state creep rate decreases with time. In general it is very low, typically in the range of 10⁻⁷ h⁻¹. For the first 50 h, the so-called steady-state creep rate may be described as a power function of stress. The specimen failed shortly after it entered into the accelerating creep phase.