Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90

We previously reported that Antp-TPR hybrid peptide inhibited the interaction of Hsp90 with TPR2A and had selective cytotoxic activity discriminating between normal and cancer cells to induce cancer cell death. In this study, we investigated the cytotoxic activity of Antp-TPR peptide toward acute myeloid leukemia (AML) cells. It was demonstrated that Antp-TPR peptide induced AML cell death in cell lines such as U937, K562, THP-1, and HL-60 via activation of caspases 3 and 7, and disruption of mitochondrial membrane potential. Conversely, Antp-TPR peptide did not reduce the viability of normal cells including peripheral blood mononuclear cells (PBMCs), although both geldanamycin and 17-AAG, small-molecule inhibitors of Hsp90, mediated cytotoxicity to these normal cells at low concentrations. In addition, mutation analysis of TPR peptide demonstrated that the highly conserved amino acids Lys and Arg were critical to the cytotoxic activity. These results indicated that Antp-TPR hybrid peptide would provide potent and selective therapeutic options in the treatment of AML.     

Fundamental adsorption characteristics of carbonaceous adsorbents for 1,2,3,4-tetrachlorobenzene in a model gas of an incineration plant

Carbonaceous adsorbents such as activated carbon have been used to reduce the emission of organic pollutants from incineration plants. However, with this method, the amount and type of adsorbent to be used are based only on empirical results, which may lead to overuse of the adsorbents. The fundamental adsorption characteristics of several kinds of activated carbon, activated coke, and carbide wood were examined using 1 ,2,3,4-tetrachlorobenzene as an adsorbate. The removal performance and various equilibrium adsorption characteristics of these adsorbents were analyzed using laboratory-scale adsorption equipment. The equilibrium adsorption amount increased by a factor of 1.9-3.2 at 150 degrees C compared with that at 190 degrees C. The effect of the moisture content on adsorption capacity was relatively small in comparison with that of the temperature. The micropore volume for pore diameters of 2 nm or less was the most important factor governing the adsorption capacity for all adsorbents. Activated carbon showed superior adsorption ability compared to activated coke and carbide wood, although all adsorbents were sufficient for practical use.     

Analysis of enoyl-coenzyme A hydratase activity and its stereospecificity using high-performance liquid chromatography equipped with chiral separation column

Enoyl-coenzyme A (CoA) hydratase catalyzes the hydration of trans-2-enoyl-CoA to yield 3-hydroxyacyl-CoA during fatty acid degradation (β-oxidation). Although much research has focused on the stereospecificities of 2-enoyl-CoA hydratases, a direct quantification of the production of 3(R)- and 3(S)-hydroxyacyl-CoA has not yet been established. Therefore, we developed a method of concurrently quantifying 3(R)- and 3(S)-hydroxyacyl-CoA using high-performance liquid chromatography (HPLC) equipped with a chiral separation column. The optimized conditions for the separation of 3(R)-, 3(S)-hydroxyhexadecanoyl-CoA and trans-2-hexadecenoyl-CoA, were determined to be as follows: mobile phase of 35/65 (v/v) of 50 mM phosphate buffer (pH 5.0)/methanol; flow rate of 0.5 mL/min; detection at 260 nm; and column temperature of 25°C. This method was applied to subcellular fractions of rat liver; the results directly confirmed that 3(S)-hydroxyhexadecanoyl-CoA is the dominant product obtained from the heat-stable enoyl-CoA hydratase-catalyzed reaction of trans-2-hexadecenoyl-CoA. Finally, the stereospecificities of L-bifunctional protein (L-BP) and D-bifunctional protein (D-BP) were reinvestigated using this method, and it was confirmed that L- and D-BP yielded 3(S)- and 3(R)-hydroxyhexadecanoyl-CoA were yielded from trans-2-hexadecenoyl-CoA, respectively. 3(R)-Hydroxyacyl-CoA is a peroxisomal β-oxidation-specific intermediate. Therefore, this method is potentially useful not only studies regarding the stereochemistry of enoyl-CoA hydratase but also for the diagnosis of diseases caused by defects of peroxisomal enoyl-CoA hydratase.     

Synthesis of Condensed Tannin Derivatives and their Protein-Precipitating Capacity

Four regiospecifically methylated condensed tannin derivatives were synthesized by the condensation of regiospecifically methylated flavan-3, 4-diols protected by benzyl groups, and subsequent debenzylation. The monomeric flavan-3,4-diols were obtained via four reaction steps starting from phloroacetophenone derivatives and protocatechualdehyde derivatives. Protein—precipitating capacity of these synthetic condensed tannin derivatives was tested and a comparision of these capacity suggests the following results: 1) Phenolic hydroxyl groups in tannins are essential sites for protein precipitation. 2) Although the A-ring has been considered not to be important for tannin—protein interactions, it was proved that the A-ring also plays an important role together with the B-ring. 3) Both hydroxyl groups of A- and B-rings may synergistically interact with proteins.     

Relationship Between the B-Ring Hydroxylation Pattern of Condensed Tannins and their Protein-Precipitating Capacity

A series of condensed tannin derivatives with non-, mono-, di- and tri-hydroxylated B-rings were synthesized starting from phloroglucinol and benzaldehyde derivatives. The protein-precipitating capacity of these condensed tannin derivatives showed 1) A condensed tannin with only a 4′-hydroxylated B-ring has almost the same protein-precipitating capacity as that of a condensed tannin with 3′,4′-dihydroxylated or 3′,4′,5′-trihydroxylated B-rings. 2) The complexing ability of phenolic hydroxyl groups in the B-ring are effective in the order of p- > m- > o-positions.     

Perspectives paper: First principles modeling of high-k gate dielectrics

Aggressive scaling has led to silicon dioxide (SiO₂) gate dielectrics as thin as 15 Å in state-of-the-art CMOS technologies. As a consequence, static leakage power due to direct tunneling through the gate oxide has been increasing at an exponential rate. As technology roadmaps call for sub-10 Å gate oxides within the next five years, a variety of alternative high-k materials are being investigated as possible replacements for SiO₂. The higher dielectric constants in these materials allow the use of physically thicker films, potentially reducing the tunneling current while maintaining the gate capacitance needed for scaled device operation. Recognizing that the current Si/SiO₂ system benefits from nearly 30 years of research, developing a replacement material for SiO₂ presents an immense challenge. This has prompted recent interest in novel computational approaches, such as first principles density functional theory (DFT) simulations, to computationally screen candidate dielectrics by predicting their properties based on the microscopic interactions within the system. This paper provides perspectives on the application of DFT simulations to address challenging problems of high-k gate dielectric research. We provide background and motivation for the development of high-k materials and highlight opportunities for theoretical study of such materials. We also describe specific examples of recent first principles work related to two particularly promising materials systems: silicates and aluminates.     

Development of Mould Flux for High Speed Thin Slab Casting

Mould powders impact the stability of the continuous casting process for steel at all casting speeds. The main functions of mould powder are to provide sufficient lubrication and to control the mould heat transfer between the solidifying steel shell and the copper mould. At higher casting speeds associated with thin slab casting, the role of the mould powder is even more important. Actual casting speeds for the thin slab caster at Corus IJmuiden are between 5.4 and 6 m/min; the production level is around 1.3 Mt/year (coils). It has been decided to increase the production of this caster to a level of 1.8 Mt/year (coils). In order to meet this demand, the steel in mould time has to be increased to approximately 85% and the maximum casting speed will be increased to 8 m/min. A collaborative project between Sumitomo Metal Industries (SMI) and Corus IJmuiden was initiated to develop mould powders which facilitate casting speeds up to 8 m/min at the thin slab caster. Main subjects of this project are: mould powder design, characterisation of mould powder and mould slag, trials at the pilot caster of Sumitomo and finally plant trials at the thin slab caster of Corus. A special point of attention is the condition to use mould powder as a granulated material at the thin slab caster. As a consequence, the characterisation work focussed on the choice of raw materials and on the corresponding phase relations at elevated temperatures. Typical of the developed mould powders are so‐called mild cooling properties which will result in a controlled mould heat transfer during casting. In this paper, several aspects of this joint project between Sumitomo and Corus will be described.     

Combined efficacy of nisin and pediocin with sodium lactate, citric acid, phytic acid, and potassium sorbate and EDTA in reducing the Listeria monocytogenes population of inoculated fresh-cut produce

The inability of chlorine to completely inactivate human bacterial pathogens on whole and fresh-cut produce suggests a need for other antimicrobial washing treatments. Nisin (50 microg/ml) and pediocin (100 AU/ml) individually or in combination with sodium lactate (2%), potassium sorbate (0.02%), phytic acid (0.02%), and citric acid (10 mM) were tested as possible sanitizer treatments for reducing the population of Listeria monocytogenes on cabbage, broccoli, and mung bean sprouts. Cabbage, broccoli, and mung bean sprouts were inoculated with a five-strain cocktail of L. monocytogenes at 4.61, 4.34, and 4.67 log CFU/g, respectively. Inoculated produce was left at room temperature (25 degrees C) for up to 4 h before antimicrobial treatment. Washing treatments were applied to inoculated produce for 1 min, and surviving bacterial populations were determined. When tested alone, all compounds resulted in 2.20- to 4.35-log reductions of L. monocytogenes on mung bean, cabbage, and broccoli, respectively. The combination treatments nisin-phytic acid and nisin-pediocin-phytic acid caused significant (P < 0.05) reductions of L. monocytogenes on cabbage and broccoli but not on mung bean sprouts. Pediocin treatment alone or in combination with any of the organic acid tested was more effective in reducing L. monocytogenes populations than the nisin treatment alone. Although none of the combination treatments completely eliminated the pathogen on the produce, the results suggest that some of the treatments evaluated in this study can be used to improve the microbial safety of fresh-cut cabbage, broccoli, and mung bean sprouts.     

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.     

Double cancer of the stomach, one AFP-producing tumor

In recent years, many cases of alpha-fetoprotein-producing gastric cancer (AFPGC) characterized by increased serum levels of alpha-fetoprotein (AFP) and AFP positivity of the gastric cancer have been reported. Here we present a case of AFPGC coexistent with a different histological type of gastric cancer: The AFPGC was Borrmann type 1 advanced gastric cancer with multiple liver metastasis and appeared to produce both AFP and des-gamma-carboxy prothrombin (PIVKA-II). The second cancer was IIc type early gastric cancer and did not produce AFP. Despite receiving palliative chemotherapy, the patient died, due to hepatic failure, 45 days after admission.