Heat-Induced Drug Release Rate and Maximal Targeting Index of Thermosensitive Liposome in Tumor-Bearing Mice

To evaluate the rate of drug release at the tumor and maximal drug targeting after administration of thermosensitive liposomes with hy-perthermia, a theoretical and experimental method was derived assessing the fraction of drug released from liposomes in a single pass through the heated tumor, F, and the drug targeting index when drug release occurs completely in response to heat (F = 1), DTI_max. The F and DTImax were evaluated for four types of liposomes (LUV-1 and LUV-2, thermosensitive large unilamellar liposomes; LUV-3, a nonthermosensitive large unilamellar liposome; and SUV-1, a thermosensitive small unilamellar liposome) using reported data on blood liposome levels and tumor drug levels after the liposomes were administered to tumor bearing mice. DTI_max values for LUV-1 and SUV-1 were approximately 6, while the value for LUV-2 with a relatively large systemic clearance was only 2.3. The F values for LUV-1, LUV-2, and SUV-1 with hyperthermia were 0.71, 1.17, and 0.34, respectively, whereas the values for these liposomes without hyperthermia and for LUV-3 with or without hyperthermia were nearly zero. These results confirm earlier findings that LUV-1 and LUV-2 release CDDP almost completely at the heated tumor and that the large DTI value obtained in LUV-1 (DTI = 4.6) was due to its high heat sensitivity and its small systemic clearance.     

Free internal mammary artery for coronary bypass

We studied 12 cases of free internal mammary artery (IMA) grafting. We used IMAs as free grafts mainly because of its shortness (6 cases 50%) and injury during dissection (4 cases 33%) and found the varicose change of saphenous vein in 5 cases (42%). Most of the grafting sites are distal parts of coronary arteries. Proximal anastomosis sites are other vein grafts (3 cases), other IMA grafts (3 cases), vein grafts interposing to the aorta (3 cases), and aorta (1 case). Patency rate of the free IMA grafts 4 weeks after operations was good (82%). Free IMA grafting is safe alternative to in situ IMA grafting when IMA grafts are short or injured and saphenous vein grafting is impossible.     

RETINOID STIMULATES EPIDERMAL OUTGROWTH OF PIG SKIN EXPLANTS

Using a pig explant culture system, the effects of retinoids on pig epidermal cells were studied. Ro 10-9359 slightly stimulated epidermal outgrowth, but this effect was not significant. Ro 10-1670 (a metabolite of Ro 10-9359) significantly stimulated epidermal outgrowth. Cytochalasin B and colchicine markedly inhibited the stimulatory effect of Ro 10-1670, but hydroxyurea or cycloheximide did not completely block this stimulatory effect. During a migratory period, cytochalasin B completely blocked it. Neither Ro 10-1670 nor Ro 10-9359 effected a change in mitotic index. Histological studies revealed that Ro 10-1670-treated epidermal cells did not form any keratin layers. These results suggest that Ro 10-1670 stimulated outgrowth, particularly migratory outgrowth, of epidermal cells, resulting in reduced keratin formation.     

Systematic classification of alleles of the glycophorin A (MN blood group) gene

Ten alleles (five M and five N alleles) of the MN blood group system with normal antigenicity were found by sequencing the glycophorin A (GPA) gene. This study demonstrates the systematic classification of these alleles to major or minor variations of the standard alleles. GPA-specific fragments ranging from 150 to 3.8 kb in length were amplified from the templates, and exons 1–7 and introns 1–6 were sequenced. The data were analyzed phylogenetically to classify these alleles into major groups or clusters. The ten alleles were grouped into four major clusters M10X (M101–M103), M20X (M201 and M202), N10X (N101–N104) and N20X (N201), where X represents a digit indicating minor variations. This grouping was supported by phylogenetic analysis. The cluster system of GPA alleles is highly informative for genetic screening.     

Public appraisal of government efforts and participation intent in medico-ethical policymaking in Japan: a large scale national survey concerning brain death and organ transplant

Background  

Public satisfaction with policy process influences the legitimacy and acceptance of policies, and conditions the future political process, especially when contending ethical value judgments are involved. On the other hand, public involvement is required if effective policy is to be developed and accepted.     

Prominent dominant negative effect of a mutant Fas molecule lacking death domain on cell-mediated induction of apoptosis

Using a panel of transfectant B lymphoma cells expressing varying amounts of the mutant Fas together with the endogenous wild type Fas, semi-quantitative studies on the dominant negative effect of a murine mutant Fas molecule lacking death domain were carried out. In anti-Fas antibody-mediated induction of apoptosis, the mutant molecules exerted significant dominant-negative effect only when their expression level was comparable to or higher than that of wild type molecules, or when exposed to low amounts of the antibody. The inhibitory effect was accompanied by the failure in DISC formation in spite of Fas aggregation. When they were subjected to T cell-mediated Fas-based induction of apoptosis, however, the dominant negative effect was prominent such that the expression of even a small amount of the mutant molecules resulted in significant inhibition. Such a strong inhibitory effect explains the dominant phenotype of this type of mutant Fas molecules in ALPS heterozygous patients and also implies that the physiological effectors for Fas in vivo are cells, i.e., FasL-expressing activated T cells.     

Dietary bioflavonoids induce apoptosis in human leukemia cells

Dietary bioflavonoids are secondary metabolites of plants that are known to have a variety of bio-effects, including anti-cancer activity. In this study, we examined the effects of flavonoids on the growth of human leukemia cells and found that certain flavonoids induce apoptosis in a variety of human leukemia cells. The apoptosis induced by bioflavonoids was dose-dependent and was accompanied by a disruption of the mitochondrial transmembrane potential and the activation of caspase. Our data suggests that dietary bioflavonoids may be useful chemotherapeutic reagents for leukemia patients.     

Ursolic acid promotes the release of macrophage migration inhibitory factor via ERK2 activation in resting mouse macrophages

Macrophage migration inhibitory factor (MIF) plays some pivotal roles in innate immunity and inflammation. Ursolic acid (UA), an anti-inflammatory triterpene carboxylic acid, was recently reported to induce the release of pro-inflammatory mediators in resting macrophages (Mvarphi). We investigated the effects of UA on MIF protein release in resting RAW264.7 mouse Mvarphi, and found that it decreased intracellular MIF protein levels and promoted the release of MIF into the culture media in dose- and time-dependent manners, without affecting mRNA levels. Further, the triterpene strikingly induced activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) within 30min, whereas no phosphorylation of p38 MAPK or JNK protein was observed. In addition, UA-promoted MIF release was significantly inhibited by PD98059, a MEK1/2 inhibitor, while siRNA for ERK2, but not ERK1, significantly decreased the amount of MIF protein released. These results suggest that UA triggers the release of intracellular MIF protein through the ERK2 activation.