A comparison of thyroidal protection by iodine and perchlorate against radioiodine exposure in Caucasians and Japanese.

Radioactive iodine released in nuclear accidents may accumulate in the thyroid and by irradiation enhances the risk of cancer. Radioiodine uptake into the gland can be inhibited by large doses of stable iodine or perchlorate. Nutritional iodine daily intake may impact thyroid physiology, so that radiological doses absorbed by the thyroid as well as thyroid blocking efficacy may differ in Japanese with a very rich iodine diet compared to Caucasians. Based on established biokinetic-dosimetric models for the thyroid, we derived the parameters for Caucasians and Japanese to quantitatively compare the effects of radioiodine exposure and the protective efficacy of thyroid blocking by stable iodine at the officially recommended dosages (100 mg in Germany, 76 mg in Japan) or perchlorate. The maximum transport capacity for iodine uptake into the thyroid is lower in Japanese compared to Caucasians. For the same radioiodine exposure pattern, the radiological equivalent thyroid dose is substantially lower in Japanese in the absence of thyroid blocking treatments. In the case of acute radioiodine exposure, stable iodine is less potent in Japanese (ED50 = 41.6 mg) than in Caucasians (ED50 = 2.7 mg) and confers less thyroid protection at the recommended dosages because of a delayed responsiveness to iodine saturation of the gland (Wolff-Chaikoff effect). Perchlorate (ED50 = 10 mg in Caucasians) at a dose of 1000 mg has roughly the same thyroid blocking effect as 100 mg iodine in Caucasians, whereas it confers a much better protection than 76 mg iodine in Japanese. For prolonged exposures, a single dose of iodine offer substantially lower protection than after acute radioiodine exposure in both groups. Repetitive daily iodine administrations improve efficacy without reaching levels after acute radioiodine exposure and achieve only slightly better protection in Japanese than in Caucasians. However, in the case of continuous radioiodine exposure, daily doses of 1000 mg perchlorate achieve a high protective efficacy in Caucasians as well as Japanese (> 0.98). In Caucasians, iodine (100 mg) and perchlorate (1000 mg) at the recommended dosages seem alternatives in case of acute radioiodine exposure, whereas perchlorate has a higher protective efficacy in the case of longer lasting radioiodine exposures. In Japanese, considering protective efficacy, preference should be given to perchlorate in acute as well as prolonged radioiodine exposure scenarios.

Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression.

Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

Photodynamic therapy mediates innate immune responses via fibroblast-macrophage interactions.

Antibacterial photodynamic therapy (PDT) has come to attract attention as an alternative therapy for drug-resistant bacteria. Recent reports revealed that antibacterial PDT induces innate immune response and stimulates abundant cytokine secretion as a part of inflammatory responses. However, the underlying mechanism how antibacterial PDT interacts with immune cells responsible for cytokine secretion has not been well outlined. In this study, we aimed to clarify the difference in gene expression and cytokine secretion between combined culture of fibroblasts and macrophages and their independent cultures. SCRC-1008, mouse fibroblast cell line and J774, mouse macrophage-like cell line were co-cultured and PDT treatments with different parameters were carried out. After various incubation periods (1-24 h), cells and culture medium were collected, and mRNA and protein levels for cytokines were measured using real-time PCR and ELISA, respectively. Our results showed that fibroblasts and macrophages interact with each other to mediate the immune response. We propose that fibroblasts initially respond to PDT by expressing Hspa1b, which regulates the NF-κB pathway via Tlr2 and Tlr4. Activation of the NF-κB pathway then results in an enhanced secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and neutrophil chemoattractant MIP-2 and KC from macrophages.

High-temperature-required protein A2 as a predictive marker for response to chemotherapy and prognosis in patients with high-grade serous ovarian cancers.

BACKGROUND: High-temperature-required protein A2 (HtrA2), a protein relating with apoptosis in a caspases-dependent and non-dependent manner, has been reported to be associated with chemosensitivity in several human cancers. METHODS: Tissue microarrays made from 142 patients with high-grade serous ovarian adenocarcinoma were evaluated to assess whether HtrA2 expression was related with several clinical parameters. RESULTS: Negative HtrA2 expression was observed in 36 cases (25%) of the patients, and related with significantly lower response rates of primary chemotherapy than those with positive HtrA2 expression (56% vs 83%, P<0.01). In addition, negative HtrA2 expression was identified as an independent worse prognostic factor for progression-free survival and overall survival by multivariate analyses. Furthermore, HtrA2 downregulation modulated sensitivity to platinum in serous ovarian cancer cells in vitro. CONCLUSIONS: HtrA2 expression was a predictor for sensitivity to chemotherapy, and could be a candidate of molecular target in the treatment of high-grade serous ovarian cancers.

X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary.

BACKGROUND: X-chromosome-linked inhibitor of apoptosis (XIAP) is one of the anti-apoptotic proteins leading to chemoresistance in several cancers. The aim of this study is to evaluate the impact of XIAP expression upon ovarian clear cell carcinoma (CCC) that has a platinum-resistant phenotype. METHODS: Tissue microarrays made from 90 CCC patients were analysed for immunohistochemical expression levels of XIAP, c-Met, p-Akt and Bcl-XL. In addition, CCC cell lines were evaluated whether XIAP silencing could modulate sensitivity to platinum agent in vitro. RESULTS: High XIAP expression was observed in 30 (33%) of 90 CCC cases, and was associated with c-Met (<0.01) and Bcl-XL (<0.01) expression. Cases with high XIAP expression had lower response rate to primary platinum-based chemotherapy (10% vs 65%, P=0.02). In stages II-IV tumours, high XIAP expression was related with worse progression-free survival (PFS, P=0.02). Furthermore, high XIAP expression was identified as an independent worse prognostic factor for PFS and overall survival. Finally, downregulation of XIAP using XIAP-specific small interfering RNA increased sensitivity to cisplatin in human cancer cells derived from CCC. CONCLUSIONS: X-chromosome-linked inhibitor of apoptosis expression was correlated with chemoresistance of primary chemotherapy, and identified as a prognostic marker for CCC. X-chromosome-linked inhibitor of apoptosis could be a candidate for new therapeutic target in CCC.

Looking at the formulation of national biosecurity education action plans.

In order for states to be assured of their compliance with the requirements of the Biological and Toxin Weapons Convention, it is necessary that all those science and policy stakeholders working within that state should be aware of their responsibilities under the Convention. This can only be achieved through a comprehensive national biosecurity education programme. We propose that each state should produce a national biosecurity action plan, with accompanying resources and materials to achieve this. A number of resources are already available online to support states in this challenge. We present a model for a national biosecurity action plan and propose a number of ways in which this may be achieved.

Identification of ABCG2 dysfunction as a major factor contributing to gout.

The ATP-binding cassette, subfamily G, member 2 gene ABCG2/BCRP locates in a gout-susceptibility locus (MIM 138900) on chromosome 4q. Recent genome-wide association studies also showed that the ABCG2 gene relates to serum uric acid levels and gout. Since ABCG2 is also known as a transporter of nucleotide analogs that are structurally similar to urate, and is an exporter that has common polymorphic reduced functionality variants, ABCG2 could be a urate secretion transporter and a gene causing gout. To find candidate mutations in ABCG2, we performed a mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia and found six non-synonymous mutations. Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those who had dysfunctional ABCG2 had an increased risk of gout, and that a remarkable risk was observed in those with ≤1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 × 10(-21)). In 2,150 Japanese individuals, the frequency of those with dysfunctional ABCG2 was more than 50%. Our function-based clinicogenetic analysis identified the combinations of dysfunctional variants of ABCG2 as a major contributing factor in Japanese patients with gout.

Pathogenic GLUT9 mutations causing renal hypouricemia type 2 (RHUC2).

Renal hypouricemia (MIM 220150) is an inherited disorder characterized by low serum uric acid levels and has severe complications such as exercise-induced acute renal failure and urolithiasis. We have previously reported that URAT1/SLC22A12 encodes a renal urate-anion exchanger and that its mutations cause renal hypouricemia type 1 (RHUC1). With the large health-examination database of the Japan Maritime Self-Defense Force, we found two missense mutations (R198C and R380W) of GLUT9/SLC2A9 in hypouricemia patients. R198C and R380W occur in highly conserved amino acid motifs in the "sugar transport proteins signatures" that are observed in GLUT family transporters. The corresponding mutations in GLUT1 (R153C and R333W) are known to cause GLUT1 deficiency syndrome because arginine residues in this motif are reportedly important as the determinants of the membrane topology of human GLUT1. Therefore, on the basis of membrane topology, the same may be true of GLUT9. GLUT9 mutants showed markedly reduced urate transport in oocyte expression studies, which would be the result of the loss of positive charges in those conserved amino acid motifs. Together with previous reports on GLUT9 localization, our findings suggest that these GLUT9 mutations cause renal hypouricemia type 2 (RHUC2) by their decreased urate reabsorption on both sides of the renal proximal tubule cells. However, a previously reported GLUT9 mutation, P412R, was unlikely to be pathogenic. These findings also enable us to propose a physiological model of the renal urate reabsorption via GLUT9 and URAT1 and can lead to a promising therapeutic target for gout and related cardiovascular diseases.

Mice deficient in Vbeta8+NKT cells are resistant to experimental hepatitis but are partially susceptible to generalised Shwartzman reaction.

NKT cells are responsible for hepatitis induced either by concanavalin A (Con-A) or alpha-galactosylceramide (alpha-GalCer), and they are also profoundly involved in the generalised Shwartzman reaction (GSR) induced by consecutive injections of interleukin (IL)-12 and lipopolysaccharide (LPS). In the present study, using NC/Nga (NC) mice and SJL mice lacking the Vbeta(+)8 gene, we examined the role of Vbeta(+)8+NKT cells in hepatitis models and in the GSR. The absence of Vbeta(+)8+NKT cells in the liver mononuclear cells (MNC) was confirmed by the alpha-GalCer/CD1d/Ig dimer. Unexpectedly, other dimer+NKT cells including Vbeta7(+)NKT cells in these mice were found to decrease in comparison to that of C57BL/6 mice. No significant hepatocyte injury was observed after alpha-GalCer or Con-A administration in either mice. The serum interferon (IFN)-gamma, IL-4 and tumour necrosis factor (TNF) levels did not increase in these mice after alpha-GalCer injection, however these cytokines substantially increased after Con-A administration, thus suggesting that the roles of NKT cells differ between the two hepatitis models. However, in GSR, although neither mice showed lower IFN-gamma levels after a priming IL-12 injection, they showed TNF levels comparable to those in normal mice after LPS injection, and thus resulted in a decreased but substantial mortality. Although liver MNC from IL-12-injected SJL mice showed an impaired antitumour cytotoxicity, liver MNC of NC mice exhibited a greater antitumour cytotoxicity than that of C57BL/6 mice because liver NK cells proportionally increased in NC mice. These results confirm the critical role that Vbeta8(+)NKT cells play in both liver and multi-organ injury.

Induction of CD16+ CD56bright NK cells with antitumour cytotoxicity not only from CD16- CD56bright NK Cells but also from CD16- CD56dim NK cells.

The aim of this study was to examine the effect of cytokines on different subsets of NK cells, while especially focusing on CD16(-) CD56(dim) cells and CD16(-) CD56(bright) cells. When human peripheral blood mononuclear cells (PBMC) were cultured with a combination of IL-2, IL-12 and IL-15 for several days, a minor population of CD56(bright) NK cells expanded up to 15%, and also showed potent cytotoxicities against various cancer cells. Sorting experiments revealed that unconventional CD16(-) CD56(+) NK cells (CD16(-) CD56(dim) NK cells and CD16(-) CD56(bright) NK cells, both of which are less than 1% in PBMC) much more vigorously proliferated after cytokine stimulation, whereas predominant CD16(+) CD56(dim) NK cells proliferated poorly. In addition, many of the resting CD16(-) CD56(bright) NK cells developed into CD16(+) CD56(bright) NK cells, and CD16(-) CD56(dim) NK cells developed into CD16(-) CD56(bright) NK cells and also further into CD16(+) CD56(bright) NK cells by the cytokines. CSFE label experiments further substantiated the proliferation capacity of each subset and the developmental process of CD16(+) CD56(bright) NK cells. Both CD16(-) CD56(dim) NK cells and CD16(-) CD56(bright) NK cells produced large amounts of IFN-gamma and Fas-ligands. The CD16(+) CD56(bright) NK cells showed strong cytotoxicities against not only MHC class I (-) but also MHC class I (+) tumours regardless of their expression of CD94/NKG2A presumably because they expressed NKG2D as well as natural cytotoxicity receptors. The proliferation of CD16(+) CD56(bright) NK cells was also induced when PBMC were stimulated with penicillin-treated Streptococcus pyogenes, thus suggesting their role in tumour immunity and bacterial infections.

Multiple interleukin-18 injections promote both mouse Th1 and Th2 responses after sublethal Escherichia coli infection.

Interleukin (IL)-18 is considered to induce exclusively the Th1 immune response but not the Th2 response in the presence of adequate IL-12 stimulation in bacterial infections. However, we demonstrate herein that multiple IL-18 injections to the mice not only enhance the early Th1 response but also stimulate the Th2 response later after viable Escherichia coli infection. Multiple IL-18 injections (three alternate-day injections) raised the serum interferon (IFN)-gamma level at 6 h and serum Th2 cytokine levels, such as IL-4, IL-10 and IL-13, at 48 h after infection, while a single IL-18 injection increased only the serum IFN-gamma level. Depletion of mouse CD4+ cells suppressed the IL-18-induced Th2 cytokines, IL-4, IL-10 and IL-13. In contrast, depletion of natural killer (NK)1.1+ cells reduced the IFN-gamma and IL-13 levels. Moreover, multiple IL-18 injections up-regulated the serum IgM level at 72 h after infection while a single IL-18 injection did not. Interestingly, neutralization of IL-4 but not IFN-gamma partially suppressed the increased serum IgM. Liver mononuclear cells (MNCs) from the mice treated with multiple IL-18 injections significantly increased more production of not only IFN-gamma but also Th2 cytokines and IgM by in vitro lipopolysaccharide (LPS) stimulation than those from the phosphate-buffered saline (PBS)-treated mice, while liver MNCs from the single IL-18-injected mice also increased IFN-gamma production but significantly suppressed IL-4 and IgM production compared to those from the PBS-treated mice. Our findings suggest that multiple injections of IL-18 up-regulate both the cellular and humoral innate immunities, thereby enhancing host defence against bacterial infections.

A defective Th1 response of the spleen in the initial phase may explain why splenectomy helps prevent a Listeria infection.

Listeria monocytogenes (Listeria) are known to grow and proliferate in the liver while a splenectomy induces host resistance against a Listeria infection despite the fact that a splenectomy inhibits the Th1 response. Therefore, the mechanism by which a splenectomy helps to prevent the growth of Listeria still remains to be elucidated. After an i.v. challenge of Listeria (1 x 10(6) CFU) in C57BL/6 mice, Listeria rapidly increased in the spleen but not in the liver until 48 h. However, after this initial phase, Listeria remarkably grew in the liver. In contrast, when the mice received a splenectomy beforehand, no remarkable growth of Listeria in the liver was observed after Listeria challenge despite the fact that serum IFN-gamma and IL-12 levels at 24 h after Listeria challenge were significantly lower than those in the sham mice. However, the liver leucocytes from mice by 6 h after infection produced a substantial amount of IFN-gamma while spleen MNC did not, whereas spleen leucocytes at 24 h after Listeria challenge did. Consistently, the IFN-gamma and IL-12 levels in the tissue homogenates of the spleen were significantly lower than in those of the liver until 6 h after infection. This defective spleen Th1 response in the early phase of Listeria infection was corrected by an IL-18 i.p. injection just after the Listeria challenge. Our findings suggest that Listeria exploit the defective Th1 environment of the spleen in the initial phase and afterwards overcome the host defense mechanism of the liver.

Analysis of the susceptibility of CD57 T cells to CD3-mediated apoptosis.

After stimulation with anti-CD3 antibody in vitro, CD57(+) T cells showed a greater susceptibility to apoptosis than CD57(-)alphabetaT cell receptor (TCR)(+) T cells (regular alphabeta T cells). The apoptotic fraction of CD57(+) T cells showed an increased production of active caspase-3. An increase in both Fas expression and Fas-ligand (FasL) production was also observed in CD57(+) T cells, whereas the expression of survivin was suppressed in CD57(+) T cells compared to that of regular alphabeta T cells. CD57(+) T cells display a biased expansion of a few Vbeta T cell fractions in individuals, but such Vbeta T cells were not specifically susceptible to CD3-mediated apoptosis. The TCR expression level of CD57(+) T cells was much lower than that of regular T cells and anti-TCR antibody stimulation induced a smaller apoptotic proportion of CD57(+) T cells than did anti-CD3 antibody. Although the CD3epsilon expression levels were similar in both T cell subsets, the CD3zeta level of CD57(+) T cells was significantly higher than that of regular T cells. These results suggest that several apoptotic and anti-apoptotic molecules are involved in the CD3-induced apoptosis of CD57(+) T cells and raise the possibility that the imbalance in expression of the CD3epsilon and CD3zeta chains may also contribute to the susceptibility of CD57(+) T cells to undergo apoptosis.

Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study.

BACKGROUND: The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs. METHODS: LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased. RESULTS: The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs. CONCLUSIONS: These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.

Telomerase activity and expression of human telomerase RNA component and human telomerase reverse transcriptase in lung carcinomas.

The aim of this study was to evaluate the usefulness of determination of telomerase activity and expression of human telomerase RNA component (hTERC) and human telomerase reverse transcriptase (hTERT) for the diagnosis of lung carcinomas. The tissues studied consisted of 115 carcinomas and adjacent nonneoplastic lung, which were removed surgically without previous chemotherapy or radiotherapy. Telomerase activity was determined using a semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) assay. The results obtained were classified into high and low telomerase groups. Localization of expression was examined by using in situ hybridization and immunohistochemistry. The correlation between telomerase activity in lung carcinoma and clinicopathologic features, including prognosis, was investigated. Telomerase activity in lung carcinomas was detected in 107 of 115 (93%) lung carcinomas, but not in any adjacent noncancerous tissues, and was significantly higher in small cell carcinoma than in any other histologic type. This activity also was significantly higher in poorly differentiated than in well-differentiated squamous cell carcinomas and adenocarcinomas. The overall survival rate (P =.020) was significantly lower in the high telomerase group. Messenger RNAs for hTERC and hTERT were mainly detected in the cytoplasm of cancer cells by in situ hybridization, and TERT protein was localized in the nuclei of these cells by immunohistochemical staining. Determinations of telomerase activity by in situ hybridization, immunohistochemistry, and TRAP assay are useful for evaluating the diagnosis and prognosis of lung carcinomas.

Maternal germinal mosaicism of X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by abnormalities in tyrosine kinase (BTK), and is characterized by a deficiency of peripheral blood B cells. We studied cytoplasmic expression of BTK protein and analyzed the BTK gene (BTK) in peripheral blood mononuclear cells from two siblings with XLA and additional family members. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient with XLA. A single base deletion (C563) in BTK-exon 6, which encodes the TH domain, was identified in both XLA patients. However, normal cytoplasmic expression of BTK protein in monocytes was detected in their mother without any BTK mutation. These results strongly suggest germinal mosaicism in the mother.

Telomerase activation and MAPK pathways in regenerating hepatocytes.

Although there have been many reports on the relationship between the activation of telomerase and carcinogenesis, the role of telomerase in normal cellular growth is still unclear. Recently, the telomerase upregulation during the process of liver regeneration has been reported, but the precise time course of its activity and factors contributing to the activation of telomerase have not yet been fully elucidated. In the present review, we demonstrate the relationship between the activation of the telomerase, the cell cycle progression and the growth-related signaling during the liver regeneration process using an in vivo mouse partial hepatectomy model. Moreover, the importance of the role of the MAPK pathways on the telomerase activity in regenerating hepatocytes is also displayed by using an in vitro culture model. In conclusion, the telomerase activity is upregulated before hepatocytes enter the S phase, and some growth factors such as EGF and HGF contribute to this process. The activation of the growth-related signaling pathways seems to play essential roles in the upregulation of the telomerase activity.

New concepts in radiation-induced apoptosis: 'premitotic apoptosis' and 'postmitotic apoptosis'.

Formerly, the mechanisms responsible for the killing of cells by ionizing radiation were regarded as being divided into two distinct forms, interphase death and reproductive death. Since they were defined based on the classical radiobiological concepts using a clonogenic cell survival assay, biochemical and molecular biological mechanisms involved in the induction of radiation-induced cell death were not fully understood in relation to the modes of cell death. Recent multidisciplinary approaches to cell death mechanism have revealed that radiation-induced cell death is divided into several distinct pathways by the time course and cell-cycle position, and that apoptotic cell death plays a key role in almost every mode of cell death. This review discusses the mechanisms of radiation-induced apoptosis in relation to cell-cycle progression and highlights a new concept of the mode of cell death: 'premitotic apoptosis' and 'postmitotic apoptosis'. The former is a rapid apoptotic cell death associated with a prompt activation of caspase-3, a key enzyme of intracellular signaling of apoptosis. A rapid execution of cell killing in premitotic apoptosis is presumably due to the prompt activation of a set of pre-existed molecules following DNA damages. In contrast, the latter is a delayed apoptotic cell death after cell division, and unlike premitotic apoptosis, it neither requires a rapid activation of caspase-3 nor is inhibited by a specific inhibitor, Ac-DEVD-CHO. A downregulation of anti-apoptotic genes such as MAPK and Bcl-2 may play a key role in this mode of cell death. Characterization of these two types of apoptotic cell death regarding the cell cycle regulation and intracellular signaling will greatly help to understand the mechanisms of radiation-induced apoptosis.

Urokinase type plasminogen activator and its receptor regulate the invasive potential of gastric cancer cell lines.

To assess the role of urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) on the invasive potential of cancer cells, in vitro experiments were performed using two human gastric cancer cell lines, NUGC-3 and MKN-28. NUGC-3 cells secreted a higher level of uPA than MKN-28 cells, while the uPAR expression of NUGC-3 cells was lower than that of MKN-28 cells. Both cancer cell lines expressed Met protein and did not express hepatocyte growth factor (HGF). In Matrigel invasion assay, MKN-28 cells demonstrated significantly lower invasion index than NUGC-3 cells. The addition of exogenous uPA significantly increased the invasive activity of MKN-28 cells. The uPA expression in NUGC-3 cells was enhanced by adding conditioned media of fibroblast cells or HGF. These results suggest that uPA promotes the invasive capacity of the uPAR-positive cancer cells, and that stromal cells may play an important role in cancer cell invasion by supplying uPA and/or promoting uPA production.