Association between information provision and decisional conflict in cancer patients.

BACKGROUND: In this study, we aimed to identify demographic and clinical variables that correlate with perceived information provision among cancer patients and determine the association of information provision with decisional conflict (DC). PATIENTS AND METHODS: We enrolled a total of 625 patients with cancer from two Korean hospitals in 2012. We used the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-INFO26) to assess patients' perception of the information received from their doctors and the Decisional Conflict Scale (DCS) to assess DC. To identify predictive sociodemographic and clinical variables for adequate information provision, backward selective logistic regression analyses were conducted. In addition, adjusted multivariate logistic regression analyses were carried out to identify clinically meaningful differences of perceived level of information subscales associated with high DC. RESULTS: More than half of patients with cancer showed insufficient satisfaction with medical information about disease (56%), treatment (73%), other services (83%), and global score (80%). In multiple logistic regression analyses, lower income and education, female, unmarried status, type of cancer with good prognosis, and early stage of treatment process were associated with patients' perception of inadequate information provision. In addition, Information about the medical tests with high DCS values clarity [adjusted odds ratio (aOR), 0.54; 95% confidence interval (CI) 0.30-0.97] and support (aOR, 0.53; 95% CI 0.33-0.85) showed negative significance. For inadequate information perception about treatments and other services, all 5 DCS scales (uncertainty, informed, values clarity, support, and effective decision) were negatively related. Global score of inadequate information provision also showed negative association with high DCS effective decision (aOR, 0.43; 95% CI 0.26-0.71) and DCS uncertainty (aOR, 0.46; 95% CI 0.27-0.77). CONCLUSION: This study found that inadequate levels of perceived information correlated with several demographic and clinical characteristics. In addition, sufficient perceived information levels may be related to low levels of DC.

Spontaneous resolution of post-transplant localized cytomegalovirus lymphadenitis mimicking tumor recurrence.

Compromised T-cell immunity persists for up to 1 year after autologous stem cell transplantation (ASCT), and patients treated with ASCT are more likely to develop atypical lymphoid hyperplasia that mimics tumor recurrence. Here, we present a case of cervical lymphadenitis due to cytomegalovirus (CMV) reactivation in a patient who had undergone ASCT for Burkitt lymphoma, which mimicked tumor recurrence on computed tomography and positron emission tomography-computed tomography 6 months after ASCT. This lesion was confined to the regional lymph nodes and was not accompanied by signs of systemic involvement, such as fever, splenomegaly, an elevated C-reactive protein level, or viremia. The localized CMV lymphadenitis resolved spontaneously without treatment after 6 months (12 months after ASCT) and the elevated CMV immunoglobulin-M titer normalized 6 months after resolution. Our experience with this case suggests that cautious follow-up without anti-CMV treatment should be considered in cases of post-ASCT localized CMV lymphadenitis without systemic involvement in patients with complete engraftment.

Isolated schwannoma attached to the paratenon of semitendinosus muscle.

Schwannomas are benign tumors arising from the peripheral nerves with a Schwann cell sheath. Schwannomas can be found in almost every region, but are usually associated with cranial, spinal, sympathetic and peripheral nerves. Schwannoma in lower extremity is relatively common and most are associated with sciatic nerve, peroneal nerve and tibial nerve. However, schwannoma arising in the tendon or paratenon is extremely rare. We report a rare case of a 25-year-old male patient with a schwannoma originating from the paratenon of semitendinosus muscle without evidences of any neurologic symptoms. The clinical history, plain radiographs, magnetic resonance imaging, and pathologic findings of the reported patient have been reviewed. The tumor was fully excised by dissecting a tendon sheath of semitendinosus muscle.

Monitoring differentiated thyroid cancer patients with negative serum thyroglobulin. Diagnostic implication of TSH-stimulated antithyroglobulin antibody.

AIM: Serum antithyroglobulin antibody (TgAb) has been reported as a surrogate marker for differentiated thyroid cancer (DTC) in some conditions. We investigated changes in serum TgAb levels after stimulation with thyroid-stimulating hormone (TSH) and the clinical implications for monitoring DTC. PATIENTS, METHODS: We retrospectively enrolled 53 DTC patients who had undergone total thyroidectomy and were negative for serum Tg and positive for TgAb. Patients underwent high-dose radioactive iodine treatment, and serum TgAb was measured before (TgAbBAS) and after TSH stimulation (TgAbSTIM). TgAb was followed up 6 to 12 months later (TgAbF/U). The change in TgAb after TSH stimulation (∆TgAbSTIM) was calculated as a percentage of the baseline level. Patient disease status was classified into no residual disease (ND) and residual or recurred disease (RD) by follow-up imaging studies and pathologic data. The characteristics and diagnostic value of serum TgAb levels and ∆ TgAbSTIM were investigated with respect to disease status. RESULTS: 38 patients were in the ND group and 15 were in the RD group. TgAbBAS, TgAbSTIM and TgAbF/U were significantly higher in the RD compared to the ND group (p = 0.0008, 0.0002, and < 0.0001, respectively). ∆TgAbSTIM was also significantly higher in the RD group (p = 0.0009). In the patients who presented with obviously high (≥ 50%) or low (< -50%) ∆ TgAbSTIM, the proportions in the RD group were markedly different at 100% and 7%, respectively. ∆ TgAbSTIM had significant diagnostic value for RD (p < 0.001). CONCLUSION: The change in serum TgAb level after TSH stimulation is different between the RD and ND groups, and thus, it may be used as a surrogate diagnostic marker for DTC when the serum Tg is negative and TgAb is positive.

Transcriptional regulation of MDR-1 by HOXC6 in multidrug-resistant cells.

Resistance to chemotherapeutic drugs is a significant clinical problem in the treatment of cancer and this resistance has been linked to the cellular expression of multidrug-efflux transporters. The aim of this study was to explore the role of HOXC6 in the regulation of multidrug resistance (MDR) to chemotherapeutic drugs. The HOXC6 gene was identified as being overexpressed in drug-resistant cells compared with parental cell lines. Transfection assays demonstrated that HOXC6 activated MDR-1 promoter activity. A series of MDR-1 promoter deletion mutants was examined and the minimal HOXC6-responsive region was identified to be in the TAAT motif (-2243 bp) of the MDR-1 promoter. Interestingly, overexpression of HOXC6 in the parental cell lines resulted in the upregulation of MDR-1 expression. The inhibition of HOXC6 using small interfering RNA led to the repression of MDR-1. We determined that knockdown of HOXC6 expression in MDR cells increased their sensitivity to paclitaxel. Flow cytometry analysis suggested that siHOXC6 could induce paclitaxel-induced apoptosis and that this was accompanied by an increased accumulation and a decreased release of paclitaxel. Taken together, our findings suggest that HOXC6 expression is an important mechanism of chemotherapeutic drug resistance via its regulation of MDR-1.

Uncertainty studies of topographical measurements on steel surface corrosion by 3D scanning electron microscopy.

Pitting corrosion is a damage mechanism quite serious and dangerous in both carbon steel boiler tubes for power plants which are vital to most industries and stainless steels for orthopedic human implants whose demand, due to the increase of life expectation and rate of traffic accidents, has sharply increased. Reliable methods to characterize this kind of damage are becoming increasingly necessary, when trying to evaluate the advance of damage and to establish the best procedures for component inspection in order to determine remaining lives and failure mitigation. A study about the uncertainties on the topographies of corrosion pits from 3D SEM images, obtained at low magnifications (where errors are greater) and different stage tilt angles were carried out using an in-house software previously developed. Additionally, measurements of pit depths on biomaterial surfaces, subjected to two different surface treatments on stainless steels, were carried out. The different depth distributions observed were in agreement with electrochemical measurements.

Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells.

Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1(-/-) mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1(+/+) MEFs, whereas CDK10 protein was downregulated in the rescued Pin1(-/-) MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and Tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.

Ginsenoside Rd enhances glutathione levels in H4IIE cells via NF-kappaB-dependent gamma-glutamylcysteine ligase induction.

Panax ginseng is widely used as herbal medicine in East Asia and the pharmacological effects of P. ginseng against certain chronic diseases might be explained by its antioxidative effects. Here, we show that ginsenoside Rd significantly increases both cellular glutathione (GSH) contents and the protein level of gamma-glutamylcysteine ligase (gamma-GCL) heavy chain in H4IIE cells (a rat hepatocyte cell line). Subcellular fractionation and Western blot analysis revealed that ginsenoside Rd increased the nuclear level of p65, but not of Nrf2. Moreover, ginsenoside Rd increased luciferase reporter gene activity in cells transfected with nuclear factor-kappaB (NF-kappaB) binding site-containing -1088 bp gamma-GCL promoter. However, ginsenoside Rd-inducible reporter activity was abolished when cells were transfected with NF-kappaB deletion mutant. These effectsof ginsenoside Rd are suggested to underlie the putative anti-oxidative effect of Panax ginseng.

Screening of new chemopreventive compounds from Digitalis purpurea.

Chemopreventive agents induce a battery of genes whose protein products can protect cells from chemical-induced carcinogenesis. In this study, we isolated four different glycosides (1 acteoside; 2 purpureaside A; 3 calceolarioside B; and 4, plantainoside D) from the leaves of Digitalis purpurea and studied their abilities to induce glutathione S-transferase (GST) and their protective efficiencies against aflatoxin B1-induced cytotoxicity in H4IIE cells. Of these four glycosides, acteoside significantly inhibited the cytotoxicity induced by aflatoxin B1 (AFB1) and also selectively increased GSTalpha protein levels. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays, revealed that GSTalpha induction by acteoside might be associated with Nrf2/ARE activation. The results suggest that acteoside possesses a potent hepatoprotective effect against AFB1 and that it can be applied as a potential chemopreventive agent.

Mandibular symphyseal distraction osteogenesis with stepwise osteotomy in adult skeletal class III patient.

This technical note reports the use of symphyseal distraction with stepwise osteotomy in a case of lower anterior crowding and rotation in the incisor area. This technique allows for easy dental decompensation and reduced presurgical orthodontic time in skeletal class III cases.

Amentoflavone inhibits the induction of nitric oxide synthase by inhibiting NF-kappaB activation in macrophages.

Amentoflavone is a bi-flavonoid compound with anti-fungal and anti-inflammatory activities. We isolated amentoflavone from Selaginella tamariscina (Selaginellaceae) and studied its effects on nuclear factor-kappaB (NF-kappaB)-mediated inducible nitric oxide synthase (iNOS) gene expression in RAW 264.7 cells. Amentoflavone inhibited the production of nitric oxide in a concentration-dependent manner and also blocked the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS). To clarify the mechanistic basis for its inhibition of iNOS induction, we examined the effect of amentoflavone on the transactivation of iNOS gene by luciferase reporter activity using -1.59 kb flanking region. Amentoflavone potently suppressed the reporter gene activity. The LPS-induced activation of NF-kappaB was also found to be significantly blocked by amentoflavone, but AP-1 activation was unaffected. Furthermore, the nuclear translocation of p65 by LPS was inhibited by amentoflavone. NF-kappaB activation is controlled by the phosphorylation and subsequent degradation of I-kappaBalpha, and the cytosolic degradation of I-kappaBalpha was found to be inhibited by amentoflavone. These findings suggest that the inhibition of LPS-induced NO formation by amentoflavone is due to its inhibition of NF-kappaB by blocking I-kappaBalpha degradation, which may be the mechanistic basis of the anti-inflammatory effects of amentoflavone.

Potentiation of cadmium-induced cytotoxicity by sulfur amino acid deprivation through activation of extracellular signal-regulated kinase1/2 (ERK1/2) in conjunction with p38 kinase or c-jun N-terminal kinase (JNK). Complete inhibition of the potentiated toxicity by U0126 an ERK1/2 and p38 kinase inhibitor.

The mechanisms of cadmium-induced toxicity may include oxidative stress, altered redox homeostasis, and injuries to organelles. The current study was designed to study the effect of decreased cellular glutathione (GSH) content by sulfur amino acid deprivation on cadmium toxicity and to identify the signaling pathways responsible for the cytotoxicity. GSH content was increased by cadmium in H4IIE cells prior to cell death, which was prevented by excess GSH or cysteine. Cell viability, however, was not improved by GSH or cysteine complexation of cadmium. Cadmium-induced cytotoxicity was 40-fold potentiated in cells with decreased GSH by sulfur amino acid deprivation. Cadmium in combination with decreased GSH markedly increased apoptotic cell death. Mitogen-activated protein kinases including extracellular signal-regulated kinase 1/2, p38 kinase and c-Jun N-terminal kinase (JNK) were all activated 1-12 hr after sulfur amino acid deprivation. U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), which inhibited activation of extracellular signal-regulated kinase1/2 and p38 kinase in cells under sulfur amino acid deprivation, completely prevented potentiation in Cd-induced cytotoxicity and apoptosis. Potentiation of cadmium toxicity by sulfur amino acid deprivation was prevented in part by either PD98059 or SB203580, or in cells stably expressing dominant negative mutant of JNK1, and to greater extents by PD98059 in combination with either SB203580 or JNK1(-) transfection. These results demonstrated that decreased cellular GSH content potentiated cytotoxicity induced by cadmium at the level of human exposure, and that the potentiation of cytotoxicity resulted from activation of extracellular signal-regulated kinase1/2 in conjunction with p38 kinase or JNK.

2-(Allylthio)pyrazine, a cancer chemopreventive agent, inhibits liver fibrosis induced by dimethylnitrosamine in rats: role of inhibition of transforming growth factor-beta1 expression.

Exposure to nitrosamines may be the occupational risk factor for liver cirrhosis. 2-(Allylthio)pyrazine, a chemopreventive agent, inhibits CYP2E1 and induces phase II enzymes. We examined the effects of 2-(allylthio)pyrazine on hepatic fibrosis, a prepathologic state of cirrhosis, and on the expression of transforming growth factor-beta1 induced by dimethylnitrosamine. Treatment of rats with dimethylnitrosamine for 4 weeks increased plasma alanine/aspartate amino-transferase and y-glutamyl transpeptidase activities, and bilirubin content, whereas the total plasma protein and albumin levels were decreased. 2-(Allylthio)pyrazine inhibited dimethylnitrosamine-induced increases in the enzyme activities and bilirubin, and restored the plasma protein and albumin contents. Masson's trichrome staining showed that dimethylnitrosamine induced liver fibrosis, the extent of which was reduced by 2-(allylthio)pyrazine treatments. Reverse transcription-polymerase chain reaction analysis revealed that 2-(allylthio)pyrazine inhibited production of transforming growth factor-beta1 mRNA by dimethylnitrosamine. These results demonstrated that 2-(allylthio)pyrazine might inhibit dimethylnitrosamine-induced liver fibrosis due to suppression of CYP2E1 expression and transforming growth factor-beta1 production.

DA-125, a novel anthracycline derivative showing high-affinity DNA binding and topoisomerase II inhibitory activities, exerts cytotoxicity via c-Jun N-terminal kinase pathway.

PURPOSE: DA-125 [(8S,10S)-8-(3-Aminopropanoyloxyacetyl)-10-[(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacene-dione hydrochloride] is a novel anthracycline derivative with anticancer activity. In the present study, we compared the cytotoxicity of DA-125 with that of doxorubicin in H4IIE rat hepatoma cells and investigated the mechanistic basis. Because activation of MAP kinases, in particular c-Jun N-terminal kinase (JNK), is implicated in apoptotic cell death, the signaling pathways responsible for DA-125-induced apoptosis were studied. METHODS: Cytotoxicity and apoptosis were measured in H4IIE cells and cells were stably transfected with a dominant-negative mutant of JNK1 (JNK1-) by MTT and TUNEL assays. Inhibition of topoisomerase II activity was determined in vitro. Drug accumulation and DNA binding affinity were determined by fluorescence spectroscopy. RESULTS: The cytotoxicity of DA-125 was greater than that of doxorubicin (IC50 11.5 vs 70 microM). DA-125 induced apoptosis with 30-fold greater potency than doxorubicin. Inhibition of topoisomerase II by DA-125 was fourfold greater. The presence of excess beta-alanine, a DA-125 moiety, failed to alter cytotoxicity and accumulation of DA-125, indicating that the improved cytotoxicity of DA-125 did not result from the beta-alanine moiety. Greater cellular accumulation of DA-125 correlated with its high-affinity DNA binding. Although neither PD98059 nor SB203580 altered the degree of cytotoxicity induced by DA-125, JNK1 cells exhibited about a twofold greater viability than control cells. DA-125-induced apoptosis was also decreased in JNK1- -transfected cells. CONCLUSIONS: DA-125 potently inhibited topoisomerase II activity and induced apoptosis by a high rate of prooxidant production. DA-125 exhibited high-affinity DNA binding with improved cellular drug accumulation. Apoptosis induced by DA-125 involved the pathway of JNK1, but not ERK1/2 or p38 kinase.

Activation of phosphatidylinositol 3-kinase by oxidative stress leads to the induction of microsomal epoxide hydrolase in H4IIE cells.

We have shown that PI3-kinase played an essential role in the ARE-mediated rGSTA2 induction by oxidative stress following SAAD (Mol. Pharmacol. 58 (2000) 1017). Microsomal epoxide hydrolase (mEH), which detoxifies a variety of epoxide intermediates produced from various xenobiotics, is inducible by oxidative stress. In the present study, we studied whether sulfur amino acid deprivation (SAAD) activated phosphatidylinositol 3-kinase (PI3-kinase)/Akt and induced mEH in H4IIE cells. The role of PI3-kinase activation on the mEH induction by SAAD was also investigated. PI3-kinase was activated from 10 min through 12 h after SAAD, the activity of which returned to control level at 24 h. The activation of PI3-kinase led to increases in the activity of Akt at the same time points. Northern and Western blot analyses revealed that the mEH mRNA level was four-fold increased at 48 h, which accompanied the induction of mEH protein. Wortmannin or LY294002, PI3-kinase inhibitors, completely inhibited the increases in mEH mRNA and protein by SAAD. These results demonstrated that SAAD activated the PI3-kinase/Akt pathway at early stages and induced mEH, presumably as an adaptive response, and that the PI3-kinase/Akt pathway played a crucial role in the induction of mEH.

Potentiation of arsenic-induced cytotoxicity by sulfur amino acid deprivation (SAAD) through activation of ERK1/2, p38 kinase and JNK1: the distinct role of JNK1 in SAAD-potentiated mercury toxicity.

Sulfur amino acid deficiency occurs in certain pathophysiological situations (e.g. protein-calorie malnutrition). Previous studies revealed that sulfur amino acid deprivation (SAAD) activated MAP kinases and potentiated cadmium-induced cytotoxicity by activation of ERK1/2 in conjunction with p38 kinase or JNK. The present study was designed to determine susceptibility of cells to a variety of heavy metals in combination with SAAD. Viability was assessed in H4IIE cells treated with sodium arsenite, mercuric chloride, sodium selenite, lead acetate, chromium trioxide or manganese chloride. SAAD potentiated the cytotoxicity of H4IIE cells by arsenic or mercury (i.e. EC50, 19 and 5 microM in SAAD vs. 401 and 42 microM in control medium, respectively). TUNEL assays revealed that the potentiated arsenic or mercury toxicity involved apoptotic cell death. Lead or selenite moderately elicited cell death, which was not enhanced by SAAD. Chromium or manganese caused no significant cytotoxicity. Treatment of cells with U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] an ERK1/2 inhibitor or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] a p38 kinase inhibitor effectively prevented SAAD-potentiated arsenic toxicity. The potentiated arsenic toxicity was also inhibited in cells stably expressing a dominant negative mutant of c-Jun N-terminal kinase 1 [JNK1(-)]. The inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 kinase failed to prevent mercury-induced toxicity enhanced by SAAD. JNK1(-) cells were minimally susceptible to mercury in SAAD medium. These results demonstrated that SAAD potentiated cytotoxicity induced by arsenic or mercury and that activation of ERK1/2, p38 kinase and JNK1 was responsible for the potentiated arsenic toxicity, whereas the mercury toxicity enhanced by SAAD was mediated with the activity of JNK1.

Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.

The protective adaptive response to electrophiles and reactive oxygen species is mediated by enhanced expression of phase II detoxifying genes, including glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of phosphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhydroquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatment of H4IIE cells with t-BHQ. The rGSTA2 mRNA level was elevated 6 to 24 h after t-BHQ treatment, which led to the enzyme induction. Activities of PI3-kinase and Akt were increased 10 min through 6 h after t-BHQ treatment, whereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished ARE binding activity and increases in rGSTA2 mRNA and protein. Extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun N-terminal kinase (JNK) were all activated by t-BHQ. Treatment with PD98059, an ERK inhibitor, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expression of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negative mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstrated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE-mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 expression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.

Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that can activate the c-Jun N-terminal kinase and the p38 signaling pathways. It plays a critical role in cytokine- and stress-induced apoptosis. To further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the yeast two-hybrid method. The yeast two-hybrid assay indicated that mouse glutathione S-transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently confirmed that mGSTM1-1 physically associated with ASK1 both in vivo and in vitro. The in vitro binding assay indicated that the C-terminal portion of mGSTM1-1 and the N-terminal region of ASK1 were crucial for binding one another. Furthermore, mGSTM1-1 suppressed stress-stimulated ASK1 activity in cultured cells. mGSTM1-1 also blocked ASK1 oligomerization. The ASK1 inhibition by mGSTM1-1 occurred independently of the glutathione-conjugating activity of mGSTM1-1. Moreover, mGSTM1-1 repressed ASK1-dependent apoptotic cell death. Taken together, our findings suggest that mGSTM1-1 functions as an endogenous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insofar as mGSTM1-1 may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.

Diagnostic performance of [18F]FDG-PET and ictal [99mTc]-HMPAO SPECT in occipital lobe epilepsy.

PURPOSE: We investigated whether interictal F-18 fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) or ictal [99mTc]-HMPAO single-photon emission computed tomography (SPECT) was useful to find epileptogenic zones in occipital lobe epilepsy (OLE). METHODS: We reviewed visually and quantified patterns of hypometabolism in interictal [18F]FDG-PET and those of hyperperfusion in ictal SPECT in 17 OLE patients (27 plus minus 6.8 years old; M/F, 10/7; injection time, 30 plus minus 17 s). OLE was diagnosed based on invasive electroencephalography, surgery, and postsurgical outcome (Engel class I in all at an average of 26 months after surgery). RESULTS: Epileptogenic zones were correctly localized in nine (60%) of 15 patients by interictal [18F]FDG-PET, and asymmetric indices corroborated visual diagnosis. Epileptogenic hemispheres were correctly lateralized in 14 (93%) of 15 patients on [18F]FDG-PET. Epileptogenic hemispheres were correctly lateralized in 13 (76%) of 17 patients using ictal SPECT, but localization was possible in only five (29%) patients. Interictal [18F]FDG-PET was helpful in two of the patients who showed no abnormality on magnetic resonance imaging (MRI) and no possible localization with ictal SPECT. CONCLUSIONS: In OLE, ictal SPECT was helpful in lateralization, but less helpful in localization. Interictal [18F]FDG-PET was helpful in localization or lateralization of epileptogenic zones, even in patients with ambiguous MRI or ictal SPECT findings.

The essential role of phosphatidylinositol 3-kinase and of p38 mitogen-activated protein kinase activation in the antioxidant response element-mediated rGSTA2 induction by decreased glutathione in H4IIE hepatoma cells.

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the enhanced expression of the phase II detoxifying genes through antioxidant response elements (AREs). The current study was designed to identify the signaling pathways responsible for the expression of rGSTA2 in response to cellular oxidative stress and to establish the molecular mechanistic basis. Deprivation of cystine and methionine caused oxidative stress in H4IIE hepatoma cells as evidenced by a marked decrease in the reduced glutathione (first order rate constant = 0.056 h(-1); t(1/2) = 12.6 h) and an increase in pro-oxidant production. Electrophoretic mobility shift assay revealed that the ARE complex, consisting of Nrf-1/2 and Maf proteins, was activated 12 to 48 h after sulfur amino acid deprivation (SAAD). The rGSTA2 mRNA level was elevated by SAAD beginning at 24 h, whereas the rGSTA2 subunit was maximally induced at 48 h. Nuclear ARE activation and rGSTA2 mRNA increase were both completely inhibited by wortmannin or LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. The p38 mitogen-activated protein (MAP) kinase was activated at 0.5 to 3 h after SAAD, followed by sustained diminished activation up to 12 h. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The activation of p38 MAP kinase, however, failed to be inhibited by wortmannin or LY294002, showing that PI3-kinase is not involved in the activation of p38 MAP kinase. Data showed that PI3-kinase plays an essential role in the ARE-mediated rGSTA2 induction by oxidative stress after SAAD, which activates the p38 MAP kinase and leads to rGSTA2 induction.