Randomised, double-blind, parallel group comparison of Ashitaba (Angelica Keiskei) chalcone effects on visceral fat areas and waist circumference of overweight persons.

This randomised, placebo-controlled, double-blind, parallel-group study aimed to determine whether encapsulated Ashitaba chalcone (16 mg comprising 10.1 mg 4-hydroxyderricin and 5.9 mg xanthoangelol) could reduce obesity in 17 men and 25 women with a body mass index (BMI) of 25 to < 30. Participants ingested capsules containing either the chalcone or a placebo daily for 12 weeks. The primary endpoint was changes in visceral fat areas determined by computed tomography (CT) at baseline, and at 8 and 12 weeks later. The primary endpoint, abdominal visceral fat area, was significantly reduced in the chalcone, compared with a placebo group 12 weeks after screening (p < 0.05). The secondary endpoint, waist circumference, was significantly decreased in the chalcone, compared with the placebo group at weeks 8 and 12 (p < 0.05 at week 8; p < 0.01 at week 12). Therefore, Ashitaba chalcone has anti-obesity benefits for overweight men and women.

Correlation analysis of heart rate variations and glucose fluctuations during sleep.

OBJECTIVE: The body's glucose concentration is influenced by carbohydrate intake, insulin-induced carbohydrate reduction, and hepatic glycogen breakdown induced by stress hormones. This study investigated the potential of employing glucose fluctuations as a measure of stress by examining the relationship between heart rate variability (HRV) data and glucose levels during sleep in healthy subjects. METHODS: In this cross-sectional study, a chest-worn electrocardiogram (ECG) and continuous glucose monitoring device (CGM) were respectively used to monitor the heart rate intervals and glucose fluctuations of five subjects (two males, three females) during sleep. A time-series correlation analysis was performed on the HRV data extracted from heart rate intervals and the corresponding glucose fluctuation data. RESULTS: The time-series analysis of ECG and CGM data collected from subjects during sleep (n = 25 nights) revealed a moderate negative correlation between glucose levels and HRV, with a cross-correlation coefficient of r = -0.453. CONCLUSION: Similar to HRV, changes in stress levels can be detected by observing glucose fluctuations, particularly during sleep when the impact of food intake can be eliminated. Our findings highlight a significant correlation between glucose levels and HRV, indicating that glucose fluctuations can be used as an indicator of autonomic nervous system activity in an exploratory study.

Effect of pre-operative HbA1c and blood glucose level on the surgical site infection after lumbar instrumentation surgery.

BACKGROUND: This study aims to investigate the effect of pre-operative hemoglobin A1c (HbA1c) and pre-operative blood glucose control on the rate of surgical site infection (SSI) after posterior lumbar instrumentation surgery in diabetes mellitus (DM) patients. METHODS: A total of 1046 patients who had undergone posterior lumbar instrumentation surgery were reviewed. Based on pre-operative HbA1c, patients were divided into three groups: non-DM group, low HbA1c group (HbA1c < 7.0 % in DM) and high HbA1c group (≥7.0). As well, based on the status of blood glucose control in DM patients immediately before surgery, patients were divided into two groups: good control group (post-prandial blood glucose [PBG] < 200 mg/dl) and poor control group (≥200). The rate of SSI was compared among these groups. RESULTS: SSI occurred in 1.9 % in non-DM group, 2.4 % in low HbA1c group, and 9.3 % in high HbA1c group. Compared with non-DM group, high HbA1c group had significantly higher rate of SSI (p = 0.001). There was not statistically different between non-DM and low HbA1c groups (p = 0.550). SSI occurred in 2.2 % in good control group, and 10.2 % in poor control group. The rate of SSI was significantly lower in good control group (p = 0.013). CONCLUSION: This study showed that the rate of SSI after posterior lumbar instrumentation surgery tend to be higher in DM patients with high HbA1c. However, the rate might be reduced to the same level as that of non-DM group by lowering PBG to <200 mg/dl immediately before surgery.

Biogenesis of fibrils requires C-mannosylation of PMEL.

Premelanosome protein (PMEL), a melanocyte-specific glycoprotein, has an essential role in melanosome maturation, assembling amyloid fibrils for melanin deposition. PMEL undergoes several post-translational modifications, including N- and O-glycosylations, which are associated with proper melanosome development. C-mannosylation is a rare type of protein glycosylation at a tryptophan residue that might regulate the secretion and localization of proteins. PMEL has one putative C-mannosylation site in its core amyloid fragment (CAF); however, there is no report focusing on C-mannosylation of PMEL. To investigate this, we expressed recombinant PMEL in SK-MEL-28 human melanoma cells and purified the protein. Mass spectrometry analyses demonstrated that human PMEL is C-mannosylated at multiple tryptophan residues in its CAF and N-terminal fragment (NTF). In addition to the W153 or W156 residue (CAF), which lies in the consensus sequence for C-mannosylation, the W104 residue (NTF) was C-mannosylated without the consensus sequence. To determine the effects of the modifications, we deleted the PMEL gene by using CRISPR/Cas9 technology and re-expressed wild-type or C-mannosylation-defective mutants of PMEL, in which the C-mannosylated tryptophan was replaced with a phenylalanine residue (WF mutation), in SK-MEL-28 cells. Importantly, fibril-containing melanosomes were significantly decreased in W104F mutant PMEL-re-expressing cells compared with wild-type PMEL, observed using transmission electron microscopy. Furthermore, western blot and immunofluorescence analysis suggested that the W104F mutation may cause mild endoplasmic reticulumretention, possibly associated with early misfolding, and lysosomal misaggregation, thus reducing functional fibril formation. Our results demonstrate that C-mannosylation of PMEL is required for proper melanosome development by regulating PMEL-derived fibril formation.

Anti­tumor effects of anti­epileptic drugs in malignant glioma cells.

Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, perampanel, carbamazepine (CBZ), sodium valproate (VPA) and levetiracetam (LEV), which are expected to have antitumor effects, and determined the most beneficial drug for the treatment of malignant glioma by comparing antitumor effects such as inhibition of cell proliferation and suppression of migration and invasion (using Transwell assays). The inhibition of cell growth was investigated using six malignant glioma cell lines (A­172, AM­38, T98G, U­138MG, U­251MG and YH­13). Significant inhibition of cell proliferation was observed in all six cell lines treated with perampanel, three cell lines treated with CBZ, four cell lines treated with VPA and two cell lines treated with LEV at the therapeutic blood concentration levels for the drugs to be used as antiepileptics. Further antitumor effects in combination with temozolomide were investigated using T98G and U­251MG cell lines, and were confirmed in both cell lines with perampanel and in T98G cells with LEV, but not observed with CBZ and VPA. Cell migration was significantly suppressed in both T98G and U­251MG cell lines with perampanel, but not with CBZ, VPA or LEV. To investigate the mechanisms by which perampanel suppresses the migration of malignant glioma cells, the expression of mRNA related to epithelial­mesenchymal transition following perampanel treatment was analyzed using reverse transcription­quantitative PCR in the T98G and U­251MG cell lines. The expression of Rac1 and RhoA, which constitute the cytoskeleton that enhances cell motility, were reduced in both cell lines. Furthermore, the expression of the mesenchymal marker N­cadherin, which promotes cell migration and infiltration, was decreased, but the expression of the epithelial marker E­cadherin, which strengthens cell­cell adhesion and reduces cell motility, was increased. Furthermore, the expression of matrix metalloproteinase­2, a proteolytic enzyme, was reduced. These effects may reduce cell motility and increase adhesion between cells, suggesting that perampanel treatment suppressed cell migration. In conclusion, the present study suggests that perampanel may be more beneficial in terms of antitumor efficacy than other antiepileptic drugs for the treatment of malignant glioma.

Anti-tumor effects of perampanel in malignant glioma cells.

Glioblastoma has a poor prognosis even after multimodal treatment, such as surgery, chemotherapy and radiation therapy. Patients with glioblastoma frequently develop epileptic seizures during the clinical course of the disease and often require antiepileptic drugs. Therefore, agents with both antiepileptic and antitumoral effects may be very useful for glioblastoma treatment. Perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, is an antiepileptic drug that is widely used for intractable epilepsy. The present study aimed to assess the potential antitumoral effects of perampanel using malignant glioma cell lines. The cell proliferation inhibitory effect was evaluated using six malignant glioma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13). A dose-dependent inhibitory effect of perampanel on cell viability was demonstrated; however, the sensitivity of cells to perampanel varied and further antitumoral effects were demonstrated in combination with temozolomide (TMZ) in certain malignant glioma cells. Furthermore, cell cycle distribution and apoptosis induction analyses were performed in T98G and U-251MG cells using a fluorescence activated cell sorter (FACS) and the expression levels of apoptosis-related proteins were evaluated using western blotting. No significant change was demonstrated in the proportions of cells in the G0/G1, S and G2/M phases under 1.0 µM perampanel treatment, whereas induction of apoptosis was demonstrated using FACS at 10 µM perampanel and western blotting at 1.0 µM perampanel in both glioma cell lines. Overexpression of SERPINE1 may be related to poor prognosis in patients with gliomas. The combination of 1.0 µM perampanel and 5.0 µM tiplaxtinin, a SERPINE1 inhibitor, demonstrated further reduced cell viability in perampanel-resistant U-138MG cells, which have high expression levels of SERPINE1. These results indicated that the antitumor effect of perampanel may not be expected for malignant gliomas with higher expression levels of SERPINE1. The findings of the present study suggested that the antiepileptic drug perampanel may also have an antitumor effect through the induction of apoptosis, which is increased when combined with TMZ in certain malignant glioma cells. These findings also suggested that SERPINE1 expression may be involved in perampanel susceptibility. These results may lead to new therapeutic strategies for malignant glioma.

Combination of serum 5-S-cysteinyldopa, melanoma inhibitory activity and IL-8 improves the diagnostic accuracy of malignant melanoma compared with individual markers.

Early diagnosis of malignant melanoma is critical for effective treatment and reduced patient mortality. However, current clinical and histological variables show limited accuracy in diagnosis. Serum or urine level of 5-S-cysteinyldopa (5-S-CD) is a commonly used melanoma biomarker in Japan owing to its increased sensitivity compared with other melanoma markers. However, its use as a diagnostic marker has shown some limitations. Therefore, here we examined the combination of 5-S-CD with melanoma inhibitory activity, which showed sensitivity in detecting melanoma comparable with that of 5-S-CD, and interleukin-8, a cytokine linked with melanoma progression, in a cohort of Japanese patients with melanoma. Our results revealed that the triple combination of 5-S-CD, melanoma inhibitory activity, and interleukin-8 showed high diagnostic accuracy in detecting melanoma compared with each of the individual factors. Importantly, the triple marker showed specificity and utility in detecting early-stage melanoma. Our results suggest the utility of the triple marker as a diagnostic biomarker for melanoma patients.

Five-year outcomes after coronary artery bypass grafting and percutaneous coronary intervention in octogenarians with complex coronary artery disease.

OBJECTIVE: We assessed the clinical effectiveness of coronary artery bypass grafting (CABG) in comparison with that of percutaneous coronary intervention (PCI) in octogenarians with triple-vessel disease (TVD) or left main coronary artery (LMCA) disease. METHODS: From the CREDO-Kyoto registry cohort-2, 527 patients, who were ≥ 80 years of age and underwent the first coronary revascularization for TVD or LMCA disease, were divided into the CABG group (N = 151) and the PCI group (N = 376). RESULTS: The median and interquartile range of patient's age was 82 (81-84) in the CABG group and 83 (81-85) in the PCI group (P = 0.10). Patients > = 85 years of age accounted for 19% and 31% in the CABG and PCI groups, respectively (P = 0.01). The cumulative 5-year incidence of all-cause death was similar between CABG and PCI groups (35.8% vs. 42.9%, log-rank P = 0.18), while CABG showed a lower rate of the composite of cardiac death/MI than PCI (21.7% vs. 33.9%, log-rank P = 0.005). After adjusting for confounders, the lower risk of CABG relative to PCI was significant for all-cause death (HR 0.61, 95% CI 0.43-0.86, P = 0.005), any coronary revascularization (HR 0.25, 95% CI 0.14-0.43, P < 0.001) and the composite of cardiac death/MI (HR 0.52, 95% CI 0.32-0.85, P = 0.009). CONCLUSIONS: CABG compared with PCI was associated with a lower adjusted risk for all-cause death, any coronary revascularization, and a composite of cardiac death/MI in very elderly patients with TVD or LMCA disease. CABG seemed an acceptable option for selected octogenarians with severe coronary artery disease.

Clinical Outcomes and Postoperative Radiographic Assessment of Osteoplastic Hemilaminectomy in the Treatment of Lumbar Foraminal Nerve Root Compression.

INTRODUCTION: Osteoplastic hemilaminectomy for the treatment of lumbar foraminal nerve root compression is a safe technique as the exiting nerve root can be directly observed during neuroforaminal decompression without spinal fusion. Moreover, this procedure allows anatomical reconstruction of the posterior elements. However, there might be a potential risk for the progression of lumbar segmental instability after performing this procedure. This study aimed to review the radiographic and clinical outcomes of osteoplastic hemilaminectomy for the treatment of lumbar foraminal nerve root compression. METHODS: We retrospectively reviewed 51 patients who underwent osteoplastic hemilaminectomy with a minimum follow-up of 2 years. The clinical outcomes were evaluated using the visual analog scale (VAS) for low back pain, leg pain, and numbness and the Japanese Orthopaedic Association (JOA) score. Lumbar segmental instability was evaluated as a radiographic assessment using functional radiography. The mean follow-up period was 65 months. RESULTS: The preoperative VASs for low back pain, leg pain, and numbness were 46±31, 72±26, and 43±34, respectively, which were improved to 24±23, 19±23, and 19±23, respectively. The JOA score was also improved from 14±5 to 22±4. Three patients (5.9%) were reoperated due to recurrent disc herniation within 2 years following surgery. In addition, three patients (5.9%) developed postoperative lumbar segmental instability but did not require additional surgery. CONCLUSIONS: The current study revealed that 94.1% of the patients who underwent osteoplastic hemilaminectomy achieved a significant improvement in the clinical outcomes and did not require additional surgery within 2 years following the procedure. Over a 5-year follow-up on average, 5.9% of the subjects developed postoperative lumbar segmental instability; however, they have maintained acceptable clinical conditions.

Pulmonary vein reconstruction for pulmonary vein stenosis and occlusion after surgical ablation.

Acquired pulmonary vein (PV) stenosis (PVS) is a complication following cardiac catheter intervention. However, very few cases of PVS after surgical ablation have been reported. We herein report a case of stenosis and occlusion at the left atrium to each pulmonary vein after surgical ablation. A 73-year-old woman who had received aortic valve replacement and pulmonary vein isolation 10 months earlier was diagnosed with congestive heart failure accompanied by pulmonary hypertension. Contrast-enhanced computed tomography revealed stenosis and complete occlusion of the left atrium to all four pulmonary veins. Surgical repair was performed via pericardial patch reconstruction of the left atrium to each PV. Treating multiple PV lesions with involvement of the left atrium wall requires tailored methods. However, there have been few reports concerning such methods of reconstruction. We herein report a method of reconstructing the left atrium and pulmonary veins at the same time.

Antitumor effects of ribavirin in combination with TMZ and IFN-ß in malignant glioma cells.

The prognosis of gioblastoma, the standard chemotherapy agent for which is temozolomide (TMZ), remains poor despite recent advances in multimodal treatments. Therefore, it is necessary to identify and develop novel therapeutics for this malignant disease. Ribavirin, an anti-viral agent which is one of the standard agents for treatment of chronic hepatitis C in combination with interferon (IFN), was recently revealed to have an antitumor potential towards various tumor cells, including malignant glioma cells. The aim of the present study was to examine the antitumor effect of ribavirin in combination with TMZ and IFN-ß on glioma cells and to evaluate the possibility that such combinations might represent a novel candidate for glioblastoma therapy. The combination of ribavirin with TMZ and IFN-ß displayed a significant cell growth inhibitory effect with a ribavirin dose-dependency, including a relatively low concentration of ribavirin, on not only TMZ-sensitive but also TMZ-resistant malignant glioma cells. The antitumor efficacy of such a combination further indicated a synergistic interaction when assessed by the Chou-Talalay method. Furthermore, flow cytometry analysis suggested that apoptosis induction was one of the possible biological processes underlying the synergistic antitumor effect of these triple combination treatments. Therefore, such combinations may be potentially important in the clinical setting for glioblastoma treatment, although further detailed studies, e.g. on the adverse effects, are required.

Surgical treatment for a pulmonary artery aneurysm with stenosis of the quadricuspid pulmonary valve.

We report a case of pulmonary artery aneurysm and pulmonary stenosis with a quadricuspid pulmonary valve in a 64-year-old woman. While pulmonary artery disease had been found as a child, she needed no treatment because of the absence of symptoms and her normal physical development. She began experiencing dyspnoea on exertion 3 years ago. Echocardiography showed pulmonary artery aneurysm and severe pulmonary stenosis with a quadricuspid valve. Computed tomography showed a pulmonary artery aneurysm extending from its main trunk to the bilateral branches. The pulmonary valve was replaced, and the pulmonary trunk and its bilateral branch were reconstructed. The patient's postoperative course was uneventful.

Antitumor effect of lenalidomide in malignant glioma cell lines.

Glioblastoma is a malignant brain tumor exhibiting highly aggressive proliferation and invasion capacities. Despite treatment by aggressive surgical resection and adjuvant therapy including temozolomide and radiation therapy, patient prognosis remains poor. Lenalidomide, a derivative of thalidomide, is known to be an immunomodulatory agent that has been used to treat hematopoietic malignancies. There are numerous studies revealing an antitumor effect of lenalidomide in hematopoietic cells, but not in glioma cells. The present study aimed to demonstrate the antitumor effect of lenalidomide on malignant glioma cell lines. The growth inhibition of malignant glioma cells (A­172, AM­38, T98G, U­138MG, U­251MG, and YH­13) by lenalidomide was assessed using a Coulter counter. The mechanism of the antitumor effect of lenalidomide was examined employing a fluorescence­activated cell sorter, western blot analysis, and quantitative real­time reverse transcriptional polymerase chain reaction (RT­qPCR) in malignant glioma cell lines (A­172, AM­38). The results revealed that the number of malignant glioma cells was decreased in a concentration­dependent manner by lenalidomide. DNA flow cytometric analysis demonstrated an increase in the ratio of cells at the G0/G1 phase following lenalidomide treatment. Western blot analysis and RT­qPCR revealed that p53 activation and the expression of p21 were increased in glioma cells treated with lenalidomide. Western blot analysis revealed that cleavage of PARP did not occur; however, increased expression of Bax protein, cleavage of caspase­9 and cleavage of caspase­3 were confirmed. Analysis by FACS also supported the conclusion that little apoptosis induction occurred following lenalidomide treatment of malignant glioma cell lines. In conclusion, lenalidomide exerts an antitumor effect on glioma cells due to alterations in cell cycle distribution.

Indoleamine 2,3-dioxygenase 1 is highly expressed in glioma stem cells.

Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.

IFN­ß sensitizes TRAIL­induced apoptosis by upregulation of death receptor 5 in malignant glioma cells.

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL­induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL­based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon­ß (IFN­ß) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL­induced apoptosis using glioma cell lines. TRAIL exhibited a dose­dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN­ß (clinically relevant concentration: 10 IU/ml) in A­172, AM­38, T98G, U­138MG and U­251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN­ß may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U­138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN­ß may offer a new therapeutic strategy for malignant gliomas.

Interferon-ß sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy.

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)­α2b and interleukin­2 have been approved for adjuvant immuno­chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN­ß has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN­ß in malignant melanoma. We evaluated the efficacy of TMZ and IFN­ß by comparing O6­methylguanine­DNA transferase (MGMT)­proficient and ­deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN­ß suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN­ß enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN­ß in combination with TMZ.

Promotion of TRAIL/Apo2L-induced apoptosis by low-dose interferon-ß in human malignant melanoma cells.

Interferon ß (IFN-ß) is considered a signaling molecule with important therapeutic potential in cancer since IFN-ß-induced gene transcription mediates antiproliferation and cell death induction. Whereas, TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) has emerged as a promising anticancer agent because it induces apoptosis specifically in cancer cells. In this study, we elucidated that IFN-ß augments TRAIL-induced apoptosis synergistically using five human malignant melanoma cells. All of these cells were induced apoptosis by TRAIL. Whereas, the response against IFN-ß was different in amelanotic cells (A375 and CRL1579) and melanotic cells (G361, SK-MEL-28, and MeWo). The responsibility of amelanotic cells against IFN-ß was higher than those of melanotic cells. The synergism of IFN-ß and TRAIL were correlated with the responsibilities of the cells against IFN-ß. The synergistic interaction was confirmed by a combination index based on the Chou-Talalay method. The upregulation of apoptosis in amelanotic cells was caused by very low doses of IFN-ß (over 0.1 IU/ml). Both of p53-mediated intrinsic pathway and Fas-related extrinsic pathway were activated by IFN-ß alone and combination with TRAIL. Further, TRAIL death receptors (DR4 and DR5) were upregulated by a low-dose IFN-ß (over 0.1 IU/ml) and the expression was more promoted by the combination with TRAIL. It was clarified that the upregulation of DR5 is associated with the declination of viability.

Intense water-window soft x-ray emission by spectral control using dual laser pulses.

We demonstrate intense emission in the water-window soft x-ray spectral region by controlling the spectral behavior through changing the balance between emissivity and self-absorption in an expanding plasma. The number of photons obtained from a dual laser irradiated target with a 150-ps pre-pulse was maximized at 3.8 × 1014 photons/sr in λ = 2.34 - 4.38 nm at a pulse separation time of 7 - 10 ns. Enhancement of the number of photons is attributed to efficient coupling with the main laser pulse while maintaining a tiny source size.