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A 39-year-old man was admitted because of cardiac arrest. Emergent coronary angiography revealed a preserved coronary blood flow; however, multiple-row detector computed tomography (MDCT) revealed that the proximal right coronary artery (RCA) was running inside the aortic wall, creating proximal stenosis without atherosclerotic changes. Surgical intervention with unroofing was performed; however, postoperative stenosis of the proximal RCA required additional coronary artery bypass grafting (CABG). Intraoperative findings during CABG did not reveal hematoma or coronary dissection. However, MDCT one year after CABG depicted improvement of the RCA and graft stenoses, suggesting that the post-unroof stenosis may have been caused by an inflammatory reaction after surgical intervention.

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)—a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)—a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. Conclusions: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.

One of the hallmarks of atherosclerosis is ongoing accumulation of macrophages in the artery intima beginning at disease onset. Monocyte recruitment contributes to increasing macrophage abundance at early stages of atherosclerosis. Although the chemokine CCL5 (RANTES) has been studied in atherosclerosis, its role in the recruitment of monocytes to early lesions has not been elucidated. We show that expression of Ccl5 mRNA, as well as other ligands of the CCR5 receptor (Ccl3 and Ccl4), is induced in the aortic intima of Ldlr−/− mice 3 weeks after the initiation of cholesterol-rich diet (CRD)-induced hypercholesterolemia. En face immunostaining revealed that CCL5 protein expression is also upregulated at 3 weeks of CRD. Blockade of CCR5 significantly reduced monocyte recruitment to 3-week lesions, suggesting that chemokine signaling through CCR5 is critical. However, we observed that Ccl5-deficiency had no effect on early lesion formation and CCL5-blockade did not affect monocyte recruitment in Ldlr−/− mice. Immunostaining of the lesions in Ldlr−/− mice and reciprocal bone marrow transplantation (BMT) of Ccl5+/+ and Ccl5−/− mice revealed that CCL5 is expressed by both myeloid and endothelial cells. BMT experiments were carried out to determine if CCL5 produced by distinct cells has functions that may be concealed in Ccl5−/−Ldlr−/− mice. We found that hematopoietic cell-derived CCL5 regulates monocyte recruitment and the abundance of intimal macrophages in 3-week lesions of Ldlr−/− mice but plays a minor role in 6-week lesions. Our findings suggest that there is a short window in early lesion formation during which myeloid cell-derived CCL5 has a critical role in monocyte recruitment and macrophage abundance.

In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development. Abbreviations: AAA, abdominal aortic aneurysm; CAT, catalase; DAB, diaminobenzidine; DMOG, dimethyloxaloylglycine; ECM, extracellular matrix; EPO, erythropoietin; EVG, elastica Van Gieson; H/E, haematoxylin and eosin; HIF, hypoxia-inducible factor; HPRT, hypoxanthine phosphoribosyl transferase; IL, interleukin; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NF-κB, nuclear factor κB; PHD, prolyl hydroxylase domain protein; qRT-PCR, quantitative real-time reverse transcription–PCR; ROS, reactive oxygen species; SOD1, superoxide dismutase 1; TNFα, tumour necrosis factor α; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell

Donepezil {(RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one} is a reversible acetylcholinesterase inhibitor and used for treatment of patients with AD (Alzheimer's disease). Recent studies showed that treatment with donepezil reduced production of inflammatory cytokines in PBMCs (peripheral blood mononuclear cells). It was also reported that muscle-derived inflammatory cytokines play a critical role in neovascularization in a hindlimb ischaemia model. We sought to determine whether donepezil affects angiogenesis. A hindlimb ischaemia model was created by unilateral femoral artery ligation. Blood flow recovery examined by laser Doppler perfusion imaging and capillary density by immunohistochemical staining of CD31-positive cells in the ischaemic hindlimb were significantly decreased in donepezil- and physostigmine-treated mice compared with control mice after 2 weeks. Donepezil reduced expression of IL (interleukin)-1β and VEGF (vascular endothelial growth factor) in the ischaemic hindlimb. Intramuscular injections of IL-1β to the ischaemic hindlimb reversed the donepezil-induced VEGF down-regulation and the anti-angiogenic effect. Hypoxia induced IL-1β expression in C2C12 myoblast cells, which was inhibited by pre-incubation with ACh (acetylcholine) or LY294002, a PI3K (phosphoinositide 3-kinase) inhibitor. Donepezil inhibited phosphorylation of Akt [also known as PKB (protein kinase B)], a downstream kinase of PI3K, in the ischaemic hindlimb. These findings suggest that cholinergic stimulation by acetylcholinesterase inhibitors suppresses angiogenesis through inhibition of PI3K-mediated IL-1β induction, which is followed by reduction of VEGF expression. Acetylcholinesterase inhibitor may be a novel anti-angiogenic therapy.

Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin-angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT 1 R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT 1 R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT 1 R expression. Cobalt chloride diminished angiotensin II–induced extracellular signal–regulated kinase phosphorylation. Cobalt chloride decreased AT 1 R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT 1 R downregulation.

Aims Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodelling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation. Methods and results Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs. Conclusions The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.

The combination of carboplatin and paclitaxel is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC) patients. The expression of excision repair cross-complementation group 1 (ERCC1) is reported to be correlated with resistance to platinum-based drugs. Class III β-tubulin is reported to be correlated with resistance to taxanes. We evaluated whether ERCC1 and class III β-tubulin expression could predict progression-free and/or overall survival in relapsed NSCLC patients treated with carboplatin and paclitaxel. Immunohistochemistry was used to examine the expression of these two proteins in resected lung tumor samples obtained from 45 patients treated with carboplatin and paclitaxel against recurrent tumors after curative resection. Immunostaining for ERCC1 and class III β-tubulin was positive in 20 and 16 patients, respectively. Patients negative for ERCC1 had a significantly longer median progression-free (44 weeks vs. 28 weeks, P = 0.046) and overall (102 weeks vs. 56 weeks, P = 0.010) survival than those positive for ERCC1. Patients negative for class III β-tubulin expression had a significantly longer median progression-free (40 weeks vs. 35 weeks, P = 0.031), but not overall (78 weeks vs. 57 weeks, P = 0.087), survival than those positive for class III β-tubulin expression. In particular, patients negative for both ERCC1 and class III β-tubulin had significantly longer progression-free ( P = 0.036) and overall survival ( P = 0.015), compared with those positive for ERCC1 and/or class III β-tubulin. In multivariate analysis, negative class III β-tubulin expression (hazard ratio = 1.912, P = 0.048) was significantly favorable factor for progression-free survival, and negative ERCC1 expression (hazard ratio = 2.580, P = 0.014) and better performance status (hazard ratio = 3.287, P = 0.007) were significantly favorable factors for overall survival. This retrospective study indicates that immunostaining for ERCC1 and class III β-tubulin may be useful for predicting survival in NSCLC patients receiving carboplatin and paclitaxel against recurrent tumors after curative resection and can provide information critical for planning personalized chemotherapy.

The expression of excision repair cross-complementation group 1 (ERCC1) is reported to be correlated with resistance to platinum-based drugs. Class III beta-tubulin is reported to be correlated with resistance to taxanes.In the present study, we evaluated whether ERCC1 and class III beta-tubulin expression could be used to predict progression-free and/or overall survival in 34 patients with locally advanced non-small cell lung cancer (NSCLC) receiving concurrent chemoradiation therapy with cisplatin and docetaxel, and immunohistochemistry was used to examine the expression of these two proteins in tumor samples obtained from the patients.Immunostaining for ERCC1 and class III beta-tubulin was positive in 16 and 12 patients, respectively. A significant correlation was observed between ERCC1 expression and response to chemotherapy (P = 0.012), and between class III beta-tubulin expression and histology (P = 0.029). Patients negative for ERCC1 had a significantly longer median progression-free (62.5 vs. 36 weeks, P = 0.009), but not overall (171 vs. 50.5 weeks, P = 0.208), survival than those positive for ERCC1. Expression of class III beta-tubulin was not correlated with progression-free or overall survival (P = 0.563 and P = 0.265, respectively). Multivariate analysis adjusting for possible confounding factors showed that negative ERCC1 expression (hazard ratio = 3.972, P = 0.009) was a significantly favorable factor for progression-free survival.This retrospective study indicates that immunostaining for ERCC1 may be useful for predicting survival in NSCLC patients receiving concurrent chemoradiotherapy with cisplatin and docetaxel, and can provide information critical for planning personalized chemotherapy.

Objective Previous studies have reported that serum IL-18 levels are increased in some cancers. We investigated whether IL-18 production is increased in sera and cancer cells of patients with non-small cell lung cancer (NSCLC). Patients or Materials Serum levels of IFN-γ and IL-18 and thioredoxin 1 (TRX1) were measured in 79 patients (51 males, 28 females, median age 67 years) with advanced NSCLC (57 adenocarcinoma, 22 squamous cell carcinoma; TNM stages IIIA [n=11], IIIB [n=24], and IV [n=44]) and 75 healthy age-matched controls (44 males, 31 females, median age 65 years) by enzyme-linked immunosorbent assay. We examined IL-18 production in the lungs and sites of bone metastasis of adenocarcinoma by immunohistochemistry. Results Serum IL-18, IFN-γ, and TRX1 levels in NSCLC patients were significantly (p

In order to establish a high strain rolling process for the production of ultrafine-grained steels, a new lubricant showing stable biting between rolls and workpieces as well as a lubricating effect inside the hot rolls is required. We focused on glass materials for the stable biting property in view of their hardness and investigated the possibility of applying blast furnace (BF) slag and waste glass as the lubricant. The addition of a lubricating property to these glass materials was attempted by water introduction with a hydrothermal treatment, using the water release with heating that leads to a structural change inside the hot rolls. For that purpose, the hydrothermal treatment of the BF slag and waste glass was carried out, and the water release with re-heating was investigated. Furthermore, friction properties of the synthesized lubricants containing the hydrothermally treated materials were measured by a Timken extreme pressure tester at 373–1173 K.

A single-center phase I trial was designed to determine both the dose-limiting toxicities and the maximum tolerated dose (MTD) for amrubicin hydrochloride in combination therapy with cisplatin for advanced non-small cell lung cancer (NSCLC) patients with prior chemotherapy.Eligible patients received amrubicin and cisplatin on days 1 through 3 every 3 or 4 weeks. Cisplatin was administered at a fixed dosage of 20 mg/m(2) while the administered dose of amrubicin was started at 20 mg/m(2). Each group comprised 3 or 6 patients. When dose limiting toxicities were noted in three or more of six patients at a particular level, that level was estimated to be the MTD.Fifteen patients were enrolled in this study, including 5 males and 10 females, with a median age of 57. The dose limiting toxicities included grade 4 neutropenia which lasted 4 or more days and febrile neutropenia. The non-hematologic toxicities were well managed and rarely severe. The MTD of amrubicin in this combination regimen was estimated to be 30 mg/m(2).A partial response was observed in 4 of 15 patients (27%).The recommended dose was thus determined to be 25 mg/m(2) amrubicin with 20 mg/m(2) cisplatin for 3 consecutive days. A phase II study is currently underway.

Background: The incidence of malignant pleural mesothelioma (MPM) is expected to increase due to delayed control of occupational exposure to asbestos in Japan. We investigated the use of triplet combination chemotherapy with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR) for the treatment of Japanese patients with MPM. Methods: From December 2000 to August 2003, 12 patients received the following regimen: CDDP 40 mg/m 2 , GEM 800 mg/m 2 and VNR 20 mg/m 2 on days 1 and 8 every 4 weeks. Among the 12 patients, six selected patients underwent an extrapleural pneumonectomy (EP) after a median of three cycles of triplet chemotherapy. Results: The overall response rate for all patients and the response rate for chemotherapy-naive cases were 58 and 67%, respectively. The median survival time and survival rate at 2 years for all patients were 11 months and 50%, respectively. The 2-year survival rates for the patients with and without EP were 83.3 and 16.7%, respectively. Conclusions: Triplet chemotherapy with CDDP, GEM and VNR was thus found to be highly effective for patients with MPM and its toxicity was manageable. A multi-institutional phase II trial is now being planned to establish the effectiveness of this new regimen in chemotherapy-naive patients with MPM.

A 38-year-old Japanese female was referred to Kurume University Hospital (Kurume, Japan) because of recurrent pneumonia. She had no particular medical history, had never undergone a blood transfusion and was taking no regular medication or treatment. She had a negative smoking history, did not own any pets and denied a history of dust exposure. Her family history was unremarkable. She had successfully completed three vaginal deliveries and had been well until the age of 35 years, which is when she experienced her first episode of pneumonia. The pneumonia was cured by the administration of β-lactam antibiotics. She then suffered three more episodes of pneumonia within 3 years. She denied any history of accidental aspiration, weight loss or haemoptysis, and did not have pyrexia, night sweats or sputum production between the episodes of pneumonia.

The Iron and Steel Institute of Japan, We investigated the possibility of using waste slag as a lubricant in high straining rolling for ultrafine-grained steels. When slag is applied as a lubricant, it might satisfy the requirement for stable biting workpieces because slag is as stable as glass with high hardness at the biting temperatures in rolling (100-200°C). On the other hand, ordinary slag doesn't have the fluidity necessary to provide a lubricating effect at rolling temperatures of 300-400°C since its melting temperature is usually high. However, slag containing water has been targeted as a new lubricant, and we focused on lowering the glass transition temperature and the structural change of slag containing water with the aim of improving the lubricity of slag in rolling. The microstructures of slag containing water and slag that released water were observed in the present study, along with in-situ observation of water released from the surface of slag containing water were conducted after heating in a SiO_2-Na_2O-B_2O_3 slag system. We found that water was mainly contained in the phase formed by ions dissolved from the original slag under hydrothermal conditions, and the amount of water was dependent on the state of the phase, such as glass or crystal. It was confirmed that slag containing water could provide a lubricating effect when the water is released from the slag above the glass transition temperature because a porous structure is formed due to the water release.

Summary Background and Objectives: To determine the prognostic factors for long-term survivors (LTS) with stage IV non-small cell lung cancer (NSCLC) who had undergone various treatments. Patients and methods: From 1990 to 1999, 222 NSCLC patients with stage IV disease, who had been treated in our department, were reviewed. As the initial treatment, 135 patients (48%) were treated with chemotherapy alone, 52 patients with a combination of chemotherapy and radiotherapy, 19 patients underwent an operation with or without any other therapeutic modalities and 16 were received radiotherapy alone. Results: Seventeen (7.7%) patients survived for more than 2 years, and all but one had adenocarcinoma. Among these LTS, eight patients received surgery as the initial therapy, and 16 (94.1%) received some type of local-control therapy, including surgery or radiotherapy, during the course of their disease. Regarding the clinical characteristics between LTS and others (non-LTS), an early N status, a single metastatic site, a good performance status, and surgery for initial therapy were all found to be significantly important factors for LTS. A multivariate analysis using a logistic regression model also showed an early N status and surgical treatment to be significantly associated with LTS. Conclusions: Selected patients with an early N status may be appropriate candidates for aggressive multimodality treatment including surgery, in order to provide a long-term survival for stage IV NSCLC.

Objective Visceral pleural invasion caused by non–small cell lung cancer is a factor in the poor prognosis of patients with that disease. We investigated the relationship between the diagnosis of visceral pleural invasion by using a jet stream of saline solution, which was previously reported as a new cytologic method to more accurately detect the presence of visceral pleural invasion, and prognosis. Methods From January 1992 through December 1998, 143 consecutive patients with peripheral non–small cell lung cancer that appeared to reach the visceral pleura underwent a surgical resection at the Department of Thoracic Oncology, National Kyushu Cancer Center. The surface of the visceral pleura in patients undergoing lung cancer resection was irrigated with a jet stream of saline solution. The diagnosis of visceral pleural invasion was determined by means of either a pathologic examination or by means of a jet stream of saline solution. In addition, a cytologic examination of the pleural lavage fluid obtained immediately after a thoracotomy was evaluated. Results Forty-nine (34%) resected tumors were identified as having visceral pleural invasion. The diagnosis of visceral pleural invasion in 31, 6, and 12 patients was determined by using a jet stream of saline solution alone, pathologic examination alone, or both, respectively. The visceral pleural invasion and positive findings of intrapleural lavage cytology were linked. Although there was no significant difference between the incidence of distant metastases in the patients with visceral pleural invasion and those without visceral pleural invasion, the incidence of local recurrence, especially regarding carcinomatous pleuritis (malignant pleural effusion, pleural dissemination, or both), in the patients with visceral pleural invasion was significantly higher than in those without visceral pleural invasion. The recurrence-free survival of patients with visceral pleural invasion was significantly shorter than that of patients without visceral pleural invasion ( P = .004), even patients with stage I disease ( P = .02). There was also a significant difference between the patients with or without visceral pleural invasion in the overall survival ( P = .02). Visceral pleural invasion was independently associated with a poor recurrence-free survival on the basis of multivariate analyses ( P = .03), as were sex ( P = .03), age ( P = 002), and the stage of the disease ( P Conclusions This study confirmed that the jet stream of saline solution method in addition to ordinary pathologic examination was useful for detecting visceral pleural invasion, which is considered to be one of the causes of local recurrence, especially in carcinomatous pleuritis.

Background and Objectives Surgery is a standard treatment in patients with clinical stage IB/II non-small cell lung cancer (NSCLC). We often have difficulty in treating of elderly patients due to their insufficient physiological function. To better manage such elderly patients, the clinical characteristics and prognosis of patients with these stages, who were 75 years of age or older, were reviewed. Methods From 1972 to 1999, 112 elderly patients with these stages were treated in our department. These patients comprised 88 men and 24 women. The histological types were 50 adenocarcinomas, 51 squamous cell carcinomas, 8 large cell carcinomas, and 3 adenosquamous carcinomas. Results Seventy-four patients (66%) underwent a surgical resection, including 60 surgery alone, 14 combined modality therapy. Radiotherapy, with or without chemotherapy, was given to 30 patients (27%), and chemotherapy alone to 5 (4.5%). In addition, 3 (2.7%) were given no therapy. The survivals of the surgery group at 2 and 5 years are 53% and 21% and those of the radiotherapy group are 35% and 3%, respectively. A multivariate analysis in radiotherapy group shows the predominant prognostic factor to be adenocarcinoma. The 2-year survival of the radiotherapy group in patients with adenocarcinoma is 58%, while that of patients with squamous cell carcinoma is 22%. Conclusions These above observations suggest that radiotherapy is an alternative strategy for patients who cannot undergo surgery, especially with adenocarcinoma. J. Surg. Oncol. 2004;87:134–138. © 2004 Wiley-Liss, Inc.

When electrons at relativistic velocities pass through a crystal plate, such as silicon, photons are emitted around the Bragg angle for X-ray diffraction. This phenomenon is called parametric X-ray radiation (PXR). The monochromaticity and directivity of PXR are adequate and the energy can be changed continuously by rotating the crystal. This study measured the mass attenuation coefficient around the K-shell absorption edge of Nb, Zr and Mo as a PXR application of monochromatic hard X-ray radiation sources.

Parametric X-ray radiation (PXR) at energies from 15 to 30 keV was produced by a 45 MeV electron linear accelerator (LINAC) using a silicon (Si) single crystal. The appropriate conditions for generation of good monochromatic hard X-ray fields by PXR were obtained with the LINAC by theoretical calculations and experiments. The PXR intensity increased approximately linearly with the electron energy in the electron energy range of several tens of MeV. The PXR energy increased linearly with the crystal rotation angle that depended on the reflection plane and the observation angle and did not depend on the electron energy. The obtained counts of PXR increased at large observation angles although the energy decreased. The experiments used Si plates with thicknesses of 200, 300, 400, 500, 530, and 625 μm. Differences in angular distribution by the thickness of the Si plates were established. The possibility for PXR applications to material research and other fields is discussed. The off angle of the polished (cut) plane of the crystal was accurately determined using the PXR and the attenuation coefficient around the K-shell absorption edge of Zr, Nb and Mo were measured.

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1β, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.

Objective Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA). Methods and results AAA was induced by topical application of calcium chloride (CaCl 2 ) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl 2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl 2 -induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed. Conclusion Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl 2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development.

Background: Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltration of inflammatory cells including macrophages is critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates proline residue of hypoxia-inducible factor α (HIFα) and thereby induces HIFα degradation, suppressed inflammatory responses in macrophage. We examined whether myeloid-specific PHD2 deletion affects hypertension-induced cardiovascular remodeling. Methods and Results: Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing PHD2-floxed mice with LysM-Cre transgenic mice. HIF-1α and 2α proteins were accumulated and mRNA expression of TNFα, IL-6 and IL-1β, M1 macrophage markers, and TGF-β and connective tissue growth factor (CTGF) expression were significantly decreased in peritoneal macrophages from MyPHD2KO mice compared with those from control mice. PHD2-deficient macrophage showed attenuated migration toward MCP-1. Eight to 10 week-old mice were given L-NAME (30mg/kg), an eNOS inhibitor, dissolved in 0.9% NaCl in the drinking water for 14days. Angiotensin II (AngII, 0.8 mg/kg/day) was infused subcutaneously via an osmotic mini-pump for the last 7 days of the experiment. L-NAME/AngII comparably increased systolic blood pressure in control and MyPHD2KO mice. Cardiac interstitial fibrosis (3.4±0.4 vs. 2.3±0.4%, p Conclusions: Myeloid specific PHD2 deletion attenuates cardiac hypertrophy and fibrosis induced by L-NAME/AngII, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophage. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.

Background Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 ( PHD 2), which hydroxylates the proline residues of hypoxia‐inducible factor‐α ( HIF ‐α) and thereby induces HIF ‐α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid‐specific Phd2 deletion affects hypertension‐induced cardiovascular remodeling. Methods and Results Myeloid‐specific PHD 2‐deficient mice (MyPHD2KO) were generated by crossing Phd2 ‐floxed mice with LysM‐Cre transgenic mice, resulting in the accumulation of HIF ‐1α and HIF ‐2α in macrophage. Eight‐ to ten‐week‐old mice were given N G ‐nitro‐L‐arginine methyl ester (L‐ NAME ), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L‐ NAME /Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor ‐β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L‐ NAME /Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF ‐α synthesis to L‐ NAME /Ang II‐treated MyPHD2KO mice reversed these beneficial features. Conclusions Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation‐ and fibrosis‐associated gene expression in macrophages. PHD 2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.

Background— Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2 , the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities. Methods and Results— To delete PHD2 in adipocyte, PHD2 -floxed mice were crossed with aP2-Cre transgenic mice ( Phd2 f/f /aP2-Cre) . Phd2 f/f /aP2-Cre mice were resistant to high-fat diet–induced obesity (36.7±1.7 versus 44.3±2.0 g in control; P P P Phd2 f/f /aP2-Cre mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of Phd2 f/f /aP2-Cre mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of Phd2 f/f /aP2-Cre mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation. Conclusions— PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities.

長崎県神代地方に残る歴史的日本庭園の特性を庭園実測や現地調査によって明らかにした。庭園は敷地に平行する水路から池水を引き込んでいるのが特徴である。池のタイプは池泉の水の取り入れ方や、その形で2つのタイプに分けることができる。水面率は平均13～14%であり、庭園形式は、そのほとんどが鑑賞主体の小庭で、池泉鑑賞式の形式をもつ庭園である。植栽樹は常緑樹が主であり、低木主体の庭である。

Obesity induces hypertrophy of adipocyte resulting in production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP1 (CCL2)). These cytokines play an important role in the development of insulin resistance. Beraprost sodium (BPS), a prostaglandin I2 analogue, is reported to attenuate inflammation. In this study, we examined the effect of BPS on glucose metabolism in mice fed a high-fat diet (HFD). Four-week-old C57/B6 male mice were fed a HFD for 12 weeks (HFD group) and the treatment group received oral BPS (300 μg/kg per day) for the same period. Then, glucose metabolism, histological changes, and gene expression of white adipose tissue (WAT) were examined. Body weight was increased, and glucose intolerance and insulin resistance were developed in the HFD group. Treatment with BPS improved glucose tolerance and insulin action without body weight change. Histological analysis of WAT showed an increase in the size of adipocyte and macrophage infiltration in the HFD group, which was attenuated by BPS treatment. BPS reduced HFD-induced expression of MCP1 and TNF-α in WAT. BPS also attenuated hepatic steatosis induced by the HFD. These results suggest that BPS improved glucose intolerance possibly through suppression of inflammatory cytokines in WAT. BPS may be beneficial for the treatment of obesity-associated glucose intolerance.

Objective— Prolyl hydroxylase domain-containing proteins (PHDs) play pivotal roles in oxygen-sensing system through the regulation of α-subunit of hypoxia-inducible factor (HIF), a key transcription factor governing a large set of gene expression to adapt hypoxia. Although tissue hypoxia plays an essential role in maintaining inflammation, the role of PHDs in the inflammatory responses has not been clearly determined. Here, we investigated the role of PHDs in lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) induction in macrophages. Methods and Results— Northern blot analysis and ELISA revealed that LPS-induced TNF-α upregulation was strongly suppressed by PHD inhibitors, dimethyloxallyl glycine (DMOG), and TM6008 in RAW264.7 macrophages. DMOG suppressed LPS-induced TNF-α upregulation in HIF-1α–depleted cells and HIF-1α overexpression failed to suppress the induction of TNF-α. DMOG rather suppressed LPS-induced NF-κB transcriptional activity. Downregulation of Phd1 or Phd2 mRNA by RNA interference partially attenuated LPS-induced TNF-α induction. DMOG also inhibited LPS-induced TNF-α production in peritoneal macrophages as well as human macrophages. Conclusions— PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-α upregulation in macrophages possibly through NF-κB inhibition, which is independent of HIF-1α accumulation. This study suggests that PHDs are positive regulators of LPS-induced inflammatory process, and therefore inhibition of PHD may be a novel strategy for the treatment of inflammatory diseases.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been reported to have a certain anti-tumor effect in previously treated patients with non-small cell lung cancer (NSCLC). However, the prognostic factors in those patients with and without a positive response to gefitinib treatment remain unclear. A retrospective chart review was performed in 131 advanced NSCLC patients who received 250 mg of gefitinib as either a second-line or even later stage treatment from July 2002 to December 2005. The clinical factors including age, gender, performance status (PS), stage, histology, the number of prior types of chemotherapy, and the response to first-line chemotherapy were analyzed. One and 38 patients experienced a complete and partial response, respectively, to gefitinib treatment with an overall response rate of 30%. The median survival time (MST) of all patients receiving gefitinib treatment was 10 months while the MST was 28 months in the 39 gefitinib responders and 6 months in the 92 non-responders. Among the 39 gefitinib responders, the predominant prognostic factor was found to be the effectiveness of the first-line chemotherapy. The MST of the 20 patients with a response to the first-line chemotherapy was 32 months while the MST of the 19 patients without a response to the chemotherapy was 22 months (p=0.025). Among the 92 gefitinib non-responders, the predominant prognostic factor was the PS (p0.001). The effectiveness of the first-line chemotherapy was therefore found to be a prognostic factor in the gefitinib responders with previously treated NSCLC, while the PS was shown to be a prognostic factor in the gefitinib non-responders.

Expression of excision repair cross-complementation group 1 (ERCC1), p53, or thioredoxin (TRX) is reported to be correlated with resistance to platinum-based drugs. The authors evaluated whether ERCC1, p53, or TRX expression could predict progression-free and/or overall survival in relapsed non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Immunohistochemistry was used to examine the expression of these three proteins in resected lung tumor samples obtained from 67 patients treated with platinum-based chemotherapy against recurrent tumors after curative resection. Immunostaining for ERCC1, p53, and TRX was positive in 29, 35, and 24 patients, respectively. Patients negative for ERCC1 had a significantly longer median progression-free (44 vs 26 weeks, P = 0.0075) and overall (73 vs 44 weeks, P = 0.0006) survival than those positive for ERCC1. Patients negative for p53 expression had a significantly longer median overall (70 vs 62 weeks, P = 0.0289), but not progression-free (37.5 vs 36 weeks, P = 0.2465), survival than those positive for p53 expression. From multivariate analysis, negative ERCC1 expression (hazard ratio [HR] = 1.3740, P = 0.0147) was a significantly favorable factor for progression-free survival, and negative ERCC1 expression (HR = 1.6533, P = 0.0018) and better performance status (HR = 1.9117, P = 0.0017) were significantly favorable factors for overall survival. This retrospective study indicates that immunostaining for ERCC1 may be useful for predicting survival in NSCLC patients receiving platinum-based chemotherapy against recurrent tumors after curative resection and can provide critical information for planning personalized chemotherapy.

Background Pulmonary giant cell carcinoma is one of the rare histological subtypes with pleomorphic, sarcomatoid or sarcomatous elements. The prognosis of patients with this tumor tends to be poor, because surgery, irradiation and chemotherapy are not usually effective. Case presentation We herein report a patient with pulmonary giant cell carcinoma with stage IV disease in whom aggressive multi-modality therapy resulted in a long-term survival. A 51-year-old male underwent an emergent operation with a partial resection of small intestinal metastases due to bleeding from the tumor. The patient also underwent a left pneumonectomy due to hemothorax as a result of the rapid growth of the primary tumor. Thereafter, two different regimens of chemotherapy and a partial resection for other site of small intestinal metastases and a splenectomy for splenic metastases were performed. The patient is presently doing well without any evidence of recurrence for 3 years after the initial operation. Conclusion This is a first report of a rare case with stage IV pulmonary giant cell carcinoma who has survived long-term after undergoing aggressive surgical treatment and chemotherapy.

The exclusion of brain metastasis is important to determine the optimal treatment plan in patients with non-small cell lung cancer (NSCLC). However, a routine examination using magnetic resonance imaging (MRI) for the brain remains controversial in preoperative patients with resectable disease.To assess the necessity of routine brain MRI for preoperative patients, a retrospective analysis for a consecutive series of 338 patients with NSCLC was performed. Among the 338 patients, 141 patients who were considered to have potentially resectable diseases through an examination of the chest plus an upper abdominal computed tomography scan and bone radioisotope scan with no neurological symptoms received MRI for examination of brain metastasis.The incidence of brain metastasis detected by MRI was 2.1% (three of 141) in all patients, 0% (zero of 80) in patients with N0 disease, 5.2% (one of 19) in N1, and 4.7% (two of 42) in N2 cases.In patients with resectable NSCLC, a brain MRI is not considered to be useful due to the low incidence of asymptomatic brain metastasis.

Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase, which has a tumour reducing effect in non-small cell lung cancer (NSCLC). In this study, we retrospectively reviewed the clinical data from 105 patients with advanced NSCLC treated with gefitinib at our department between May 2002 and April 2004. The overall response rate was 27.8% and the median survival time was 9.3 months. Pretreatment characteristics suggested that those with no history of smoking or an elevated serum carcinoembryonic antigen (CEA) level were more likely to be sensitive to gefitinib (P = 0.009). A multivariate analysis indicated good PS (P < 0.0001) and elevated serum CEA level (P = 0.0027) to be independent prognostic factors. These data show that the serum CEA level can be a predictive factor for the efficacy of gefitinib treatment while it is also a prognostic factor for advanced NSCLC patients undergoing this treatment.

Background Combination chemotherapy using an oral combination of uracil and tegafur (UFT) plus cisplatin and concurrent thoracic radiotherapy is reported to have a high response rate and less toxicity for locally advanced non–small-cell lung cancer (NSCLC) patients. We performed a phase II trial using this chemoradiotherapy as an induction treatment. Methods Patients with marginally resectable stage IIIB NSCLC, an age younger than 70 years, a performance status of 0 or 1, and good organ function were eligible. The UFT (400 mg/m 2 ) was administered orally on days 1 through 14 and 22 through 35 and cisplatin (80 mg/m 2 ) was injected intravenously on days 8 and 29. Radiotherapy with a total dose of 40 Gy was delivered in 20 fractions from day 1. A surgical resection was performed from 3 to 6 weeks after completing the induction treatment. Results Twenty-seven patients, 18 male and 9 female with a median age of 56 years and ranging from 36 to 69 years, were entered into the phase II trial. Clinical T4 and N3 cancers were observed in 22 and 7 patients, respectively. Twenty-five (93%) achieved a partial response. The most frequently observed adverse event was grade 3 leukopenia in 26%. Of 25 patients who underwent a thoracotomy, 22 had a tumor resection. In all 22 patients a complex resection including a resection of the superior vena cava, carina, and vertebrae was required. Operative morbidity and mortality rates were 36% and 4% respectively. The calculated 1-year and 3-year survival rates of all 27 patients were 73% and 56% respectively. Conclusions Chemotherapy using UFT plus cisplatin and concurrent radiotherapy as induction treatment and a surgical resection for patients with marginally resectable stage IIIB NSCLC is feasible and promising. However it is difficult to conduct multi-institutional trials even for selected stage IIIB disease as a complex resection in almost all patients is necessary.

We report the case of a 58-year-old man who underwent complete resection for locally advanced non-small-cell lung cancer (cT4N2M0). The patient received UFT (400 mg/m2 orally on days 1-14 and 22-35) and cisplatin (80 mg/m2 intravenously on days 8, 29) with a total 40 Gy, delivered in 20 fractions on days 1-26. The tumor reduction rate was 76%, and no remarkable toxicities were observed. The patient underwent complete resection and a pathologic complete response was observed. This induction concurrent chemoradiotherapy (followed by surgery) is considered to be effective and safe.

A male skull with gashes by swords on its left temporal and left facial skeleton was found at Karasuma-Demizu, Kamigyo, Kyoto. The skull which was supposed to be reburied there in 16 century A. D. shows the craniometrical chracteristics both of the Medieval people and of his individuality.

This paper describes a human skeletal remain from the Himrin basin of Iraq affected by tumor-like lesions localized in the skull, mandible, scapulae, humeri, ribs, sternum, vertebrae including sacrum, hip bones, and femora.After anthropological, anatomical, and roentgenological observations and comparison with various diseases resulting in osteolytic destructive lesion with characteristic features, the authors conclude that a slow-growing benign tumor involved the skeleton because of the age at death, the multifocal osteolytic lesions in a number of the bones and their distribution, the appearances and size of the lesions, and the slight sclerotic reaction.Not only this paper is the first paleopathological description on the disease in Iraq, but also the case is rare and valuable to the paleopathological field.