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Biomedical subjects

Ryuzo Ueda

Publications and source records attributed to Ryuzo Ueda.

At least 55 records · Page 3Linked to original sources
PubMed2005

Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor.

Involvement of nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-kappaB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-kappaB in addition to the phosphorylation of IkappaBalpha and the activation of NF-kappaB DNA binding and that various target genes of NF-kappaB including bcl-x(L), XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IkappaB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC(50) values ranging from 18 to 35 mumol/L concomitantly with inhibition of the phosphorylation of IkappaBalpha/p65 and NF-kappaB DNA-binding, down-regulation of the NF-kappaB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IkappaB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-kappaB.

Cell Proliferation↗
PubMed2005

Production and characterization of an active single-chain variable fragment antibody recognizing CD25.

The alpha subunit of the interleukin-2 receptor (IL-2Ralpha, CD25) is a potential target in therapeutic approaches for hematolopoietic malignancies expressing CD25 on their cell surface, such as adult T cell leukemia/lymphomas. Recent reports have demonstrated that depletion of CD4+CD25+ regulatory T cells with anti-CD25 antibodies may enhance host tumor immunity. We previously raised a mouse monoclonal antibody (mAb), Ta60b mAb (IgG1kappa), specifically recognizing CD25, and an attempt was made here to produce a single chain Fv fragment (scFv) from this mAb as an initial step to development of scFv-based therapeutics. cDNA fragments encoding for the variable regions of the light and heavy chains of the Ta60b mAb were thus isolated by polymerase chain reaction-mediated cloning, and, an expression vector constructed to express Ta60b scFv fused with the maltose binding protein (MBP) in the periplasm of Escherichia coli. The soluble form of MBP-Ta60b fused scFv could be extracted and affinity-purified with an amylose/agarose column, allowing its immunoreactivity to be analyzed by enzyme-linked immunosorbent assay (ELISA), mixed hemadsorption assay, and fluorescence activated cell sorting. In addition, binding activity was studied by competitive ELISA and surface plasmon resonance. The results showed that Ta60b scFv obtained from periplasm retains good reactivity, although its KD value was 4-fold lower than that of the whole Ta60b antibody, suggesting possible clinical use for treatment of patients with CD25-expressing tumors and also for enhancing anti-tumor immunity.

Amino Acid Sequence↗
PubMed2005

Effects of atorvastatin on inflammation and oxidative stress.

Treatment with inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (statins) reduces the incidence of cardiovascular events, but it is unclear whether the beneficial effects are mediated solely by their lipid-lowering properties. We therefore investigated whether atorvastatin reduces inflammation and oxidative stress independently of its lipid-lowering effects. The subjects comprised 71 hyperlipidemic patients (64+/-9 years old, mean+/-SD) who were not receiving medical treatment. Serum lipid and C-reactive protein (CRP) levels, and urine 8-isoprostane level (an index of oxidative stress) were measured before and after 4 weeks of treatment with atorvastatin at 10 mg/day. In 38 patients, these biochemical variables and carotid intima-media thickness (IMT) were also measured after 6 months of treatment with atorvastatin. Atorvastatin markedly reduced CRP (from 0.69+/-0.36 to 0.42+/-0.20 and 0.35+/-0.19 mg/l, median+/-median absolute deviation, P<0.0001), 8-isoprostane (from 225+/-99 to 178+/-75 and 179+/-60 ng/g creatinine, P<0.05), and low density-lipoprotein cholesterol (LDLC; from 165+/-21 to 106+/-18 and 112+/-17 mg/dl, P<0.0001) after 4 weeks and 6 months of treatment, respectively. However, the reductions in CRP and 8-isoprostane were not correlated with those of LDLC. After 6 months of treatment, IMT was significantly decreased compared with the baseline value (from 0.94+/-0.26 to 0.90+/-0.20 mm, P<0.05), but this was not correlated with the reduction in LDLC. These results suggest that atorvastatin has beneficial effects on inflammation, oxidative stress, and the lipid profile in patients with hyperlipidemia. The extra-lipid effects are not attributable to the lipid-lowering effect of the statin, suggesting that the pleiotropic effects of atorvastatin are independent of its effects on the lipid profile.

Atorvastatin↗
PubMed2005

Pyogenic granuloma of the stomach successfully treated by endoscopic resection after transarterial embolization of the feeding artery.

Pyogenic granulomas represent the aquisition of vasodilative granulation tissue in the skin or mucosa. They are extremely rare in the alimentary tract, other than in the oral cavity. Here, we report a case of pyogenic granuloma arising from the gastric mucosa. An 82-year-old man was admitted to our hospital because of melena of more than 3 months, duration. Esophagogastroduodenoscopy (EGD) revealed a 30-mm-diameter semipedunculated lesion with an irregular surface in the fundus of the stomach. During hospitalization, the patient's anemia worsened due to loss of blood from the lesion, with the level of hemoglobin declining to 6 g/dl, and a blood transfusion was required. Because radiological and endoscopic findings indicated the lesion was hypervascular, transarterial embolization of the nutritional artery of the lesion was performed before endoscopic resection of the lesion. One week after the embolotherapy, endoscopic mucosal resection was performed, without any complications, such as massive bleeding. Histological studies of the resected specimen revealed many capillaries of various sizes, lined with plump endothelial cells, and accompanied by acute and chronic inflammatory infiltrates. On the basis of these observations, the lesion was diagnosed as a pyogenic granuloma. One year later, the patient was asymptomatic and there was no evidence of tumor recurrence on follow-up EGD.

Aged↗
PubMed2005

Normotensive scleroderma renal crisis with diffuse alveolar damage after corticosteroid therapy.

A 68-year-old woman with systemic sclerosis developed acute respiratory failure due to diffuse alveolar hemorrhage and normotensive scleroderma renal crisis (SRC) shortly after the initiation of corticosteroid therapy. Treatment with angiotensin-converting enzyme inhibitor and plasmapheresis had failed in this patient. Autopsy showed diffuse alveolar damage and thrombotic micro-angiopathy. The sequence of events in this patient clarifies the pathologic process of normotensive SRC, and suggests a causative role of corticosteroid therapy and normotensive SRC.

Journal Article↗
PubMed2005

Circulating levels of myocardial proteins predict future deterioration of congestive heart failure.

BACKGROUND: This study was designed to test whether circulating levels of myocardium-specific proteins serve as useful markers for the prognosis of patients with congestive heart failure. METHODS AND RESULTS: Seventy-eight patients with congestive heart failure from dilated cardiomyopathy but in a stable condition were enrolled, and their blood was sampled for measurements of myosin light chain-I (MLC-I), troponin T (TnT), heart fatty-acid-binding protein (H-FABP), and creatine kinase isoenzyme MB (CK-MB). The patients were then followed up for 951 +/- 68 days, with the endpoint being acute deterioration. A univariate analysis revealed that MLC-I, TnT, H-FABP, and CK-MB were significant predictors for acute deterioration of heart failure. Application of the Kaplan-Meier method using cutoff values determined by analysis of receiver operating characteristics curves demonstrated that the incidence of acute deterioration was significantly higher in patients with higher values of MLC-I (61.9%), TnT (52.4%), H-FABP (50.0%), or CK-MB (38.6%) than in those with lower values of these markers (15.8%, 20.4%, 13.6%, and 16.1%, respectively). CONCLUSIONS: Increased circulating levels of the specific myocardial proteins are related to a higher probability of future acute deterioration of congestive heart failure in patients in a stable condition associated with dilated cardiomyopathy.

Age Factors↗
PubMed2005

The role of thymidylate synthase and dihydropyrimidine dehydrogenase in resistance to 5-fluorouracil in human lung cancer cells.

The expressions of thymidylate synthase (TS) and intracellular metabolic enzymes have been reported to be associated with the sensitivity and/or resistance to 5-fluorouracil (5-FU). However, since the role of these enzymes in the mechanism of resistance to 5-FU has not been fully examined in lung cancer, in the present study we measured the expression levels of TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT) genes in lung cancer cell lines by real-time PCR, and the sensitivity to 5-FU using the MTS assay. The expression of DPD was significantly correlated with the concentration of 5-FU for 50% cell survival in 15 non-small-cell lung cancer (NSCLC) cell lines (p<0.05), but the expressions of TS, TP, and OPRT were not. Treatment with 5-chloro-2,4-dihydroxypyridine, an inhibitor of DPD, altered the sensitivity to 5-FU in DPD-expressing RERF-LC-MT cells, indicating that modulation of DPD activity could increase the 5-FU sensitivity in lung cancer. In contrast, TS expression was dramatically higher in a 5-FU-resistant small-cell lung cancer cell line than in the parent cell line, whereas the expressions of DPD, TP, and OPRT genes were not markedly different. In order to examine the effect of other cytotoxic agents on TS and DPD expression, we compared the expressions of both genes between cisplatin-, paclitaxel-, gemcitabine-, or 7-ethyl-10-hydroxycamptothecin-resistant lung cancer cells and their respective parent cells, but found no differences between any pair of resistant subline and the corresponding parent cell line. Our results indicate that degradation of 5-FU due to DPD is an important determinant in 5-FU sensitivity, while induction of TS contributes to acquired resistance against 5-FU in lung cancer. Therefore, the expression levels of TS and DPD genes may be useful indicators of 5-FU activity in lung cancer.

Antimetabolites, Antineoplastic↗
PubMed2005

p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis.

p16/INK4a gene alterations have been associated with tumor progression in lymphoid malignancies. However, their significance in mucosa-associated lymphoid tissue (MALT) lymphoma is unclear. We investigated p16 gene methylation and mutation in a large series of untreated cases of pulmonary MALT lymphoma and diffuse large B-cell lymphoma (DLBL), and correlated p16 gene alterations with a MALT lymphoma-specific API2-MALT1 fusion and the clinicopathologic features of MALT lymphoma. The API2-MALT1 fusion was detected by multiplex reverse transcription polymerase chain reaction in 25/60 (42%) cases of MALT lymphoma, but none of 11 DLBLs. Methylation-sensitive single-strand conformation analysis showed that p16 gene methylation was frequently detected in 36/60 (60%) cases of MALT lymphoma. The gene was similarly methylated in DLBL cases (6/11, 55%). A p16 gene mutation was found in one (p16 gene-methylation) of 44 MALT lymphomas and in none of six diffuse large B-cell lymphomas. Statistical analysis showed that the p16 gene methylation status did not correlate with API2-MALT1 fusion or any of the clinicopathologic factors including serum LDH, clinical stage, and increased large cells. These findings suggest that p16 methylation is not associated with tumor progression, but may be an early event in MALT lymphomagenesis that might be maintained through the progression of the tumor.

Adult↗
PubMed2005

Impact of occult hepatitis B virus infection on efficacy and prognosis of interferon-alpha therapy for patients with chronic hepatitis C.

BACKGROUND/AIMS: It is reported that some patients with undetectable hepatitis B surface antigen (HBsAg) have serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis C (HCV). The aim of this study was to elucidate the impact of occult HBV infection on the efficacy and prognosis of interferon-alpha (IFN) therapy in HCV patients. METHODS: One hundred and forty HCV patients without HBsAg who received IFN therapy were studied. Serum HBV DNA was quantified by real-time detection polymerase chain reaction. RESULTS: Of 140 patients, 11 (7.9%) were HBV DNA-positive before IFN therapy. The serum HBV DNA levels ranged from 106 to 884 copies/ml. Four of these 11 patients showed a sustained virologic response by IFN, compared with 39 of 129 without HBV DNA (P = NS). Interestingly, two of the 11 patients developed hepatocellular carcinoma (HCC) after therapy, compared with 16 of 129 without HBV DNA (P = NS). In the serial study, serum HBV DNA was transiently undetectable during and after IFN; however, most became positive during follow-up. CONCLUSIONS: Occult HBV infection may not have a significant impact on response to IFN therapy for chronic HCV and development of HCC after therapy. Occult HBV may be sensitive to IFN although HBV is not completely eradicated.

Adult↗
PubMed2005

Novel type of hepatitis B virus mutation: replacement mutation involving a hepatocyte nuclear factor 1 binding site tandem repeat in chronic hepatitis B virus genotype E.

The genetic diversity of hepatitis B virus (HBV) strains has evolved through mutations such as point mutations, deletions or insertions, and recombination. We identified and characterized a novel type of mutation which is a complex of external insertion, deletion, and internal duplication in sequences from one of six patients with chronic hepatitis B virus genotype E (HBV/E). We provisionally named this mutation a "replacement mutation"; the core promoter upstream regulatory sequence/basic core promoter was replaced with a part of the S1 promoter covering the hepatocyte nuclear factor 1 (HNF1) binding site, followed by a tandem repeat of the HNF1 site. A longitudinal analysis of the HBV population over 6 years showed the clonal change from wild-type HBV/E to replacement-mutant type, resulting in a lower hepatitis B (HB) e antigen titer, a high HBV DNA level in serum, and progression of liver fibrosis. In an in vitro study using a replication model, the replacement-mutant HBV showed higher replication levels than the wild-type HBV/E replicon, probably mediated by altered transcription factor binding. Additionally, this HNF1 site replacement mutation was associated with excessive HB nucleocapsid protein expression in hepatocytes, in both in vivo and in vitro studies. This novel mutation may be specific to HBV genotype E, and its prevalence requires further investigation.

Base Sequence↗
PubMed2005

Differences of hepatocellular carcinoma patients with hepatitis B virus genotypes of Ba, Bj or C in Japan.

Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are prevalent in Asia. Recently HBV/B has been classified into two subtypes, HBV/Ba which is ubiquitously found in Asia, and HBV/Bj which is specific in Japan. In addition, the frequency of positive HBeAg has been reported to be higher in patients with HBV/Ba than those with HBV/Bj. However, little is known about the differences between patients with various genotypes who developed hepatocellular carcinoma (HCC). In 296 serum samples of HCC patients collected from all over Japan, HBV genotypes were determined with the restriction fragment length polymorphism. HBV/A was detected in 1.0%, HBV/Ba in 4.4%, HBV/Bj in 7.4%, and HBV/C in 86.5%. In the Tohoku district and Okinawa, HBV/Ba, HBV/Bj and HBV/C were found in 6.7, 40.0 and 48.9%, compared to 4.0, 1.6 and 93.2% in the other districts in Japan. HBV/Bj patients were more frequently found in the group older than 65 years while HBV/Ba patients were found in all age groups. The frequency of positive HBeAg in HBV/Bj patients was significantly low compared to that in the other patients. More than 60% of the patients with HCC had cirrhosis as the underlying liver diseases. However, in HBV/Ba patients aged 50 years or younger, 80% of them had chronic hepatitis, while 87.5% of those aged older than 50 years had cirrhosis. These data suggest that great differences exist among patients with HCC infected with different genotypes.

Adult↗
PubMed2005

Detection of API2-MALT1 fusion transcripts in cytologic specimens of patients with pulmonary mucosa-associated lymphoid tissue lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma constitutes up to 90% of primary pulmonary lymphomas, but its diagnosis is often difficult. API2-MALT1 fusion is specific to MALT lymphoma and is detected in nearly half of the pulmonary cases. Cytologic examinations have played a pivotal role in the diagnosis of pulmonary tumors; however, cytologic specimens have only infrequently been used for molecular studies. In this study, we performed a multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay to detect the API2-MALT1 fusion transcript in archival cytologic specimens used as RNA sources. We studied 3 pulmonary MALT lymphoma cases that were positive for the fusion gene as detected with RNA extracted from diagnostic histologic specimens. In 1 case, a conventional PCR clonality assay for the immunoglobulin heavy chain gene rearrangement failed to detect the monoclonality. In all 3 cases, the fusion transcript was successfully detected in the cytologic specimens of sputum, bronchoalveolar lavage fluid, bone marrow smears, and pleural effusions. This finding suggests that such specimens can be used as RNA sources in multiplex RT-PCR assays for the API2-MALT1 fusion transcript. The detection of API2-MALT1 fusion as carried out with these specimens would be useful as an ancillary assay for the diagnosis, staging, and follow-up of pulmonary MALT lymphoma.

Aged↗
PubMed2005

Spontaneous hepatic rupture due to metastatic tumor of lung adenocarcinoma.

A 64-year-old man diagnosed as lung adenocarcinoma with hepatic tumor was admitted to our hospital. He carried the hepatitis B virus but was negative for PIVKA-II and alpha-fetoprotein, and hence we diagnosed a case of stage IV lung adenocarcinoma. We planned to administer systemic chemotherapy, but he experienced sudden-onset abdominal discomfort accompanied with decreased blood pressure. We diagnosed hemorrhagic ascites due to spontaneous rupture of the liver tumor. Emergency angiography and therapeutic embolization stabilized his clinical condition. Hemorrhagic ascites due to metastatic liver tumor is rare and the sudden onset of abdominal symptoms is an indicator of rupture.

Adenocarcinoma↗
PubMed2005

Cryptogenic organizing pneumonia after radiotherapy for breast cancer.

We report a case of lasting fever and cough with pulmonary infiltrates progressing 4 months after adjuvant radiotherapy following surgery for breast cancer. Chest radiography and computed tomography demonstrated alveolar opacities outside the irradiated pulmonary area. Laboratory data revealed neutrophilia and increased levels of C-reactive protein. Bronchoalveolar lavage fluid displayed increased lymphocyte counts, and transbronchial lung biopsy revealed histological patterns compatible with cryptogenic organizing pneumonia (COP). Corticosteroid therapy resulted in marked clinical improvement. From the histological and clinical findings, this case was judged to be a case of COP induced after radiotherapy for breast cancer, similar to those reported recently.

Adrenal Cortex Hormones↗
PubMed2005

[A case of thymic carcinoma responding to combination chemotherapy with nedaplatin, etoposide, and ifosfamide].

We described a case of thymic carcinoma that responded remarkably to combined chemotherapy with etoposide (ETP), ifosfamide (IFO) and nedaplatin. A 68-year-old woman was admitted to our hospital because of hoarseness and dysphasia. Chest computed tomographic (CT) scans showed an anterior mediastinal tumor. Using CT-guided needle biopsy, the diagnosis was squamous cell type of thymic carcinoma. We gave her modified VIP therapy with ETP, IFO and nedaplatin. The tumor contraction response was evident after 3 courses of treatment. This case suggested that nedaplatin may be one of the promising agents for thymic carcinoma chemotherapy.

Aged↗
PubMed2005

Global real-time quantification/reverse transcription-polymerase chain reaction for detecting proto-oncogenes associated with 14q32 chromosomal translocation in multiple myeloma.

A global real-time quantitative/reverse transcription-polymerase chain reaction technique for detecting the expression of six 14q32 chromosomal translocation-associated proto-oncogenes in marrow plasma cells was established and applied to myeloma specimens. This technique is an alternative method of detecting 14q32 rearrangements and allows investigation of the relationship between proto-oncogene expression and clinical features.

Chromosomes, Human, Pair 14↗
PubMed2005

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms in sarcoidosis patients.

BACKGROUND AND AIM: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a co-stimulatory molecule that is expressed on activated T-cells, and is an important regulator of T-cell activation in T-cell-dependent immune responses. CTLA-4 signals lead to the downregulation of T-cell proliferation and activation. Sarcoidosis is a systemic granulomatous disorder of unknown etiology, which shows abnormal regulation of T cell activation. Polymorphisms of CTLA-4 have been reported to alter CTLA-4 expression, and are associated with many diseases. In the present study we investigated CTLA-4 polymorphisms of promoter -318(C/T) and exon 1 +49(A/G) in sarcoidosis patients and control subjects to determine whether these genetic variations affect sarcoidosis. METHODS: One hundred and six sarcoidosis patients and 100 healthy control subjects were studied. The polymerase chain reaction technique and direct genomic sequencing were used to determine the genotypes of promoter -318(C/T) and exon 1 +49(A/G) in the CTLA-4 gene. RESULTS: We found no difference in the distribution of either genotype between the healthy control subjects and sarcoidosis patients. Among the sarcoidosis patients, the -318(C/T) CC genotype (p = 0.011) and AG or GG genotype at position +49(A/G) (p = 0.004) were increased with ocular involvement compared with those patients without ocular involvement. Furthermore, the +49(A/G) GG genotype was increased in patients with three or more organs affected compared with patients with fewer organs affected (p = 0.019). CONCLUSIONS: The CTLA-4 polymorphisms are not associated with disease susceptibility of sarcoidosis, but these genetic variations significantly influence phenotypes of sarcoidosis.

Abatacept↗