A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase.
Explore the source record for details and available documents.
3T3 Cells↗
Biomedical subjects
T Kamei
Publications and source records attributed to T Kamei.
Activity of gemcitabine in non-small-cell lung cancer: results of the Japan gemcitabine group (A) phase II study.
PURPOSE: This phase II study was conducted to determine the response and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in chemotherapy-naive patients with non-small-cell lung cancer (NSCLC). METHODS: A group of 73 patients were entered into the study. The patients had received no previous chemotherapy and all had measurable disease. The initial starting dose of gemcitabine was 1000 mg/m2 per week x 3 followed by a week of rest, and was escalated for the next cycle to 1250 mg/m2, provided there were no signs of hematologic toxicity (WBC < 3000/microl and/or platelets < 70,000/microl) in the previous cycle. RESULTS: Among 73 eligible patients, there were 19 partial responses (PRs), with an overall response rate of 26.0% (95% confidence interval 16.5-37.6%). The response rate for stage IIIa and IIIb disease was significantly higher than that for stage IV disease [41.4% (12/29) vs 15.9% (7/44); P = 0.028]. The median duration of response in patients showing a PR was 4.6 months (1.7 10.4 months). The median number of cycles given was two per patient (range one to seven). Grade 3 anemia, leukopenia and neutropenia occurred in 15 patients (20.5%), 7 patients (9.6%) and 20 patients (27.4%), respectively. Grade 3 thrombocytopenia occurred in one patient (1.4%) which was not associated with any bleeding. There was no evidence of cumulative toxicity in the later courses of gemcitabine treatment with regard to leukopenia and thrombocytopenia. Other toxicities, including hepatic toxicity, fatigue, nausea/vomiting and fever were mild (grade 2 or less) and transient. One patient was withdrawn from the trial because of a rash. Pulmonary toxicity was experienced in two patients and one patient died of respiratory insufficiency which was thought to be drug-related. CONCLUSIONS: Gemcitabine as a single agent has proven to be an active drug for NSCLC with a favorable, generally mild side-effect profile. Further trials in combination with other agents for this disease are currently underway.
Adult↗
Overexpression of p53 protein in interstitial lung diseases.
The p53 gene is well known as a tumour suppressor gene. In addition, the mutated p53 gene is detected in a variety of human cancers including lung cancer, and is considered as an oncogene. Lung cancer is also frequently associated with interstitial lung diseases. Therefore, it may be possible to hypothesize that there might be some abnormality of p53 gene in interstitial lung diseases. This work examined the relationship between the p53 protein and gene in lung tissues of 28 patients with interstitial lung diseases. Among 28 patients, 13 cases were pathologically diagnosed to have usual interstitial pneumonia (UIP), 12 cases were diagnosed as having collagen vascular lung diseases, and three cases were diagnosed to have a non-specific interstitial pneumonia. Twenty-three tissue samples were obtained by open lung biopsy and five samples were taken by autopsy. Paraffin-embedded tissues were treated by microwave, and stained with an anti-p53 antibody (DO7) by the Avidin-Biotin-Peroxidase (ABC) method. In selected patients, mutations in exons 5-8 of the p53 gene were also examined by single-strand conformation polymorphism (SSCP) analysis and DNA sequence. In addition, the presence of anti-p53 antibodies in patients' sera was screened for by ELISA. Fifteen samples (53.6%) revealed overexpression of the p53 protein in the nuclei of alveolar epithelial cells. However, SSCP or sequence analysis, which was performed in 13 tissues, showed no mutations in exons 5-8 of the p53 gene. In conclusion, p53 proteins were overexpressed in interstitial lung diseases, and the expressed p53 protein was considered to be wild-type. This wild-type p53 protein may play a role in blocking the transformation of proliferative epithelial cells.
Adult↗
Measurement of hepatocyte growth factor in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis.
The present study evaluated the clinical significance of hepatocyte growth factor (HGF) in patients with pulmonary fibrosis. Twenty-one patients with a diagnosis of pulmonary fibrosis [14 with idiopathic pulmonary fibrosis (IPF) and seven with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD]) and 21 normal subjects as control were studied. HGF levels in sera of patients with pulmonary fibrosis (0.34 +/- 0.02 ng ml-1) were elevated significantly as compared with normal subjects (0.21 +/- 0.01 ng ml-1) (P < 0.0001). HGF/albumin levels in broncho-alveolar lavage fluid (BALF) of patients with pulmonary fibrosis (72 +/- 17 ng g-1 albumin) were also significantly elevated as compared with normal subjects (under the detection limit) (P < 0.01). HGF levels in sera correlated significantly with elastase levels in sera and C-reactive protein, and correlated negatively with PaO2. HGF levels in sera were significantly higher in smokers with pulmonary fibrosis (0.42 +/- 0.03 ng ml-1) as compared with non-smokers with pulmonary fibrosis (0.29 +/- 0.03 ng ml-1) (P < 0.005). HGF/albumin levels in BALF correlated significantly with elastase/albumin levels in BALF, lactate dehydrogenase/albumin in BALF, Immunoglobulin A/albumin in BALF, total cell count/albumin in BALF, total number of alveolar macrophage/albumin in BALF, total number of neutrophil/albumin in BALF, CEA/albumin in BALF, CA19-9/albumin in BALF, and SCC/albumin in BALF. These results suggest that following lung injury, HGF may be a mediator involved in the repair which leads to pulmonary fibrosis.
Adult↗
Multihormone-producing islet cell tumor of the pancreas associated with somatostatin-immunoreactive amyloid: immunohistochemical and immunoelectron microscopic studies.
Pancreatic islet cell tumors, especially insulinomas, are often associated with amyloid deposition in the tumor tissue. Biochemical analysis has demonstrated that the amyloid protein from insulinoma is derived from islet amyloid polypeptide (or amylin) that is produced by tumor cells originating from beta cells of the islet of Langerhans. We examined a case of malignant pancreatic islet cell tumor with amyloid deposition in the tumor tissue using immunohistochemistry and double-labeling immunogold electron microscopy. The tumors were composed of cells producing multiple hormones, including somatostatin, gastrin, amylin, insulin, calcitonin gene-related polypeptide, and calcitonin. Amyloid deposits reacted with antisomatostatin antiserum but not with other antisera, including antiamylin. The present study demonstrated for the first time that amyloid associated with islet cell tumors is not always derived from amylin and can come from somatostatin.
Aged↗
J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.
Farnesylation of the activated ras oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Because squalene synthase and FTase recruit farnesyl pyrophosphate as a common substrate, we modified squalene synthase (SS) inhibitors to develop FTase inhibitors. Among the compounds tested, a novel FTase inhibitor termed J-104,871 inhibited rat brain FTase with an IC50 of 3.9 nM in the presence of 0.6 microM farnesyl pyrophosphate (FPP), whereas it scarcely inhibited rat brain protein geranylgeranyltransferase-I or SS. The in vitro inhibition of rat brain FTase by J-104,871 depends on the FPP concentration but not on the concentration of Ras peptide. Thus, in vitro studies strongly suggest that J-series compounds have an FPP-competitive nature. J-104,871 also inhibited Ras processing in activated H-ras-transformed NIH3T3 cells with an IC50 value of 3.1 microM. We tested the effects of lovastatin and zaragozic acid A, which modify cellular FPP levels, on Ras processing of J-104,871. Lovastatin, a hepatic hydroxymenthyl coenzyme A reductase inhibitor that reduced the cellular FPP pool, increased the activity of J-104,871, whereas 3 microM zaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 microM. These results suggest that J-104,871 inhibits FTase in an FPP-competitive manner in whole cells as well as in the in vitro system. Furthermore, J-104,871 suppressed tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells.
3T3 Cells↗
Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders.
BACKGROUND: It has been suggested that the humoral immune system plays a role in the pathogenesis of cryptogenic fibrosing alveolitis (CFA). Although circulating autoantibodies to lung protein(s) have been suggested, none of the lung proteins have been characterised. The purpose of this study was to determine the antigen to which the serum from patients with pulmonary fibrosis reacted. METHODS: The anti-A549 cell antibody was characterised in a patient with CFA using Western immunoblotting and immunohistochemical staining of A549 cells. As we identified that one of the antibodies against A549 cells was anti-cytokeratin 8, the expression of mRNA of cytokeratin 8 in A549 cells was evaluated. In addition, we attempted to establish an enzyme linked immunosorbent assay to measure the levels of anti-cytokeratin 8 antibody in the serum of patients with CFA and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). RESULTS: Initially two anti-A549 cell antibodies were detected in the serum of patients with pulmonary fibrosis, one of which was characterised as anticytokeratin 8 antibody by Western immunoblotting. We were able to establish an ELISA to measure anti-cytokeratin 8 antibody and found significantly higher levels in patients with CFA and PF-CVD than in normal volunteers, patients with sarcoidosis, pneumonia, and pulmonary emphysema. CONCLUSIONS: One of the anti-A549 cell antibodies in the serum of patients with CFA was against cytokeratin 8. The serum levels of anti-cytokeratin 8 antibody were increased in patients with CFA and PF-CVD. These results suggest that anticytokeratin 8 antibody may be involved in the process of lung injury in pulmonary fibrosis.
Adult↗
Response of healthy individuals to ninjin-yoei-to extract--enhancement of natural killer cell activity.
After administering 15 g/day of Ninjin-Yoei-To (NYT) for one week to healthy people whose NK activity had already been increased by physiological response, a further increase in NK activity was observed after two days. This increased level of NK activity continued during the administration of NYT for a one-week period. The maintaining and reinforcing effect on the immune surveillance system by NYT may be useful for prevention of carcinogenesis.
Adult↗
Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis.
It was hypothesized that neutrophil elastase released from activated neutrophils may play an important role in the pathogenesis of pulmonary fibrosis. In the present study, we measured the neutrophil elastase:alpha-1-proteinase inhibitor complex (E-PI) in serum and bronchoalveolar lavage fluid (BALF) in 26 patients with pulmonary fibrosis and evaluated the correlation between E-PI levels and several parameters. E-PI levels in serum of patients with pulmonary fibrosis (635.8+/-112.0 ng.mL(-1)) were significantly elevated compared to normal nonsmokers (122.0+/-4.0 ng.mL(-1)) as well as normal smokers (132.8+/-8.4 ng.mL(-1)) (p<0.01). E-PI levels in serum significantly correlated with hepatocyte growth factor (HGF) levels in serum, C-reactive protein (CRP), and negatively correlated with arterial oxygen tension (Pa,O2), and arterial carbon dioxide tension (Pa,CO2). E-PI/albumin levels in BALF significantly correlated with HGF/albumin levels in BALF, lactate dehydrogenase (LDH)/albumin in BALF, total number of inflammatory cells (alveolar macrophages and neutrophils) in BALF, and several markers derived from epithelial cells in BALF. Our data demonstrated: 1) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum increased in patients with pulmonary fibrosis; and 2) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid correlated with clinical parameters in pulmonary fibrosis. These results suggest that neutrophil elastase may play a significant role in the process of lung injury in pulmonary fibrosis.
Adult↗
Heterogeneous point mutations of the p53 gene in pulmonary fibrosis.
Lung cancer is a frequent complication in pulmonary fibrosis. Overexpression of p53 proteins has been demonstrated by immunostaining in bronchoepithelial cells in patients with idiopathic pulmonary fibrosis. However, it is still unclear whether this overexpressed p53 protein is wild-type or mutant. It was hypothesized that pulmonary fibrosis may be a precancerous lesion with deoxyribonucleic acid point mutations in bronchoepithelial cells. Mutations of the p53 gene were tested for by fluorescence-based single-strand conformation polymorphism (FSSCP), cloning-sequencing and immunostaining techniques. Out of 10 tissue samples that demonstrated overexpression of p53 protein by immunostaining, nine (90%) exhibited point mutations and eight (80%) exhibited heterogeneous point mutations of the p53 gene. The mutations found in pulmonary fibrosis were scattered throughout the central part of the p53 gene, and both guanine (G):cytosine (C) to adenine (A):thymine (T) and A:T to G:C transitions were frequently observed. In conclusion, frequent heterogeneous point mutations of the p53 gene were detected in pulmonary fibrosis. These mutations may have resulted from several types of deoxyribonucleic acid damage that occurred in bronchoepithelial cells and this may explain previous findings of a very high incidence of lung cancer complicating pulmonary fibrosis.
Adult↗
Two cases of myelodysplastic syndrome with extramedullary polyclonal plasma cell proliferation and autoantibody production: possible role of soluble Fas antigen for production of excessive self-reactive B cells.
Two cases of myelodysplastic syndrome (MDS) with extramedullary polyclonal plasma cell proliferation and autoantibody production are reported. These cases, which showed leukemic change of refractory anemia with excess of blast (RAEB), developed lymph node swelling and muscle abscess; both were infiltrated mainly with plasma cells, without preceding infection. The proliferation of plasma cells was polyclonal and was proven by negative rearrangement of immunoglobulin heavy chain gene or polyclonal staining of immunoglobulin light chains. These patients showed polyclonal gammopathy and autoantibody production such as positive antinuclear factor and direct antiglobulin test. As was observed in one of the present cases, and as we reported previously, the elevated level of soluble Fas antigen in MDS patients, and its inhibition of apoptotic signaling may be responsible for the excessive accumulation of self-reactive B cells, resulting in these clinical manifestations.
Aged↗
Influences of long- and short-distance driving on alpha waves and natural killer cell activity.
We examined the effective amplitudes of alpha waves (using a mean frequency with a range of +/- 0.5 Hz), and activity of natural killer cells in six subjects, before and after a short-distance (43 km, 1 hr.) drive, and after a midnight (am 0:00-am 7:00 to 8:00) long-distance (550 km on average, for 7 to 8 hr.) drive. Following a long-distance drive, the activity of natural killer cells tended to decrease, and the effective amplitudes of alpha waves in the photic feedback period were greater than those observed during the rest period, showing that photic driving had occurred even under physically and mentally stressful conditions. However, after short-distance driving, no photic driving response occurred and activity of natural killer cells tended to increase, possibly related to mental concentration. Avoiding midnight long-distance driving may help prevent excessive stress and preserve high activity in natural killer cells.
Adult↗
[A case of lung abscess caused by Eikenella corrodens].
We report a case of lung abscess caused by Eikenella corrodens and reviewed the literature. A 51-year-old man was hospitalized because of an infiltrative shadow in the left upper lung on chest X-ray. The patient was intravenously given CEZ (2 g/day) followed by CEZ (4 g/day) and AMK (200 mg/day). We nevertheless deteriorated and was subsequently treated with CTM (4 g/day) and LCM (6 g/day), and the shadow improved but remained. Only Eikenella corrodens was isolated from aspiration materials obtained from the resected lung. We examined the susceptibility of 60 strains of Eikenella corrodens to various antimicrobial against. The organisms were very susceptible to PCG, ABPC, PIPC, CTM, CTX and LMOX, but were all resistant to LCM, CLDM, GM and AMK.
Aminoglycosides↗
Clinical features of non-tuberculous mycobacterial disease: comparisons between smear-positive and smear-negative cases, and between Mycobacterium avium and Mycobacterium intracellulare.
OBJECTIVE: To evaluate the differences in clinical symptoms and radiological findings between smear-positive non-tuberculous mycobacteria (NTM) and smear-negative, culture-positive NTM. Also, to evaluate the differences in clinical symptoms and radiological findings between Mycobacterium avium and M. intracellulare. DESIGN: A retrospective study was performed of 200 cases with positive pulmonary cultures for NTM between January 1989 and December 1996. It was determined whether or not pulmonary disease was caused by NTM using the 1990 criteria recommended by the American Thoracic Society. Clinical symptoms and radiological findings were compared between groups. RESULTS: Fever and hemoptysis were more frequently observed in smear-positive patients (26/50, 52%, and 24/50, 48%, respectively) than in smear-negative, culture-positive patients (8/38, 21.1%, P < 0.005, 8/38, 21.1%, P < 0.01, respectively). In addition, cavity formation was more frequently observed in chest computed tomography scans of smear-positive patients (19/36, 52.8%) than in smear-negative patients (6/31, 19.4%, P < 0.005). Finally, cavity formation tended to be more frequently observed with M. avium than with M. intracellulare. CONCLUSION: The present study demonstrates differences in clinical symptoms and radiological findings between smear-positive and smear-negative NTM cases, as well as between M. avium and M. intracellulare.
Female↗
Structure and alternative promoters of the mouse glutamic acid decarboxylase 67 gene.
gamma-Aminobutyric acid is synthesized by glutamic acid decarboxylase (GAD), which has two forms, GAD65 and GAD67. Genomic clones coding mouse GAD67 (mGAD67) have been isolated. The restriction map of the overlapping clones covers a region of more than 45 kb of genomic DNA. The mGAD67 gene contains 16 translated exons in addition to an exon which is preferentially expressed in foetal brain. The rapid amplification of 5'-cDNA ends showed that mGAD67 gene transcripts have two different 5'-untranslated regions. Analysis of the genomic clones encompassing the 5'-exons revealed that the two transcripts arose from a single gene by alternative splicing using two different donor sites and a common acceptor. The exons were found 1.5 and 0.6 kb upstream of exon 1. The corresponding promoter regions of these exons have a number of putative regulatory elements, including Sp1- and Krox-24-binding sites. Analysis of mGAD67 transcripts demonstrated that each of the 5'-untranslated exons was expressed in mouse brain. In contrast, exon 0A, but not exon 0B, was expressed in mouse testis and pancreas. These results suggest that these transcripts may be regulated under the control of independent promoters.
Alternative Splicing↗
Determination of simvastatin and its active metabolite in human plasma by column-switching high-performance liquid chromatography with fluorescence detection after derivatization with 1-bromoacetylpyrene.
By using a fluorescent derivatization and column-switching technique, a highly sensitive and selective high-performance liquid chromatographic (HPLC) method has been developed for the determination of simvastatin (I, beta-hydroxy-delta-lactone form) and its active hydrolyzed metabolite (II, beta,delta-dihydroxy acid form of I) in human plasma. A plasma sample spiked with internal standards was applied to a C8 solid-phase extraction column. Compounds I and II were separately extracted from plasma into two fractions. Compound I in one of the fractions was hydrolyzed to II. A fluorescent derivative was prepared by esterification of II with 1-bromoacetylpyrene in the presence of 18-crown-6 for both fractions. The pyrenacyl ester of II thus obtained was purified on a phenylboronic acid (PBA) solid-phase extraction column, and was measured by column-switching HPLC with fluorescence detection. The calibration curves for both I and II were linear in the concentration range of 0.1-10 ng/ml. The intra-day coefficients of variation were less than 11.0%, and the accuracies were between 91.7% and 117% within the concentration range for both analytes. The limits of quantification (LOQ) for both analytes were set to 0.1 ng/ml. This assay method has adequate sensitivity and selectivity to measure the concentrations of I and II in human plasma from clinical studies.
Anticholesteremic Agents↗
Bni1p and Bnr1p: downstream targets of the Rho family small G-proteins which interact with profilin and regulate actin cytoskeleton in Saccharomyces cerevisiae.
The RHO1 gene encodes a homologue of mammalian RhoA small G-protein in the yeast Saccharomyces cerevisiae. Rho1p is required for bud formation and is localized at a bud tip or a cytokinesis site. We have recently shown that Bni1p is a potential target of Rho1p. Bni1p shares the FH1 and FH2 domains with proteins involved in cytokinesis or establishment of cell polarity. In S. cerevisiae, there is an open reading frame (YIL159W) which encodes another protein having the FH1 and FH2 domains and we have named this gene BNR1 (BNI1 Related). Bnr1p interacts with another Rho family member, Rho4p, but not with Rho1p. Disruption of BNI1 or BNR1 does not show any deleterious effect on cell growth, but the bni1 bnr1 mutant shows a severe temperature-sensitive growth phenotype. Cells of the bni1 bnr1 mutant arrested at the restrictive temperature are deficient in bud emergence, exhibit a random distribution of cortical actin patches and often become multinucleate. These phenotypes are similar to those of the mutant of PFY1, which encodes profilin, an actin-binding protein. Moreover, yeast two-hybrid and biochemical studies demonstrate that Bni1p and Bnr1p interact directly with profilin at the FH1 domains. These results indicate that Bni1p and Bnr1p are potential targets of the Rho family members, interact with profilin and regulate the reorganization of actin cytoskeleton.
Actins↗
Male to male transmission of supernumerary nipples.
We report on a father and his son with supernumerary nipples. No male-to-male transmission has previously been described with this trait. This observation confirms that this trait is inherited in an autosomal dominant fashion.
Child, Preschool↗