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Biomedical subjects

S Kudoh

Publications and source records attributed to S Kudoh.

At least 199 records · Page 11Linked to original sources
PubMed1996

[Phase I study on DMDC].

Phase I study on antimetabolic carcinostatic DMDC was conducted at 16 medical institutions nationwide for patients with various types of malignant tumors. DMDC was administered by intravenous infusion as per the following three schedules: single administration, single repeated administration, and 5-consecutive-day administration. The safety of the compound was examined single administration in 16 patients, by the single repeated administration in 5 patients, and by the 5 consecutive-day administration in 7 patients, for a total of 28 patients. In the single administration trial, 200 mg/m2 (1 n) was given as an initial dose, then increased stepwise to 450 mg/m2 (2.25 n). The single repeated administration trial was conducted at a single dose of 300 mg/m2. One treatment course lasts until recovery from side effects and abnormalities in laboratory test values. As a general rule, the administration was repeated for 2 treatment courses or more. In the 5-consecutive-day administration trial, an initial dose was 30 mg/m2/day (1 n), and increased to 40 mg/m2/day (1.3 n). The dose-limiting factors for both the single and 5-consecutive-day administration trials were decreases in the numbers of leukocytes and neutrophils. The maximum tolerated dose for single administration trial was over 400 mg/m2 (2 n), and for the 5-consecutive-day administration trial 40 mg/m2 (1.3 n). The decrease in the number of leukocytes and neutrophils for both the single administration and 5-consecutive-day administration trial reached its nadir one to two weeks after administration, and recovered in about one week. In the single repeated administration trial, the administration interval for patients who had completed 2 courses was 2 approximately 3 weeks. The plasma half-life of DMDC in the final phase of elimination in the single administration trial was 5.2 approximately 6.3 hours, and no differences were seen among dose levels. The urinary excretion rate was between 32.0 approximately 61.5% until 48 hours after administration. No accumulation was seen in the 5-consecutive-day administration trial. There were no findings to suggest an antitumor effect in the present study. Given the recovery pattern for suppression of marrow, the above mentioned results led us to decide that an recommended method of administration and dosage in an early phase II trial would be 300 mg/m2 per administration by an intravenous infusion every 2 approximately 3 weeks.

Aged↗
PubMed1996

[Pulmonary actinomycosis--diagnosis and therapy based on past reports of actinomycosis].

A 57-year-old man who complained of bloody sputum was admitted to the hospital because of a spherical mass on a chest X-ray film. Despite a detailed examination, no definitive diagnosis was obtained, and a left lower lobectomy was done. Histopathologic examination of tissue from the resected lobe revealed sulfur granules and branching filamentous bacteria, and therefore pulmonary actinomycosis was diagnosed. Examination of reports published in Japan in the last five years suggested a slight increase in the frequency of diagnosis before treatment of actinomycosis and a slight decrease in the frequency of surgical treatment. However, these changes are not surprising because the frequency of surgical treatment is 58%. These findings suggest that pulmonary actinomycosis should be included in the differential diagnosis of a mass on a chest X-ray film.

Actinomycosis↗
PubMed1995

T cells infiltrating non-Hodgkin's B cell lymphomas show altered tyrosine phosphorylation pattern even though T cell receptor/CD3-associated kinases are present.

Although tumor infiltrating lymphocytes (T-TIL) from B cell non-Hodgkins lymphoma patients contain tumor-reactive T cells, they display poor proliferation and IFN-gamma production when stimulated through the TCR-CD3. To determine if there was altered signaling linked to TCR-CD3 ligation, tyrosine phosphorylation was examined in T-TIL because it represents an early and critical event in T cell activation. After stimulation with anti-CD3 Ab, Western blotting with anti-phosphotyrosine showed reduced phosphorylation in T-TIL when compared with peripheral blood-derived T cells from normal individuals. The altered phosphorylation was not due to the reduced expression of signaling elements linked to the TCR-CD3 complex. T-TIL expressed normal levels of CD3 epsilon, TCR zeta chain, and the three tyrosine kinases, p56lck (Lck), p59fyn, and ZAP-70. However, in T-TIL, anti-Lck Ab reacted with a 60-kDa protein, which appears to be the phosphorylated form of Lck. Binding of anti-Lck Ab to the 60-kDa protein was blocked by Lck peptide. In addition, anti-Lck Ab immunoprecipitated a phosphorylated 60-kDa protein from gamma-32P-labeled T-TIL that was not seen in normal resting T cells. In vitro kinase assay studies also demonstrated that TCR-CD3 engagement increased the kinase activity of Lck in normal T cells but not in T-TIL. These results suggest that although T-TIL from B cell non-Hodgkins lymphoma patients contain the signal transduction molecules associated with TCR-CD3 activation pathway, they are impaired in tyrosine phosphorylation and Lck activity, which may contribute to the functional defects of these cells.

Humans↗
PubMed1995

Selective cytokine gene expression in renal cell carcinoma tumor cells and tumor-infiltrating lymphocytes.

The progression of tumors such as renal cell carcinoma (RCC), despite the presence of substantial lymphocytic infiltrates (TIL), suggests that the ability of the local immune response to control tumor growth is impaired. Cytokine gene expression was examined to further investigate the nature of this response. Initial studies were performed with frozen tumors using PCR-assisted mRNA amplification with cytokine-specific primers for interleukin 10 (IL-10), interleukin 2 (IL-2) and interferon-gamma (IFN-gamma). IL-2 mRNA was not detected, despite the presence of T cells as defined by the expression of CD3 gamma mRNA. In contrast, mRNA for IFN-gamma was expressed in 4/9 and for IL-10 in 5/9 tumors. To confirm this, 5 fresh tumor specimens were examined, and PCR demonstrated that IL-10 mRNA was detectable in 4/5 tumors from which RNA was isolated at the time of nephrectomy. In these experiments multiple cycles and dilutions were employed to semi-quantitate the expression of IL-10. To identify potential sources of this cytokine in the tumor bed, IL-10 mRNA expression in freshly isolated lymphocytes and tumor cells, TIL lines, cultured RCC and established RCC lines was examined. Our studies demonstrate that within the tumor TIL may be one source of IL-10. Lymphocyte-enriched populations from 4/5 tumors expressed IL-10 mRNA as did 4/6 freshly isolated tumor cell preparations. IL-10 gene expression was not detected, however, in tumor cells after one passage in vitro in short-term cultured RCC tumor cells (passages 2-5) or in established RCC tumor cell lines. Finally, 4/9 CD4+ and 2/5 CD8+ TIL lines expressed IL-10 mRNA either constitutively or after stimulation with anti-CD3 antibody. This finding was associated with IL-10 production in vitro. Our studies demonstrate that IL-10 mRNA is frequently present in RCC tumors and may originate from the tumor-infiltrating mononuclear cell population.

Base Sequence↗
PubMed1995

In vitro investigation of a combination of two drugs, cisplatin and carboplatin, as a function of the area under the c/t curve.

The log/log relationship between the IC50 of cisplatin or carboplatin and the exposure time, determined by human tumor clonogenic assay (HTCA) and MTTAI (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with additional incubation) using PC-14 cells, exhibited a straight line with a slope of -1, indicating that both drugs have AUC-dependent cytotoxicity (AUC, area under the c/t curve). The combined effect of cisplatin and carboplatin was estimated by the median-effect analysis using HTCA, and it was additive when the AUC ratio (AUC of free platinum from carboplatin/that from cisplatin) was low (3.2, 6.5 or 13.1 in each of PC-7, PC-9, PC-14, H-69, and K562). However, it was significantly worse at a higher AUC ratio (19.5 in PC-7, PC-9, and PC-14). The log/log relationship of each drug, determined by MTTAI using human bone marrow cells, showed that each drug exerts an AUC-dependent cytotoxicity on marrow granulocytes. When cisplatin and carboplatin were combined at an AUC ratio of 14, the therapeutic index was significantly better than that of carboplatin alone and less than that of cisplatin alone using K562, PC-9 and PC-14, indicating the usefulness of this combined therapy for tumor cells with high sensitivity to platinum compounds at this AUC ratio.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin's lymphomas.

T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon gamma (IFN gamma), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3.

Adult↗
PubMed1995

Comparison of bronchodilator responses to adrenomedullin and proadrenomedullin N-terminal 20 peptide.

This study was designed to determine and compare airway responses to synthetic human adrenomedullin(AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in anesthetized guinea pigs in vivo. 10(-7) M AM and PAMP significantly inhibited acetylcholine-and histamine-induced bronchoconstriction. However, this significant bronchodilator effect of PAMP lasted about five minutes, which was much shorter than that of AM. In addition, the bronchodilator effect of AM is approximately 100-fold more potent than PAMP. We demonstrated that PAMP had a potent bronchodilator activity, and induced a rapid and short-lasting bronchodilation. These findings suggest that AM and PAMP may play important roles in airway functions.

Acetylcholine↗
PubMed1995

Bronchoscopic findings of extramural lung cancer invading the subepithelium or submucosa.

Bronchoscopic findings from the main to segmental bronchi were compared with the histopathological findings in 185 resected cases of lung cancer, in order to determine which bronchoscopic features are associated with lung cancer invading the subepithelium or submucosa from beyond the bronchial wall. Carcinoma invaded the subepithelium or submucosa from beyond the bronchial wall in 43 cases (22.9%) out of the total of 185 cases. Bronchoscopic findings were evaluated in these 43 cases, and were summarized as follows: (1) The bronchoscopic findings in cases of subepithelial invasion consisted of vascular engorgement, bleeding, subepithelial tumor, and emphasized longitudinal relief; (2) irregularity of the mucosa was observed in cases of epithelial or muscular invasion; (3) indistinct bronchial cartilage was observed in cases of invasion proximal to the extramuscular layer; (4) accentuated irregular folds were observed in cases of invasion of the extramuscular or cartilage layers; and (5) edema and redness were not specific for malignancy. In addition, the occurrence of mediastinal lymph node metastasis was higher in cases of invasion to main or lobar bronchi. This result indicates that recognition of invasion of the subepithelium or submucosa of the central bronchus may be helpful in indicating the probability of mediastinal lymph node metastasis. Accordingly, there may be specific bronchoscopic findings which correlate with invasion of the bronchial subepithelium or submucosa. Accurate recognition of these findings may be useful in determining appropriate biopsy sites and may provide more information concerning selection of therapeutic strategy.

Bronchoscopy↗
PubMed1995

Angiotensin II stimulates peptide leukotriene production by guinea pig airway via the AT1 receptor pathway.

Angiotensin II (Ang II) regulates a variety of physiological functions, including contraction of smooth muscle. Peptide leukotrienes (LTs) have recently been reported to be potent bronchoconstrictors and may play a role in the pathogenesis of airway inflammation. However, the possibility that Ang II and peptide LTs interact in the control of airway function has not been studied. In this study, we showed that Ang II receptors are present on guinea pig airway, and that they are of the AT1 subtype. We showed the possibility that Ang II induced the release of peptide LTs from guinea pig airway by activation of the AT1 receptor pathway. Our findings thus suggest that interaction between Ang II and peptide LTs might increase airway inflammation in the guinea pig.

Airway Resistance↗
PubMed1995

Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy with cisplatin.

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

Adult↗
PubMed1995

Emergence of karyotypically unrelated clone in remission of de novo acute myeloblastic leukaemias.

Serial cytogenetic analysis revealed karyotypically unrelated clones in four patients with acute myeloblastic leukaemia (AML) in remission. At diagnosis, three patients had t(8;21)(q22;q22) and one had an inv(16)(p13q22). After 18-22 months in remission, different clones emerged in each patient with myelodysplastic features of the bone marrow cells. The emergence of clones with abnormalities of chromosome 7 in remission seems to be an unfavourable factor for prognosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy.

We have previously shown that mechanical stress induces activation of protein kinases and increases in specific gene expression and protein synthesis in cardiac myocytes, all of which are similar to those evoked by humoral factors such as growth factors and hormones. Many lines of evidence have suggested that angiotensin II (Ang II) plays a vital role in cardiac hypertrophy, and it has been reported that secretion of Ang II from cultured cardiac myocytes was induced by mechanical stretch. To examine the role of Ang II in mechanical stress-induced cardiac hypertrophy, we stretched neonatal rat cardiac myocytes in the absence or presence of the Ang II receptor antagonists saralasin (an antagonist of both type 1 and type 2 receptors), CV-11974 (a type 1 receptor-specific antagonist), and PD123319 (a type 2 receptor-specific antagonist). Stretching cardiac myocytes by 20% using deformable silicone dishes rapidly increased the activities of mitogen-activated protein (MAP) kinase kinase activators and MAP kinases. Both saralasin and CV-11974 partially inhibited the stretch-induced increases in the activities of both kinases, whereas PD123319 showed no inhibitory effects. Stretching cardiac myocytes increased amino acid incorporation, which was also inhibited by approximately 70% with the pretreatment by saralasin or CV-11974. When the culture medium conditioned by stretching cardiocytes was transferred to nonstretched cardiac myocytes, the increase in MAP kinase activity was observed, and this increase was completely suppressed by saralasin or CV-11974. These results suggest that Ang II plays an important role in mechanical stress-induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.

Angiotensin II↗
PubMed1995

Alveolar fibrosis and capillary alteration in experimental pulmonary silicosis in rats.

To analyze the evolution of fibrotic and vascular changes in pulmonary silicosis, ultrastructural and immunohistochemical studies were made of the lungs of rats given a single intratracheal injection of silica particles. Early lesions were characterized by accumulations of macrophages and neutrophils in alveolar lumina and interstitium and by damage to alveolar capillaries and epithelial cells. The intraluminal masses of inflammatory cells developed into granulomas and became associated with myofibroblasts that migrated from the interstitium through the damaged epithelial lining. Type II epithelial cells and bronchiolar cuboidal cells proliferated rapidly to line the intraluminal granulomas, incorporating them into the interstitium. This process mediated the transition from intraalveolar fibrosis to interstitial fibrosis. Vascular damage was repaired by proliferation and migration of endothelial cells. Some endothelial cells in alveolar capillaries expressed Factor VIII-related antigen at 2 wk after silica infusion. In normal animals, this feature was present in peribronchiolar but not in alveolar capillaries. Two patterns of endothelial cell migration were shown by staining for proliferating-cell nuclear antigen. The first pattern was characterized by endothelial cells that extended their cytoplasm over preexisting, denuded basement membranes and replaced necrotic cells in alveolar capillaries. At 4 mo after injury, some of these cells had developed fenestrations. The second pattern consisted of budlike sproutings that developed only in peribronchiolar connective tissue. These observations indicate that peribronchiolar vessels are sources for renewal of alveolar capillary endothelium as well as for neovascularization.

Animals↗
PubMed1995

Mechanical stress activates protein kinase cascade of phosphorylation in neonatal rat cardiac myocytes.

We have previously shown that stretching cardiac myocytes evokes activation of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and 90-kD ribosomal S6 kinase (p90rsk). To clarify the signal transduction pathways from external mechanical stress to nuclear gene expression in stretch-induced cardiac hypertrophy, we have elucidated protein kinase cascade of phosphorylation by examining the time course of activation of MAP kinase kinase kinases (MAPKKKs), MAP kinase kinase (MAPKK), MAPKs, and p90rsk in neonatal rat cardiac myocytes. Mechanical stretch transiently increased the activity of MAPKKKs. An increase in MAPKKKs activity was first detected at 1 min and maximal activation was observed at 2 min after stretch. The activity of MAPKK was increased by stretch from 1-2 min, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10 approximately 30 min after stretch, respectively. Raf-1 kinase (Raf-1) and (MAPK/extracellular signal-regulated kinase) kinase kinase (MEKK), both of which have MAPKKK activity, were also activated by stretching cardiac myocytes for 2 min. The angiotensin II receptor antagonist partially suppressed activation of Raf-1 and MAPKs by stretch. The stretch-induced hypertrophic responses such as activation of Raf-1 and MAPKs and an increase in amino acid uptake was partially dependent on PKC, while a PKC inhibitor completely abolished MAPK activation by angiotensin II. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1 and MEKK, MAPKK, MAPKs and p90rsk, and that angiotensin II, which may be secreted from stretched myocytes, may be partly involved in stretch-induced hypertrophic responses by activating PKC.

Amino Acid Sequence↗
PubMed1995

[Antibodies of IgM type against small cell lung carcinoma and 29 kD neuronal antigen of rat in a patient with paraneoplastic sensory neuropathy].

62-year old man who had small cell lung carcinoma (SCLC) with subacute sensory neuropathy had an antibody (IgM) recognizing the antigen on peripheral nerves. The antibody in the serum recognized cell surface antigen on small cell carcinoma cell lines and also reacted with peripheral nerves simultaneously, but not with central nervous system. Two months before admission, he felt difficulty in walking because of paresthesias in the extremities. He was found to have a tumor shadow in chest X-ray, and was diagnosed as SCLC by biopsy of right supraclavicular lymph node. Western blot analysis demonstrated that auto-antibody (IgM) in the serum recognizing the antigen on the neuronal axon with single band at 29 kD. Pathogenesis of carcinomatous neuropathy is still unexplained, but the findings presented here have given rise to the possibility that anti-SCLC antibody may cross-react with neuronal antigen, primarily resulting in neuronal disorder.

Animals↗
PubMed1995

Significance of serum neuron-specific enolase as a predictor of relapse of small cell lung cancer.

We conducted a prospective study to evaluate the significance of serum neuron-specific enolase (NSE) as a predictor of relapse of small cell lung cancer (SCLC). Patients entered into the study were drawn from those who had shown a complete or partial response to first-line chemotherapy with a concurrent decline in the NSE level to less than 10 ng/ml. When the serum NSE level increased to more than 15 ng/ml, the patient was restaged on the basis of clinical, radiological, and bronchoscopic examinations. During the period from August 1988 to December 1990, 57 patients with SCLC were enrolled and followed up until May 1992. Of these patients, 45 had clinical relapses, and 14 (31%) of them showed a clear elevation of the serum NSE level prior to the clinical recognition of relapse. Although one false-positive case was noted, this involved only a transient elevation of the NSE level. In patients who showed increased NSE levels, the relapses occurred in more difficult to detect silent sites such as the adrenal gland, liver, and deep lymph nodes. In addition, the percentage of patients demonstrating high NSE levels who were able to benefit from salvage chemotherapy was higher than for those who did not (RHO < 0.05). Our results indicate that serial NSE measurements are useful for the early prediction of SCLC relapse and should help to facilitate early administration of salvage chemotherapy for affected patients.

Adult↗
PubMed1995

[Giant cell interstitial pneumonia in a metal grinder with an abnormally high level of serum CA19-9].

Interstitial pneumonia and recurrent pneumothorax developed in a 48-year-old man who had worked as a metal grinder. He died of respiratory failure despite having received antibiotics and steroids, and despite having undergone pleural sclerosis therapy. Giant cell interstitial pneumonia was diagnosed; innumerable bizarre giant cells engulfing black granules were found within the alveoli. The results of high-energy dispersion X-ray microanalysis indicated that the patient had hard metal pneumoconiosis associated with tungsten in the black granules. When he was admitted to the hospital, his serum CA19-9 and SLEX concentrations were abnormally high (2600 and 200 ng/ml, respectively). Immunohistochemical analysis of lung tissue was done with anti-CA19-9 and SLEX antibodies. CA19-9 staining revealed strong bronchialization and squamous metaplasia in contrast to type II hyperplasia. SLEX staining showed strong type II hyperplasia. Further investigations will be needed to determine the mechanism of elevated tumor-associated carbohydrate antigens in serum.

Biomarkers, Tumor↗