Biomedical subjects
Publications and source records attributed to K Imamura.
New anthracycline antibiotics, 1-hydroxy-11-deoxycarminomycin II and 11-deoxycarminomycin II were produced by a blocked mutant MuW1 of Actinomadura roseoviolacea from epsilon-pyrromycinone and aklavinone, respectively. We found that the enzyme catalyzing hydroxylation at the C-11 position was not lost but was down regulated in the strain MuW1.
Cryosurgery is performed in poor risk cases of prostate carcinoma with dysuria. This modality has been reported to reduce the metastatic lesion postoperatively in cases of prostate carcinoma accompanied by metastasis and is employed as an adjuvant therapy of prostate carcinoma. However, many cases are already at an advanced stage and have undergone other therapeutic modalities and as a result the exact role of cryosurgery in prostate carcinoma is not clear. The present investigation was undertaken to clarify the effectiveness of cryosurgery in prostate carcinoma. The patients consisted of 21 untreated cases of histologically confirmed prostate carcinoma admitted our hospital during the 5-year period from December, 1982 to December, 1987, in all of whom treatment by cryosurgery alone was indicated, i.e., up stage B, and in whom changes in prostate carcinoma tumor markers, alkaline phosphatase (ALP), acid phosphatase (ACP), prostatic ACP detected enzymatically (PACP), and by radioimmunoassay (PAP), gamma-seminoprotein (gamma-Sm), and prostate specific antigen (PSA) were measured. During the same period, changes in tumor makers in 11 cases of prostate hypertrophy treated by transurethral resection of prostate (TUR-P) were also examined. The tumor markers were measured prior to cryosurgery and 1, 3, 7 and 14 days postoperatively as well as at 1, 3 and 6 months. Following TUR-P, in the cases of prostate hypertrophy, no postoperative changes in ALP, ACP or PACP were observed but there was elevation of PAP and gamma-Sm at day 1 and elevation of PSA until day 3, but none of these were statistically significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)
The colony-stimulating factor-1 (CSF-1) regulates survival, growth, and differentiation of monocytes by binding to a single class of high-affinity receptors. The CSF-1 receptor is identical to the product of the c-fms protooncogene. The present studies monitored the effects of TPA and CSF-1 on c-fms gene expression in human monocytes. The results demonstrate that TPA downmodulates the constitutive expression of c-fms mRNA to low but detectable levels. Treatment of human monocytes with TPA was similarly associated with decreases in levels of the 138- and 125-Kd c-fms-encoded proteins. However, the kinetics of c-fms protein downmodulation indicated independent effects of TPA on c-fms expression at the RNA and protein levels. Furthermore, c-fms protein levels subsequently recovered despite persistently low levels of c-fms mRNA. Although previous studies demonstrated that c-fms protein is down-regulated in the presence of CSF-1, the present results indicate that CSF-1 also downregulates levels of c-fms mRNA. Moreover, the results indicate that CSF-1 increases protein kinase C activity in the membrane fraction. Together, these findings suggest that c-fms gene expression is differentially regulated at both the RNA and protein levels after activation of protein kinase C in human monocytes treated with TPA and CSF-1.
A seventy-year-old woman was admitted to the hospital because of paresthesias and progressive weakness of the extremities. Ten months previously, tightness in the thighs and numbness in the fingers developed, with subsequent tingling sensations of the hands and feet. Three months before entry, she had difficulty in walking because of severe paresthesias in the extremities. She was found to have an abnormal mass in a X-ray film of the chest, and transferred to our hospital. Neurological examination showed generalized hyporeflexia, marked loss of deep and discriminative sensations in the distal portion of the limbs, positive Romberg sign and severely ataxic gait. Cerebellar sign was negative. Cytologic examination of a transbronchial lung biopsy disclosed small cell carcinoma of the lung. A sural nerve biopsy showed severe loss of myelinated fibers accompanied by axonal degeneration of residual fibers. Immunohistochemically antineuronal antibody was found in the serum but not in the CSF, which reacted to nuclei and cytoplasm of the dorsal root ganglion neurons as well as Purkinje cells. Titers of this autoantibody in the serum were markedly reduced after chemotherapy and irradiation. Western blot analysis demonstrated that autoantibody in the serum recognized neuronal antigen with single band at 38 kd. Pathogenesis of carcinomatous neuropathy is still unexplained, but the findings here presented have given rise to the speculation that antineuronal antibody may be a contributory factor in carcinomatous neuropathy.
Immunosuppressive acidic protein (IAP) exhibits various types of immunosuppressive activity and is said to increase in cancer hosts. Based on measurements of IAP levels in normal subjects, cases of renal cysts and 46 cases of renal cell carcinoma we reached the following conclusions: The IAP levels in normal subjects ranged from 250-530 micrograms/ml, with a mean +/- S.D. of 362.5 +/- 68.9 micrograms/ml, which was comparable to the values in renal cyst cases (250-470 micrograms/ml, mean +/- S.D.: 353 +/- 70 micrograms/ml). 475 micrograms/ml was taken as the upper limit of the normal range. The pretreatment IAP values for cases of renal cell carcinoma ranged from 330-1,780 micrograms/ml, with a mean +/- S.D. of 820 +/- 820 and 73% were considered positive (i.e. beyond the 475 micrograms/ml limit). There was a statistical significance of p less than 0.01 between normal subjects and renal cell carcinoma cases and also between renal cyst cases and renal cell carcinoma cases. When the cases of renal cell carcinoma were divided into those with a pretreatment IAP level of 475 micrograms/ml or less and those with more than 475 micrograms/ml, the 3-year survival of the former was 90%, whereas that of the latter group was 39%, showing a statistically significant difference with p less than 0.05. Comparison of the IAP levels in the group of total nephrectomy cases that did not develop recurrence and those in which recurrence was recognized, revealed significantly higher IAP levels in the latter (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the ratio of agreement between biopsy specimens and all-layer specimens in regard to growth pattern, histological classification, staging, grading, lymphatic invasion, intravenous invasion and infiltrating type of 42 cases in which it was possible to make a comparison among radical cystectomy cases treated between November 1976 and October 1988. The above 7 categories were studied according to the General Rule for Clinical and Pathological Studies on Bladder Cancer (Japanese Urological Association and Japanese Pathological Society). The result showed that the ratio of agreement between the biopsy specimens and the all-layer specimens was 90.5% according to growth pattern. The ratio of agreement was 85.7% according to histological classification but 76.2% according to staging. When grading was not based on the lower grade of cells occupying the major portion, but the higher grade of cells occupying the minor portion the ratio of agreement was 88.1%. The ratio of agreement was 76.2% according to lymphatic invasion. However, when lymphatic invasion was seen on the all-layer specimens, the ratio of agreement was 74.4% according to lymphatic invasion. The ratio of agreement was 76.2% according to intravenous invasion. However, when intravenous invasion was seen on the all-layer specimens, the ratio of agreement was 58.3% according to intravenous invasion. The ratio of agreement was 76.8% in regard to infiltrating type. Staging, grading, and vascular invasion are important prognostic factors in bladder cancer. According to our study, biopsy specimens alone are not enough to evaluate the staging and the presence of vascular invasion. For more accurate diagnosis, we must resect deep and multiple biopsy specimens.
Postural patterns in everyday life were observed in the Ryukyu Islands. Postures seem to have two dimensions. In one dimension, they consciously changed their posture in the same action according to situations. In the other dimension, they took a particular posture, e.g., sitting with one knee raised, in different actions. The former may be related to the communicative aspect of posture, while the latter to the technical aspect of posture. Further, some postures, e.g., standing while deeply bending forward, could be regarded as techniques peculiar to their culture. The relation between culture and biology is also discussed with respect to postural patterns which may be related to the traditional lifestyle in Okinawa.
The level of serum gamma-seminoprotein (gamma-Sm) was measured by enzyme immunoassay in 62 patients with untreated prostatic cancer and 89 patients with benign prostatic hypertrophy histologically diagnosed to assess the clinical usefulness as a tumor marker. The level of serum prostatic acid phosphatase (PAP) was also measured by radioimmunoassay in these patients simultaneously. Serum gamma-Sm levels in prostatic cancer were significantly higher than in benign prostatic hypertrophy. There was a tendency for serum gamma-Sm levels in prostatic cancer to increase with statistically significant difference as the stage progressed. A gamma-Sm level of over 5.0 ng/ml was considered to be positive. The positive rate of gamma-Sm was 56.5% in prostatic cancer (stage A.B: 32.3%, stage C: 75.0%, stage D: 90.9%) and 19.1% in benign prostatic hypertrophy. In stage A.B cases, the positive rate of gamma-Sm was higher than that of PAP. Therefore, the measurement of gamma-Sm is considered to be useful in the diagnosis of early prostatic cancer.
Factors influencing the healing rate were evaluated by multivariate analysis on 148 patients with gastric ulcer who were under treatment with cimetidine at a daily dose of 800 mg. Factors used were age, sex, therapeutic environment, duration of present ulcer pain, past history of gastric ulcer, the amount of tobacco, alcohol, and coffee consumed before and during the treatment, the period until symptoms disappeared after the commencement of the treatment, and the characteristics of the ulcers themselves. Of these factors, the five factors that had a significant delaying effect on the healing of gastric ulcers were: 1) having a past history of gastric ulcers, 2) symptoms not disappearing within 1 wk after the commencement of the treatment, 3) size over 20 mm, 4) ulcer located in an angle, and 5) round or oval shape of the ulcer. The patients with less than one of the unfavorable factors (n = 36) had the best healing rate (97.2%), compared with those with two (n = 61), three (n = 39), or four or more (n = 12) unfavorable factors. The healing rate of the latter three groups was 75.4%, 53.8%, and 33.3%, respectively (p less than 0.01). Thus, a prognostic score based on these five factors represents the severity of gastric ulcers with regard to the healing in patients prescribed cimetidine.
Seventy-one patients with lung tumors were studied by thoracic Ultra-low field MRI (L-MRI) and the efficacy of L-MRI is evaluated as compared with the dynamic CT scan. In staging of lung cancer, L-MRI is not useful because of its poor spatial resolution. Both T1 (Inversion recovery) and T2 (long SE) weighted images can differentiate secondary atelectasis from central tumors in 15 out of 18 (78%). This sensitivity is almost equal as that of dynamic CT. IR images with short inversion time (STIR) are particularly useful for their differentiation.
Colony-stimulating factor 1 (CSF-1) regulates the survival, growth, and differentiation of monocytes through binding to a single class of high affinity receptors. The present studies demonstrate that the interaction of CSF-1 with monocyte membranes is associated with a 2.4-fold increase in specific binding of the GTP analogue, GTP gamma S. Scatchard analysis of the GTP gamma S binding data indicated that CSF-1 stimulates GTP binding by increasing the affinity, rather than the number, of available sites. This stimulation of GTP binding by CSF-1 was also associated with an increase in GTPase activity. Furthermore, the CSF-1-induced stimulation of GTPase activity was sensitive to pertussis toxin. We also demonstrate that CSF-1 stimulates Na+ influx into monocytes by an amiloride-sensitive mechanism, presumably the Na+/H+ antiport. This CSF-1-stimulated influx of Na+ was further associated with an increase in Na+,K+-ATPase activity. Moreover, this stimulation of Na+ influx and Na+,K+-ATPase activity by CSF-1 was sensitive to pertussis toxin. Finally, we demonstrate that CSF-1-induced proliferation is also a pertussis toxin-sensitive event. The present findings thus suggest: 1) that the CSF-1 receptor is linked to a pertussis toxin-sensitive G protein; and 2) that a pertussis toxin-sensitive G protein is involved in the induction of Na+ influx by CSF-1.
Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.
Tumor necrosis factor (TNF) is a monokine that induces pleiotropic events in both transformed and normal cells. These effects are initiated by the binding of TNF to high affinity cell surface receptors. The post-receptor events and signaling mechanisms induced by TNF, however, have remained unknown. The present studies demonstrate the presence of a single class of high affinity receptors on membranes prepared from HL-60 promyelocytic leukemic cells. The interaction of TNF with these membrane receptors was associated with a 3.8-fold increase in specific binding of the GTP analogue, GTP gamma S. Scatchard analysis of GTP gamma S binding data demonstrated that TNF stimulates GTP binding by increasing the affinity of available sites. The TNF-induced stimulation of GTP binding was also associated with an increase in GTPase activity. Moreover, the increase in GTPase activity induced by TNF was sensitive to pertussis toxin. The results also demonstrate that TNF similarly increased GTP binding and pertussis toxin-sensitive GTPase activity in membranes from mouse L929 fibroblasts, thus indicating that these effects are not limited to hematopoietic cells. Analysis of HL-60 membranes after treatment with pertussis toxin in the presence of [32P]NAD revealed three substrates with relative molecular masses of approximately Mr 41,000, 40,000, and 30,000. In contrast, L929 cell membranes had only two detectable pertussis toxin substrates of approximately Mr 41,000 and 40,000. Although the Mr 41,000 pertussis toxin substrate represents the guanine nucleotide-binding inhibitory protein Gi, the identities of the Mr 40,000 and Mr 30,000 substrates remain unclear. In any event, inhibition of the TNF-induced increase in GTPase activity and ADP-ribosylation of Gi by pertussis toxin suggested that TNF might act by increasing GTPase activity of the Gi protein. However, the results further indicate that TNF has no detectable effect on basal or prostaglandin E2-stimulated cAMP levels in HL-60 cells. Taken together, these findings indicate that a pertussis toxin-sensitive GTP-binding protein other than Gi, and possibly the Mr 40,000 substrate, is involved in the action of TNF. Finally, the demonstration that pertussis toxin inhibited TNF-induced cytotoxicity in L929 cells supports the presence of a GTP-binding protein which couples TNF-induced signaling to a biologic effect.
Acutely anesthetized and paralysed kittens were monocularly exposed to TV shows for approximately 20 h, throughout which the visual cortex received a direct infusion of (-)-noradrenaline (NA) or (+)-NA. The ocular dominance distribution was found shifted toward the exposed eye in the (-)-NA-infused cortex, but not in control cortex, i.e. the drug-free kitten cortex, the kitten cortex infused with (+)-NA, and the (-)-NA-infused adult cortex. Noise patterns on the same TV screen also failed to induce a shift in the (-)-NA-infused kitten cortex. It is concluded that shift in ocular dominance takes place in kittens, even under general anesthesia and paralysis, when cortical (-)-NA infusion and pattern vision through one eye are combined.
Tumor necrosis factor (TNF) is a monokine with in vitro cytotoxicity for some but not all tumor cells. The basis for sensitivity and resistance to the antitumor effects of this agent remains unclear. The present studies have monitored the effects of TNF on 14 epithelial tumor cell lines. Eleven of these cell lines were resistant to the growth inhibitory effects of TNF (50% inhibitory concentration greater than 1,000 U/ml). 12 of the 14 tumor cell lines has detectable levels of high affinity cell surface TNF binding sites, thus suggesting that resistance was not often due to the absence of cell surface TNF receptors. Northern blot analysis demonstrated that three of the eleven resistant cell lines expressed detectable levels of TNF mRNA. Furthermore, both sensitive and resistant epithelial tumor cells had the capacity to express TNF transcripts in the presence of the protein synthesis inhibitor, cycloheximide. Finally, the presence of TNF expression at the RNA level is shown to be associated with the production of a TNF-like protein in the resistant Ov-D ovarian carcinoma cells. These findings suggest that certain human epithelial tumor cell lines inherently resistant to TNF also express this cytokine.
Regulation of tumor necrosis factor (TNF) gene expression was investigated in resting human monocytes and in 12-O-tetradecanoylphorbol-13-acetate (TPA) activated monocytes. TNF transcripts were undetectable in resting monocytes. However, in TPA-activated monocytes, TNF mRNA was first detectable by 3 h and reached maximal levels by 12 h of drug exposure. Using run-on transcription assays, the TNF gene was transcriptionally inactive in resting monocytes, but was rapidly activated after TPA exposure. The protein synthesis inhibitor, cycloheximide (CHX), had no detectable effect on levels of TNF transcripts in resting monocytes, while this agent superinduced the level of TNF mRNA by 50-fold in TPA-activated cells. TPA activated monocytes were also exposed to actinomycin D and/or CHX to determine whether transcriptional or posttranscriptional control of TNF gene expression was responsible for the induction of TNF transcripts. After 1 h of actinomycin D treatment, the amount of TNF transcripts was reduced by 75%. In contrast, no difference in TNF mRNA levels was observed in TPA-activated monocytes exposed to CHX alone or CHX in combination with actinomycin D. These findings indicated that CHX prevented the degradation of TNF mRNA by inhibiting the synthesis of a labile protein. Run-on transcription assays performed on cells exposed to either TPA or the combination of TPA and CHX further indicated that CHX treatment increased transcription of the TNF gene. Thus, TNF gene expression is controlled at the transcriptional level in resting human monocytes, while both transcriptional and posttranscriptional events regulate the level of TNF transcripts in TPA-activated cells.
Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.
Morphometrical observations were carried out on the mandibles of chimeras made from the embryos of C57BL/6 and BALB/c mice to compare with the two strains and their reciprocal F1 crosses. The results of the principal component analysis indicate that the first principal component (PC1) and the second principal component (PC2) extracted might be acceptable as size and shape factors, respectively. Variations of both PC1 and PC2 were generally larger in the chimeras than in the two component strains and their F1 crosses. The mean PC1 value of the chimeras was larger than that of the two component inbred strains, and it was similar to that of F1 crosses, or slightly larger. The overall size of the mandible represented by PC1 tended to be larger in the chimeras consisting of two component cells that were approximately equivalent than in those that shifted to either cell population. The above trend was observed in both sexes. These results indicate that chimeric heterosis due to the interaction between genetically different cells (C57BL/6 and BALB/c) has some relation to mandible size. The mean PC2 value, which was accepted as shape factor, was intermediate between the two inbred strains. The mandible size (PC1) and shape (PC2) were bilaterally symmetrical, except for the shape in the female chimeras and in (C57BL/6 x BALB/c)F1.