Biomedical subjects
Publications and source records attributed to Y Seo.
Three new 9,10-secosteroids, calicoferols C-E [2-4] have been isolated from an undescribed gorgonian of the genus Muricella, and their structures determined by a combination of spectroscopic methods. Calicoferol D [3] exhibited potent antiviral activity and brine-shrimp lethality.
The cytotoxicity of SN-38, the major metabolite of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, was compared among gastrointestinal carcinomas of every organ, and between primary and metastatic lesions of every organ-originated gastrointestinal carcinoma, by an in vitro anticancer drug sensitivity test using fixed-contact-sensitive plates. The rates of cases having a high response (percent survival 75% or lower) to SN-38 but a low response (percent survival above 75%) to cisplatin, mitomycin C (MMC), adriamycin (ADM) and 5-fluorouracil (5-FU) were 14.6, 19.4, 15.6 and 27.0%, respectively. While, the rates of cases having a high response to cisplatin, MMC, ADM and 5-FU but a low response to SN-38 were 7.3, 2.8, 9.4 and 13.5%, respectively. Each of the former rates were higher than each of the latter rates. In particular, the former rate for MMC was significantly higher than the latter rate (p = 0.04). Two cases with colon cancer showed a high response only to SN-38. The percent survival of primary lesions in colon cancer was significantly lower than that in stomach cancer. The rates of hepatocellular carcinoma cases having a high response to SN-38 but a low response to cisplatin, MMC, ADM and 5-FU were 16.7, 16.7, 0 and 25%, respectively. Only one case had a high response to 5-FU but a low response to SN-38. The percent survival of metastatic lesions in pancreatic cancer was significantly lower than that of primary lesions. From this study, we recommend the further clinical trial of CPT-11 for colon and hepato-cellular cancers.
To evaluate the effect of radiosurgery on angiographically occult vascular malformations (AOVMs), 9 patients treated with Gamma Knife surgery were followed up for 21-37 months. Eight patients had bleeding episodes, 1 had uncontrollable epilepsy. Rebleeding occurred in 3 AOVMs 5 or 6 months after treatment. One patient experienced transient radiation-induced edema. One patient underwent surgical extirpation due to uncontrollable epilepsy 21 months after Gamma Knife surgery. Histological findings revealed an arteriovenous malformation (AVM) and a cavernous angioma. There was hypertrophy of the internal membrane of the AVM, but no effect on the cavernous malformation. Radiosurgery should only be considered in cases of inoperable AOVM, because there is no definite proof that radiosurgery prevents AOVMs from rebleeding.
The diffusion coefficient of an 19F-labelled organic acid (3-trifluoromethylhippurate: TFMH) was measured in intact human red blood cells (RBCs) and sealed right-side-out ghosts at 22.5 +/- 0.05 degrees C. Diffusion coefficients were measured using stimulated echo and spin-echo pulsed field gradient sequences. The apparent diffusion coefficient (Da) of TFMH in the intracellular space was much smaller than in the extracellular medium. This was due to restricted diffusion of intracellular TFMH since i) the intracellular Da decreased when the diffusion time was increased, and ii) the smaller Da component disappeared when the membrane was permeabilized with saponin. From the intracellular Da values obtained over a range of diffusion times, from 5 ms to 1 s, the apparent radius of the diffusion barrier was estimated to be 3 +/- 1.1 micron assuming spherical geometry. Despite the high protein concentration in the intracellular space of the intact RBC, the intracellular values of Da were similar to the values obtained in the ghosts at the same diffusion times. We therefore conclude that the small diffusion coefficient of intracellular TFMH is mainly explained by the restricted diffusion due to the cell boundary.
The majority of magnetic resonance imaging (MRI) studies in neurotology concern the evaluation of retrocochlear pathologies or temporal bone lesions. Recently, quite a number of investigators have attempted to use imaging diagnosis to obtain a diagnosis and manifest the pathological findings of Meniere's disease. However, there is no evidence that endolymphatic hydrops in patients with Meniere's disease can be identified by imaging techniques. In this study we could depict Reissner's membrane clearer than before with the use of image processing. At the present time, we cannot apply the 2.11T MRI machine to patients under FDA regulation. We believe that MRI diagnoses of endolymphatic hydrops and small lesions of the internal structures of the inner ear will be possible in the near future.
We attempted to mix an anticancer drug. MMC, with a fibrinogen preparation, Beriplast P (B. P.). First, we examined how MMC was gradually released from its mixture. As the result, its release depended on the MMC concentration in B. P., and the release rate of 1.0 mg MMC from 100 microliters B. P. was 1.6 mg/30 min. Second, we examined the safety of the conjugated drug for normal tissue, because MMC is one of anticancer drugs causing serious damage to normal tissue. When the conjugation of 100 microliters B. P. and below 1.6 mg MMC was coated within one square centimeter, the drug was safe for the endothelium of artery and vein, and the intestinal wall. Third, we attempted an experiment on both the antitumor effect and the role of survival prolongation of the conjugated drug in a mouse carrying a malignant tumor. MMC conjugated with Beriplast P had a highly antitumor effect, which caused necrosis in the cancer cells in unstable conditions. Also, its conjugation drug could inhibit the growth of cancer cells in stable conditions, and prolonged the survival period. From these results, the mixture of MMC and B. P. was found to possess an MMC releasing effect, was safe for normal tissues, and showed high antitumor effect with prolongation of the survival period.
The immunopotentiating effect of a streptococcal preparation, OK-432 (Picibanil), mixed with an ointment based Lanolin, was examined. The mixture was applied to mouse abdomen. The effect of OK-432 ointment was compared with those of OK-432 ip and sc. The leucocyte count in the abdominal cavity increased in 3.6 x 10(6) and 12.5 x 10(6) on the 3rd day after ointment application and ip injection of 5 KE OK-432, respectively. The result indicated that OK-432-Lanolin applied to the abdominal skin wall affected the abdominal cavity. IL-6 and IFN-gamma in the abdominal cavity increased in 1.4 ng and 9 ng, respectively, after applying 5 KE OK-432 ointment. From these results the treatment with OK-432 ointment on the abdominal skin exhibited an immunomodulatory effect on the abdominal cavity.
Twenty-three patients with squamous cell carcinoma of the esophagus were treated with low-dose carboplatin and radiation therapy. Patients received 1.6 Gy-fractions daily; the total dose was 50-70 Gy for 14 unresectable cases, and 30-40 Gy for 8 resectable cases as preoperative irradiation. Carboplatin (30 mg/m2/day) was administered intravenously just before the irradiation; total dose was 1,100-2,000 mg for the unresectable cases, and 750-1,200 mg for the resectable cases. The response rate of the unresectable tumors was 86% (CR 5, PR 7, and NC 2). Three of the five CR patients were alive without recurrence for more than 2 years. The response rate of the resectable tumors was 75%. Although major toxicity was bone marrow suppression, there were no serious complications. These results suggest that this regimen is effective for patients with squamous cell carcinoma of the esophagus.
In 4 out of 5 patients given 400 mg orally 5'-DFUR before surgery, intratumor 5-FU concentration showed over 150 ng/g. The concentration of either 5-FU or 5'-DFUR in the portal and peripheral blood of these patients exceeded the limits of assay. 5-FU concentration in peripheral blood was less than 0.05 micrograms/ml. White blood cell and platelet counts in the patients given 1,600 mg/day (no administration for 2 days/week) of 5'-DFUR for one month were essentially the same with those at the time of start of the treatment. Two of three patients showed minor response following the treatment with 5'-DFUR. Thus, administration of 1,600 mg/day of 5'-DFUR may be considered as an effective treatment of fluopyrimidine against advanced cancer. For the prediction of gastrointestinal side effect, assay of the 5-FU concentration in the portal blood seemed to be useful.
Smoking and drinking habits as well as family history were examined in 143 men with esophageal cancer, including 30 who had associated second cancers of the upper aerodigestive tract (UADT) and 113 who did not. The risk of second cancers of UADT associated with the main lesions of the esophagus was evaluated, using odds ratios (ORs). As a result, the ORs of second cancers for current smoking and drinking were 5.3 and 7.6 respectively. The ORs significantly increased to 12.7 and 14.7 in heavy smokers and in heavy drinkers respectively. Furthermore, the risk of second cancer also significantly increased (8-fold) in patients who had close relatives with UADT cancer, compared to those without family history of any cancer. However, there were no differences in smoking or drinking habits regardless of family history. Our data thus suggest that a family history of UADT cancer as well as heavy smoking and drinking are clearly associated with multiple occurrence of UADT cancer. Therefore, careful and frequent examination for appearance of any second lesions are required for patients in these high-risk groups.
Changes in intracellular and extracellular water content have been measured in perfused rat salivary glands by repetitive application of an inversion recovery (IR) pulse sequence. The relaxation reagent Gd-DTPA (10 mM) was included in the perfusate so that the intracellular and extracellular water proton signals could be distinguished by their different longitudinal relaxation times. Changes in water content in response to altered perfusion pressure and perfusate osmolarity were determined at 30-s intervals and indicated a clear separation of the intracellular and extracellular components. Using a modification of the IR pulse sequence, changes in intracellular water content were also measured at 6-s intervals. With this time resolution, differences in the rates of cell shrinkage in response to hyperosmotic perfusates and the secretomotor agonist acetylcholine were observed. The results suggest that this approach offers a relatively noninvasive method for studying cell volume regulation in intact, perfused tissues and organs.
The involvement of large-conductance, voltage- and Ca(2+)-activated K+ channels (maxi-K+ channels) in basolateral Ca(2+)-dependent K(+)-efflux pathways and fluid secretion by the rat submandibular gland was investigated. Basolateral K+ efflux was monitored by measuring the change in K+ concentration in the perfusate collected from the vein of the isolated, perfused rat submandibular gland every 30 s. Under conditions in which the Na+/K(+)-ATPase and Na(+)-K(+)-2Cl- cotransporter were inhibited by ouabain (1 mmol/l) and bumetanide (50 mumol/l) respectively, continuous stimulation with acetylcholine (ACh) (1 mumol/l) caused a transient large net K+ efflux, followed by a smaller K+ efflux, which gradually returned to the basal level within 10 min. These two components of the K+ efflux appear to be dependent on an increase in cytosolic Ca2+ concentration. The initial transient K+ efflux was not affected by charybdotoxin (100 nmol/l) or tetraethylammonium (TEA) (5 mmol/l) but the smaller second component was strongly and reversibly inhibited by charybdotoxin (100 nmol/l) and TEA (0.1 and 5 mmol/l). The initial K+ efflux transient induced by ACh was inhibited by quinine (0.1-3 mmol/l), quinidine (1-3 mmol/l) and Ba2+ (5 mmol/l), but not by verapamil (0.1 mmol/l), lidocaine (1 mmol/l), 4-aminopyridine (1 mmol/l) or apamin (1 mumol/l). Ca(2+)-dependent transient large K+ effluxes induced by substance P (0.01 mumol/l) and A23187 (3 mumol/l) were not inhibited by TEA (5 mmol/l or 10 mmol/l). A23187 (3 mumol/l) evoked a biphasic fluid-secretory response, which was not inhibited by TEA (5 mmol/l). Patch-clamp studies confirmed that the whole-cell outward K+ current attributable to maxi-K+ channels obtained from rat submandibular endpiece cells was strongly inhibited by the addition of TEA (1-10 mmol/l) to the bath. It is concluded that maxi-K+ channels are not responsible for the major part of the Ca(2+)-dependent basolateral K+ efflux and fluid secretion by the rat submandibular gland.
An in vitro assay system for predicting the estradiol (E2) sensitivity of clinical cancer cells was applied to 54 patients with breast carcinoma to compare the responses to E2 and tamoxifen (TAM) with the estrogen receptor (ER) status. We found that 18 of the 35 cases in the ER-positive group and 6 of the 19 cases in the ER-negative group were stimulated by E2. It is suggested that ER status alone can not predict the response of cultured cells to E2 in clinical breast cancer. Cell growth of 11/35 (31%) of the ER-positive cases and that of 8/19 (42%) of the ER-negative cases was inhibited by E2. Since the cases inhibited by E2 could not be distinguished by ER status alone, an assay system based on a quantitative proliferative response was considered necessary. There were 20 (83%) cases of inhibition by TAM among the 24 stimulated by E2. Only 18/35 (51%) of the ER-positive group exhibited growth inhibition by TAM. In our (CSP) assay, 20 (83%) of the 24 cases stimulated by E2 were inhibited by TAM, 10 (91%) of the 11 E2-insensitive cases were insensitive to TAM and 13 (68%) of the 19 cases inhibited by E2 were stimulated by TAM. In short, TAM response and E2 response tended to be inversely related (43/54 = 80%, P < 0.01). Furthermore, the E2-response rate showed a good correlation with the TAM-response rate (R2 = 0.825). These results indicate the feasibility of predicting individual tumor responses to either E2 or TAM by using CSPs.
A highly sensitive and specific sandwich enzyme immunoassay for human liver-specific antigen (LSA) was developed and its forensic application using LSA as a marker for the determination of liver injury were examined. The LSA was purified from human liver by immunoaffinity chromatography. Polystyrene ball coated with affinity-purified rabbit anti-human LSA IgG was incubated with the human LSA and then with affinity-purified anti-human LSA Fab'-horseradish peroxidase conjugate. Peroxidase activity bound to the polystyrene ball was assayed by fluorometry using 3-(4-hydroxyphenyl) propionic acid as a hydrogen donor. The detection limit for human LSA was 0.52 pg per assay. The serum LSA levels determined by this assay in healthy male and female adults were 1.5-1.6 ng/ml and 0.7-1.0 ng/ml, respectively. The recovery of LSA added to 5 microliters and 10 microliters serum samples was estimated to be 53.1-55.5% and 70.6-74.8%, respectively, and no difference in recovery between serum from males and females was observed. LSA antigenic activity in bloodstains containing LSA was detectable after storage for 30 days at room temperature. High levels of LSA were proved to exist in forensic samples taken from stabbed livers, and it was clearly possible to differentiate between samples from stabbed livers and those originating from other stabbed organs. These findings demonstrate that determination of LSA from forensic samples is useful for detecting liver injuries.
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Effects of adjuvant chemotherapy following curative resection were evaluated in patients with early gastric cancer. According to postoperative chemotherapy, seven hundred and thirty-one patients were divided into four groups as follows. MMC+FT group: those who received mitomycin C and tegafur; MMC group: those receiving MMC; FT group: those given tegafur or 5-FU; NC group: those who never received chemotherapy. Postoperative recurrence was observed in 25(3.4%) of the 731 patients. Relationships between rates of recurrence or survival with clinicopathological findings were assessed among the four groups. In cases with cancer cell invasion of the intralesional veins, recurrence tended to occur less in the groups given postoperative chemotherapy, compared to the NC group. When a positive venous invasion was determined, rates of recurrence in the MMC+FT, MMC, FT and NC groups, were 7.4, 0, 0 and 35.7%, respectively. On the other hand, in relation to other clinicopathological findings, no differences were observed in rates of recurrence among those groups. As for the survival rate, no differences were observed in the clinicopathological findings among the four groups. These findings indicate that adjuvant chemotherapy may contribute to prevention of postoperative recurrence in patients with early gastric cancer, especially in cases with positive venous invasion.
The intracellular sodium of the perfused rat mandibular salivary gland was measured by double-quantum filtered 23Na-NMR spectroscopy at 2.34, 4.7 and 8.45 T. Biexponential relaxation of the intracellular 23Na signal was observed, and its intensity was increased by administration of acetylcholine with ouabain at 25 degrees C. The transverse and longitudinal relaxation rate constants were determined by the 'transverse experiment' (D-90 degrees-tau/2-180 degrees-tau/2-90 degrees-delta-90 degrees-acquire) and the 'longitudinal experiment' (D-180 degrees-tau-54.7 degrees-delta-90 degrees-acquire), respectively. From observed dependencies on B0 and temperature (5-37 degrees C), a possibility of exchange between two populations of intracellular Na+ was suggested. A small fraction of Na+ is in the slow-motion condition (with a quadrupole coupling constant of approx. 1.75 MHz and a correlation time of 6 x 10(-8) s). The major portion of intracellular Na+ is in the extreme narrowing condition with a transverse relaxation rate constant of approx. 100 s-1, which corresponds to a viscosity of approx. 5 cP.