Biomedical subjects
Publications and source records attributed to Kaoru Kobayashi.
The chemical reduction and oxidation of M@C82 (M = Y, La, and Ce) afford the corresponding anion and cation, respectively, which show unique and interesting chemical reactivities. It is found that the successful reversible gain or loss of electrons by ionization is useful for controlling the stability and reactivity of M@C82 toward both nucleophiles and electrophiles.
Mice were forced to swim for 5 min in water at a temperature of 12 degrees C (cold water swim stress) or 32 degrees C (warm water swim stress), and stress-induced analgesia (SIA) was measured using the tail-flick test. The cold water swim stress induced non-opioid SIA as well as hypothermia, whereas the warm water swim stress caused opioid SIA. The in vivo binding of [(3)H]-Ro15-4513 was measured in the stressed mice and compared with that in control mice. The specific binding of [(3)H]-Ro15-4513 in the cerebral cortex, hippocampus, and cerebellum was significantly altered by forced swimming in cold water. Apparent association and dissociation rate of [(3)H]-Ro15-4513 binding were decreased, and the change in the dissociation rate was most pronounced in the hippocampus. In contrast, no significant alterations were observed in in vitro binding. The hypothermia induced by the cold water swim stress seems to be the main reason for alterations in the specific binding of [(3)H]-Ro15-4513. The kinetics of a saturable amount of [(3)H]-Ro15-4513 in the blood and brain were also measured. The relative ratio of the radioactivity concentration in the brain to that in the blood was significantly decreased by forced swimming in cold water, indicating that the cold water swim stress induced changes in the nonspecific binding of [(3)H]-Ro15-4513 in the brain. These results together with previous reports suggested that non-opioid SIA induced by the cold water swim stress might be related to alterations in the rates of general ligand-receptor interactions including GABA(A)/benzodiazepine system. Changes in the nonspecific binding might be also involved in non-opioid SIA.
The binding kinetics of 11C-N-methyl piperidyl benzilate (11C-NMPB) in rhesus monkey brain were studied using animal positron emission tomography (PET) (SHR2000). This study is intended to assess the validity of the method using the cerebellum as a reference region, and to evaluate the effects of anesthesia on 11C-NMPB binding. Two monkeys, anesthetized with ketamine, received intravenous 11C-NMPB alone (370-760 MBq, < 1 microg/kg) or mixed with varying doses of nonradioactive NMPB (3 microg/kg, 10 microg/kg, 30 microg/kg) and were subjected to PET scans for 60 minutes. Regions of interest (ROI) were drawn on reconstructed PET images and a time-activity curve was obtained for each region. 11C-NMPB accumulated densely in the striatum and cerebral cortex with time. In contrast, the tracer accumulation significantly decreased with increased doses of nonradioactive NMPB. In the cerebellum, on the other hand, the accumulation of 11C-NMPB remained low and the tracer was slowly eliminated from the brain following the injection. 11C-NMPB binding in the cerebellum was barely affected by the increased dose of nonradioactive NMPB. We thus concluded that the specific 11C-NMPB binding was negligible in the cerebellum, and performed simplified evaluation of 11C-NMPB binding in each brain region by a graphical method using the cerebellum as a reference region. PET was conducted 26 times, in total both in ketamine-anesthetized and awake monkeys (n = 3 each). Measurements of 11C-NMPB binding showed good run-to-run reproducibility within individual animals. When 11C-NMPB binding was compared between ketamine-treated and awake animals, a significant increase in 11C-NMPB binding was observed in the striatum but not in other brain regions of ketamine-treated animals.
The kinetics of 18F-fluorodeoxyglucose (18F-FDG) in the monkey brain were monitored, and comparisons were made between the conscious state and when under ketamine and pentobarbital anesthesia. Rhesus monkeys were intravenously injected with 18F-FDG and followed by 60 min of PET scanning. In the conscious state, the 18F-FDG concentration reached a plateau 5 min after intravenous injection. Under ketamine anesthesia, the 18F-FDG concentration gradually increased with time in all monitored regions. At 60 min after injection, the concentration in the striatum was about 3.2 times greater than that in the conscious state, and about 4.5 times greater in the cerebral cortex. Under pentobarbital anesthesia, the 18F-FDG concentration in the occipital cortex was slightly lower. These findings demonstrate that 18F-FDG concentration in the monkey brain is significantly affected by anesthesia. The results also imply the existence of a short-term regulation mechanism for hexokinase activity in intact monkey brain.
The diagnosis of lymph node metastasis in patients with papillary thyroid cancer is an important factor when deciding to perform neck dissection at the initial surgery, as well as for evaluating the lymph node swelling after surgery. Ultrasound (US)-guided fine-needle aspiration biopsy cytology (FNAB-C) is the most useful technique for diagnosing lymph node metastasis. Recently, however, measurement of thyroglobulin in the wash-out of the needle (FNAB-Tg) has been proposed for early detection of neck lymph node metastasis in patients with differentiated thyroid cancer. The purpose of this study was to evaluate the usefulness of FNAB-Tg in detecting lymph node metastasis prior to initial or reoperative thyroid surgery. US-guided FNAB-C was performed on 129 enlarged lymph nodes of 111 patients before surgery. All of them were later histologically confirmed to contain metastasis. Immediately after obtaining an FNAB-C specimen, the needle was rinsed with 0.5 ml of normal saline solution, and the wash-out was subjected to measurement of the Tg level (FNAB-Tg). If the FNAB-Tg level was higher than the serum Tg of the patient, we diagnosed the lymph node as positive (metastatic lymph node). FNAB-Tg sensitivity was 81.4%, and FNAB-C sensitivity was 78.0%. Altogether, 4 (36.4%) of 11 cases judged "benign" and 6 (37.5%) of 16 cases judged "inadequate" by FNAB-C were positive by the FNAB-Tg measurement. Thyroglobulin measurement in fine-needle aspiration biopsy wash-out is thus a useful technique for diagnosing lymph node metastasis of papillary thyroid cancer.
Although fine-needle aspiration biopsy (FNAB) is a useful tool for diagnosing thyroid carcinoma, there are some risks of complications. In this study, we investigated tumor implantation by FNAB of papillary carcinoma. We compared the characteristics of the main tumors and implanted tumors of patients showing FNAB implantations. Between 1990 and 2002, 4912 patients underwent FNAB and were diagnosed as having papillary carcinoma. We encountered 7 cases of needle tract implantation, which account only for 0.14%. We reviewed these 7 cases as well as 3 other patients who underwent FNAB in other hospitals. The intervals between FNAB and detection of the implanted tumor ranged from 2 to 131 months. For these 10 patients, the main tumors in 6 were diagnosed as poorly differentiated carcinoma, and 7 showed extrathyroid extension. Five showed the development of implanted tumor after comparatively shorter intervals (2-68 months), and we classified these as the short interval group. The remaining 5 were classified as the long interval group, because tumor development occurred after 87-131 months. All 5 cases in the short interval group involved preoperatively detectable lymph node metastasis; those in the long interval group did not. The MIB-1 labeling index of the implanted tumor was high in 4 cases in the short interval group, but it was low in all cases in the long interval group. The implanted tumors could be surgically removed without recurrence at the focal sites. These findings indicate that, although high growth activity in the metastatic lesions may be a risk factor of FNAB, inducing the growth of implanted tumors along the needle tract within a short interval after the procedure, FNAB remains the most useful technique for diagnosing thyroid carcinoma. The incidence of implantation was low, and when it did occur, the tumors could be surgically removed without recurrence.
Patients who undergo thyroid surgery frequently suffer from unpleasant symptoms such as a stretching, choking, or pressing feeling or discomfort in the neck for a long time. The usefulness of rehabilitation (i.e., a stretching exercise) for reducing these symptoms after surgery has never been studied. In the present study, attempts were made to evaluate the usefulness of the stretching exercise in reducing disagreeable postoperative symptoms in the patients who had undergone thyroid surgery. A total of 409 patients, including 234 thyroid cancer patients, were randomly divided into a stretching group (n = 204) and a control group (n = 205). Patients in the stretching group were instructed that the stretching exercise was to be performed three times a day beginning the morning following surgery. A questionnaire survey was performed before surgery and then 1 week, 1 month, 6 months, and 1 year after surgery. Total symptom scores obtained from the questionnaire survey from the control group and the stretching group were compared. The use of analgesics was also investigated. Postoperative neck symptoms declined gradually over the course of a year, and the total symptom scores were significantly (p < 0.001) lower in the stretching group than in the control group at all points throughout the year (1 week, 1 month, 6 months, and 1 year). The mean requirement for the use of analgesics during hospitalization was significantly (p < 0.0001) less in the stretching group (1.6 +/- 2.3 tablets, mean +/- SD) than in the control group (3.1 +/- 3.8 tablets). The stretching exercise had effectively reduced postoperative neck symptoms and also reduced the use of analgesics after thyroid surgery.
The recent prevalence of ultrasonography has made it easier to detect lymph node metastasis in the lateral compartment of patients with thyroid carcinoma. In this study, we investigated the prognostic impact of lateral node metastasis preoperatively detectable by ultrasonography (US) and metastasis diagnosed by pathology examination but not detected on preoperative US [anatomopathologically (AP)-detectable metastasis] in 560 patients with papillary carcinoma >1 cm in diameter, who underwent thyroidectomy with modified radical neck dissection at our hospital. Patients with US-detectable metastasis (US+ patients) showed a significantly worse relapse-free survival (RFS) rate than those with no metastasis (US-/AP- patients) or AP-detectable metastasis (US-/AP+ patients) regardless of tumor size. Furthermore, the RFS of US-/AP+ patients with tumors >2 cm was worse than that of US-/AP- patients with tumors >2 cm or US-/AP+ patients with tumors measuring 1.1-2.0 cm. There was no significant difference in RFS between US-/AP+ and US-/AP- patients with tumors measuring 1.1-2.0 cm. These findings suggest that US-detectable lateral metastasis predicts a worse RFS for patients regardless of tumor size, and AP-detectable metastasis affects the RFS of patients with tumors >2 cm.
We have previously demonstrated that, although most papillary thyroid microcarcinomas (PMC) do not grow or grow only slowly, cases showing lateral node metastasis diagnosed by ultrasonography (US) show an aggressive characteristic associated with poor disease-free survival. In this study, we focused on two prominent U.S. features: tumor, edge definition and strong echoes. We investigated whether these findings reflect aggressive characteristics of PMC in a series of 155 cases. Poor edge definition was observed in 21.5% of patients, all of who showed worse disease-free survival (p = 0.0477) than those with a well-defined edge. Furthermore, this finding was directly linked to US-diagnosed lateral node metastasis (p = 0.0001). Strong echoes were observed in 63.9% of the cases, and fine strong echoes were seen in 25.2%. Cases demonstrating fine strong echoes tended to frequently show recurrence (p = 0.0902), and this finding was also significantly linked to US-diagnosed lateral node metastasis (p = 0.0494). These findings suggest that an ill-defined tumor edge is an important US feature of biologically aggressive PMC. We should carefully follow such patients, regardless of the therapeutic strategy, observation, or surgical treatment chosen.
Papillary thyroid cancer (PTC) has a good prognosis among patients younger than 45 years old, but the prognosis in elder is worse and treatment strategy is not well established. We retrospectively analyzed the clinical features and outcomes of 433 patients with PTC aged 70 years or older. The patients consisted of three groups: group A (n = 327); patients receiving surgical treatment, group B (n = 51); patients with microcancer (maximal diameter, < or = 1.0 cm) who did not undergo surgical treatment, group C (n = 55); patients in whom surgery was contraindicated due to age, high surgical risk or complication by other illnesses. In group A, the mean tumor size was 2.6 +/- 1.5 cm, and 218 patients (66.7%) had pathologically confirmed lymph node metastasis; 110 patients (33.6%) had extrathyroidal invasion. The 5- and 10-year overall survival rates (OSR) in group A were 97.2% and 85%, respectively, which was significantly higher than the 5-year OSR in group C (62.6%). The 5- and 10-year disease-specific survival rates (DSSR) in group A were 98.5% and 91.3%, respectively, which was also significantly higher than the 5-year DSSR in group C (81.8%). Although the patients in group B did not receive any treatment, none of them demonstrated cause-specific death or progression of disease. Papillary thyroid cancer in elderly patients, except for microcancers, may be biologically aggressive. Thus surgery is recommended for these patients, if their general status is judged able to tolerate the stress of anesthesia and surgery.
PURPOSE: To assess the reliability of ultrasonography (US) for detecting tracheal invasion by papillary thyroid cancer (PTC). METHODS: We reviewed the clinical and surgical data of 509 patients who underwent surgery for primary PTC during 2003, after routine preoperative US. RESULTS: Ultrasonography showed possible tracheal invasion in 43 of the 509 patients. However, the US findings could not be evaluated in 32 patients because of high tumor calcification, a tumor diameter greater than 4 cm, or tumor extension inferior to the clavicle. We shaved the tracheal wall in 11 patients and resected the tracheal wall in 2 patients. The sensitivity of US for diagnosing of tracheal invasion was 91%, the specificity 93%, the predictive value of a positive test 25%, the predictive value of a negative test 99%, and the accuracy 93%. CONCLUSION: Ultrasonography is a useful method of screening for tracheal invasion. A negative sonogram is a reliable indicator of the absence of tracheal invasion, except when tumors are highly calcified or extend inferior to the clavicle.
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
There are two prominent types of thyroid carcinoma, papillary carcinoma (PC) and follicular carcinoma (FC) arising from thyroid follicular cells, which have different biological characteristics. The follicular variant of papillary carcinoma (FVPC) has a structure similar to FC, although it is classified as a subtype of PC. We have previously demonstrated that caveolin-1, a major component of caveolae and an inhibitor of growth signal transduction, and 14-3-3 sigma, a regulator of the cell cycle and signal transduction, are frequently expressed in pure PC, but not in FC. In this study, we investigated these expressions in FVPC and FC. Caveolin-1 and 14-3-3 sigma were expressed in 96.2% and 92.3% of FVPC, respectively. However, almost all FC, with only a few exceptions, were negative for these findings, indicating that these proteins were more frequently expressed in FVPC than in FC (p < 0.0001). These findings suggest that caveolin-1 and 14-3-3 sigma positively or negatively regulate the development of FVPC but not that of FC, reflecting the difference of biological characteristics of these two types of carcinoma.
S100A9, a calcium-binding protein, is associated with myeloid cell differentiation and is expressed in some adenocarcinomas as well as in squamous epithelia and squamous cell carcinoma. In this study, we immunohistochemically investigated S100A9 expression in thyroid neoplasms. S100A9 was absent in normal follicles, follicular adenoma, and follicular and papillary carcinomas with conventional growth structures. In lesions showing a solid, trabecular, or scirrhous growth pattern, S100A9 immunoreacitivity was occasionally observed. One (5.9%) of the 17 follicular carcinomas and three (7.8%) of the 38 papillary carcinomas were regarded as positive for S100A9, but the positive cell areas always accounted for 5% or less. However, S100A9 was positive in all 19 undifferentiated carcinomas examined. Among them, the positive cell area was greater than 5% in 16 (84.2%), and greater than 25% in six (31.6%) cases. It is therefore suggested that S100A4 protein plays an important role in thyroid carcinoma dedifferentiation, and can be considered a novel characteristic of undifferentiated carcinoma.
AIMS: p27 is a prominent regulator of cell proliferation by universally inhibiting the cell cycle, while Jun activation domain-binding protein 1 (Jab1), a multifunctional cell signaling protein, contributes to carcinoma progression by degrading p27. In this study, we investigated the expression of these proteins in medullary thyroid carcinoma. METHODS: We immunohistochemically examined Jab1 and p27 expression in 64 medullary thyroid carcinomas. RESULTS: Of the 64 cases examined, decreased p27 expression was observed in 38 cases (59.4%). The p27 expression level was inversely linked to tumour size as well as plasma calcitonin level. Jab1 expression level was generally high, and 46 cases (71.9%) were classified as overexpressing Jab1. The incidence was higher than those in papillary and follicular carcinomas, which were previously reported. Jab1 expression level was inversely linked to that of p27, and all five cases with only cytoplasmic but not nuclear staining of p27 overexpressed Jab1. CONCLUSIONS: These findings suggest that (1) decrease in p27 expression may contribute to local tumour growth; (2) Jab1 expression is related to the progression of medullary carcinoma by decreasing the amount of p27 in the cell and accelerating its degradation; and (3) Jab1 may play a more vital role in the pathogenesis of medullary carcinoma than papillary and follicular carcinomas.
AIMS: Galectin-3, a member of the beta-galactoside binding family of lectins, has been regarded as a useful tool for discriminating malignant tumours from benign nodules of the thyroid, including the distinction between follicular carcinoma and adenoma. However, there are follicular tumours with unclear vascular or capsular invasion, which makes diagnosis more difficult. In this study, we investigated the relationship between galectin-3 expression and the degree of vascular or capsular invasion of follicular tumours. METHODS: We immunohistochemically investigated galectin-3 expression in 260 cases of follicular tumour with various degrees of vascular or capsular invasion classified into four categories. RESULTS: The galectin-3 expression level significantly increased with the degree of vascular or capsular invasion (p<0.0001). However, its diagnostic value for follicular carcinoma was not high because the sensitivity and specificity were 68.7% and 57.5%, respectively. CONCLUSIONS: Our findings suggest that galectin-3 plays a role in the transformation of follicular tumours from benign to malignant; however, when diagnosing follicular tumours, the presence of this protein should not be required for diagnosing malignant transformation in all cases. Therefore, we must conclude that galectin-3 should only be considered an adjuvant marker for follicular carcinoma.
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Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.