Biomedical subjects

S Sasaki

Publications and source records attributed to S Sasaki.

At least 109 records · Page 6Linked to original sources

PubMed2001

4,5,9,10-Tetrahydro-1,4-ethanobenz[b]quinolizine as a prodrug for its quinolizinium cation as a ligand to the open state of the TCP-binding site of NMDA receptors.

A new derivative of 4,5,9,10-tetrahydro-1,4-ethanobenz[b]quinolizine (2) has been designed as a prodrug for its quinolizinium cation (1) that is a potent antagonist of the TCP-binding site of NMDA receptors at the open state. The 11C-labeled 2 showed high accumulation of radioactivity in the brain in an in vivo biodistribution study. The speculation of 2 as a prodrug of 1 has been proven by the fact that 1 was observed in a high ratio to 2 in an analysis by RP-HPLC of the brain homogenates.

Animals↗

PubMed2001

Development of novel telomerase inhibitors based on a bisindole unit.

Telomerase is the enzyme that elongates telomere repeat at the ends of a chromosome. As high telomerase activity is observed in most cancer cells, inhibitors of human telomerase have been expected as new chemotherapeutic agents for cancer. We describe here the discovery of novel inhibitors with IC50 values in the submicromolar range. The structure of the novel inhibitors will be useful as a scaffold for construction of the library in the search for telomerase inhibitors.

Enzyme Inhibitors↗

PubMed2001

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression.

PURPOSE: A disruption in the balance between the matrix metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma. PATIENTS AND METHODS: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopathologic characteristics and patients' survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined. RESULTS: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells. CONCLUSION: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMPs to a different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.

Adenocarcinoma↗

PubMed2001

Selective reaction to a flipping cytidine of the duplex DNA mediated by triple helix formation.

A new nucleoside derivative (2) with a butyl spacer between the sugar part and the 2-amino-6-vinylpurine motif has been synthesized. The triplex-forming oligodeoxynucleotide incorporating 2 has achieved strand- and cytidine-selective cross-linking reaction to the G-C target site mediated by triple helix formation. It has been suggested that 2 reacts with a flipping cytidine at the target site.

Base Pair Mismatch↗

PubMed2001

Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and beta subunit of the high-affinity IgE receptor.

We report here the cloning of eight new cDNAs that encode a family of proteins related to the B-cell-specific antigen CD20, a hematopoietic-cell-specific protein HTm4, and high affinity IgE receptor beta chain (FcvarepsilonRIbeta). They include four clones from human, and another four clones from mouse. They share similar structure (four transmembrane domains) with amino acid identities of 25-40%. Therefore, they represent distinct genes and comprise a gene superfamily. This superfamily is now named membrane-spanning four-domains, subfamily A (the approved symbol is MS4A) to distinguish them from tetraspanins with similar structure. The highest homologies among these proteins are found in the transmembrane domains, especially in the first and second transmembrane domains, and conserved residues are also recognized in the inter-transmembrane domains. In northern blot, they were mostly expressed in lymphoid tissues: thymus and spleen. However, some were expressed in nonlymphoid tissues including brain, heart, kidney, liver, testis, lung, GI tracts, and pancreas. They may represent proteins functioning either directly as ligand-gated ion channels or as essential components of such channels. The identification of this relatively large gene family in various tissues will allow the further elucidation of physiological significance of this gene family, that is currently unclear.

Amino Acid Sequence↗

PubMed2001

Electron cotunneling in a semiconductor quantum dot.

We report transport measurements on a semiconductor quantum dot with a small number of confined electrons. In the Coulomb blockade regime, conduction is dominated by cotunneling processes. These can be either elastic or inelastic, depending on whether they leave the dot in its ground state or drive it into an excited state, respectively. We are able to discriminate between these two contributions and show that inelastic events can occur only if the applied bias exceeds the lowest excitation energy. Implications to energy-level spectroscopy are discussed.

Journal Article↗

PubMed2001

Optical responses to micro-application of GABA agonists in the embryonic chick brain stem.

We investigated optical responses induced by micro-application of muscimol and baclofen in the embryonic chick brain stem. Muscimol evoked biphasic optical signals which were similar to those induced by GABA. The first component was a dye-dependent absorption change that reflected membrane depolarization, and the second component was an intrinsic optical change coupled with changes in the membrane potential. On the other hand, baclofen did not elicit any optical change. The optical responses induced by muscimol persisted in the presence of picrotoxin and 2-hydroxysaclofen, suggesting that they contain a component which is not mediated by classical GABA receptors.

Animals↗

PubMed2001

Developing germ cells in mouse testis express pheromone receptors.

Pheromone receptors are expressed in the accessory olfactory system, which is vital for non-specific chemical communication and for sexual behavior. Under the hypothesis that some of the pheromone molecules released from female reproductive organs might regulate sperm chemotaxis or chemokinesis, we examined whether the V1R type pheromone receptor mRNAs are expressed in developing germ cells. By a reverse transcription-PCR method, we obtained nine kinds of cDNA fragments belonging to the receptor family. In situ hybridization analysis in testicular sections using probes of testicular pheromone receptors (TVRs) revealed that TVR mRNAs were expressed by spermatids. TVRs were also expressed in the accessory olfactory organ. In the testis, hybridization signals were localized in subsets of the seminiferous tubules, suggesting that TVRs were expressed by selective subsets of the spermatids. In situ hybridization study suggests also that each sperm expresses multiple pheromone receptors. The testicular pheromone receptors might have an important role in the maturation and/or migration of sperm.

Amino Acid Sequence↗

PubMed2001

A noninvasive measurement of reactive hyperemia that can be used to assess resistance artery endothelial function in humans.

We demonstrated that endothelial function in patients with essential hypertension is impaired by a decrease in nitric oxide production using both reactive hyperemia and acetylcholine infusion methods. This noninvasive method of evaluating reactive hyperemia is a useful alternative to intra-arterial infusions of vasoactive agents in the assessment of resistance vessels' endothelial function in forearm circulation.

Acetylcholine↗

PubMed2001

Development of a tracheal stapling device.

OBJECTIVE: Recent years have witnessed a multitude of technical advances regarding gastrointestinal and vascular anastomosis. However, difficulties still hamper tracheal and bronchial anastomosis. We have therefore developed a novel set of instruments and performed end-to-end anastomosis of the transected canine cervical trachea to establish the operative procedures. METHODS: A novel set of instruments was developed for tracheal anastomosis including two pairs of forceps for grasping the free tracheal ends, a metal connecting device, and clamping forceps for staple insertion. Briefly, the operative procedure involves fixation of forceps circumferentially to hold the cut trachea. End-to-end anastomosis is completed by joining the forceps with a clamp and stapling the tracheal ends everted outward. End-to-end anastomosis of the cervical trachea was performed on 23 dogs. Animals were monitored on a daily basis, and bronchofiberscopy was performed periodically. Deaths from all causes were evaluated by immediate necropsy. Sixteen dogs were sequentially sacrificed at 1, 2, 3 and at 6 months after surgery. RESULTS: In our dog model, stenosis at the anastomosis of the cervical trachea was found as a complication in 8 of 23 cases. Tracheal rupture occurred in a further 3 cases, slight granulation in another 4, and the remaining 8 showed no complication. Histological findings of anastomotic healing were similar to those reported for hand suture.

Anastomosis, Surgical↗

PubMed2001

Neutral endopeptidase/CD10 and aminopeptidase N/CD13 gene expression as a prognostic factor in non-small cell lung cancer.

OBJECTIVES: Neutral endopeptidase modulates the growth of lung cancer, while aminopeptidase N degrades the extracellular matrix and is involved in cell motility. We studied the metastasis mechanism to detect novel metastasis-associated molecules and to evaluate them for clinical application. METHODS: We studied the relationship between the expression of neutral endopeptidase and aminopeptidase N by quantitative reverse transcript-polymerase chain reaction analysis in 132 patients with non-small cell lung cancer undergoing radical surgery from 1991 to 1996. RESULTS: Patients with neutral endopeptidase-positive and aminopeptidase N-negative tumors were defined as group A, those with neutral endopeptidase-positive and aminopeptidase N-positive or neutral endopeptidase-negative and aminopeptidase N-negative tumors as group B, and those with neutral endopeptidase-negative and aminopeptidase N-positive tumors as group C. The 5-year survival of group A patients (92.9%) was significantly better than that of group B patients (64.7%) and much better than that of group C patients (38.2%) (P = 0.0011). Neutral endopeptidase and aminopeptidase N thus have statistically significant P in overall survival in Cox regression (P = 0.019). CONCLUSION: Neutral endopeptidase and aminopeptidase N gene expressions are significant indicators of prognosis.

Adult↗

PubMed2001

Usefulness of tc-99m MIBI SPECT in predicting multidrug resistance gene expression levels in non-small cell lung cancer--a preliminary report.

In this study we investigated whether Tc-99m hexakis 2-methoxy isobutyl isonitnile (Tc-99m MIBI) single-photon emission computed tomography (SPECT) has a correlation with the multidrug resistance (MDRI) and multidrug resistance-associated protein (MRP1) gene expression levels in non-small cell lung cancer (NSCLC). Fifteen patients with NSCLC were studied. SPECT images were obtained 15 (early) and 120 (delayed) min after injection of Tc-99m MIBI. We chose only one transverse section and set the region of interest over the tumor and out of the body. The mean counts in the tumor on early and delayed images were corrected by using those in the background and represented as Te and Td, respectively. Resected tumor specimens were frozen with liquid nitrogen and each positive control cell line was cultured. After the total ribonucleic acid (RNA) was extracted from specimens and cell lines, the complimentary deoxyribonucleic acid (cDNA) was amplified by the reverse transcription-polymerase chain reaction (RT-PCR) method. Each product was electrophoresed and fluorointensity was measured. The gene expression level was represented as the ratio of that of the positive control cell line. Te and Td indicated a significant correlation with the MDR1 gene expression level (p = 0.015 and p = 0.022), but not the gene of MRP1 (p = 0.100 and p = 0.145). In conclusion, Te and Td are useful parameters in predicting the MDRI gene expression level, but not MRPI in NSCLC.

Aged↗

PubMed2001

Neuronal nitric oxide synthase immunoreactivity in the spinal cord in amyotrophic lateral sclerosis.

We investigated the spinal cords of 15 patients with sporadic amyotrophic lateral sclerosis (ALS) immunohistochemically using an anti-human neuronal nitric oxide synthase (nNOS) antibody to examine whether there is increased nNOS immunoreactivity in anterior horn neurons. Specimens from 16 patients without any neurological disease served as controls. In the controls, nNOS immunoreactivity of large anterior horn neurons was detected in 10 out of 16 cases. However, there were few nNOS-positive neurons, and most of large anterior horn neurons were spared. In the ALS patients, the mean number of nNOS-positive anterior horn neurons per transverse section of L4 and L5 was significantly larger (16.2 +/- 10.9) than that in the controls (7.0 +/- 9.2) (P < 0.0001). Moreover, 41.4% of large anterior horn neurons in ALS showed nNOS immunoreactivity in remarkable contrast to 7.6% in the controls. All ALS patients, whether showing mild, moderate or severe depletion of anterior horn neurons, displayed a higher percentage of nNOS-positive anterior horn neurons than the control patients showing nNOS immunoreactivity (P < 0.01). Most of the remaining anterior horn neurons in ALS showed more intense nNOS immunoreactivity on the surface of the neurons and their neuronal processes compared with the controls. Degenerated anterior horn neurons frequently demonstrated more intense nNOS immunoreactivity on the surface of the neurons than normal-appearing neurons. Some anterior horn cells displayed nNOS immunoreactivity in the somata. Dot-like nNOS deposits on anterior horn neurons were also positively immunoreactive with anti-synaptophysin antibody. Thus, increased nNOS expression is located mainly at the synaptic sites on the anterior horn neurons in sporadic ALS, which may be related to the degeneration of anterior horn neurons in this disease. Further studies are needed to determine whether the increased nNOS immunoreactivity plays a neuroprotective or neurotoxic role in the anterior horn neurons, and to show nitric oxide production in ALS.

Adult↗

PubMed2001

Immunohistochemical and ultrastructural study of basophilic inclusions in adult-onset motor neuron disease.

We immunohistochemically and ultrastructurally studied basophilic inclusions (BI) in a patient with adult-onset sporadic motor neuron disease (MND). BI were frequently observed not only in degenerated anterior horn cells, such as central chromatolytic neurons, but also in normal-appearing large anterior horn neurons. They had various shapes, round, elliptical or irregular, and occasionally they had distinct basophilic rims. They also varied in size. There were no halos around them nor core in their centers. Immunohistochemically, some BI were immunostained for ubiquitin or SOD1, but BI were not immunoreactive with anti-phosphorylated neurofilament (SMI 31), phosphorylated tau, cystatin C or Golgi (MG-160) antibodies. Ubiquitin-positive skein-like inclusions (SI) were occasionally observed in the somata of anterior horn neurons. Ultrastructurally, BI consisted of filamentous structures associated with granules, which were attached to thick filaments. The thick filaments were straight without constriction or side arms and their diameter was twice that of the neurofilaments. BI occasionally contained tubular structures among the granule-associated filaments. The granulo-filamentous profiles varied from being compactly arranged to being more loosely packed. The structure of BI resembles that of the Lewy body-like hyaline inclusions (LBHI) observed in sporadic MND patients. Bundles of filaments resembling SI, which were composed of compactly packed filaments without fine granules running parallel to the longitudinal axis, were frequently observed inside or at the periphery of BI, and occasionally clustered in the perikarya. Each filament measured approximately 15-25 nm in diameter, and a bundle of these grouped filaments was sometimes surrounded by a unit membrane. We also occasionally observed in-between structures of BI and bundles of filaments resembling SI. These findings suggest a certain relationship between BI, SI and LBHI in the pathomechanism of BI development. Further studies are needed to elucidate whether sporadic adult-onset MND characterized by BI forms a different subtype of MND.

Anterior Horn Cells↗

PubMed2001

Localization of mouse CLC-6 and CLC-7 mRNA and their functional complementation of yeast CLC gene mutant.

CLC-6 and CLC-7 belong to the family of voltage-dependent chloride channels. To learn more about the in vivo roles of CLC-6 and CLC-7, we performed in situ hybridization of these CLC channels in various mouse organs. Mouse CLC-6 (mCLC-6) was expressed in the peripheral region of seminiferous tubules in the testis, tracheal epithelium, epithelium of bronchioles, alveolar cells in the lung, acinar cells in the pancreas, and intestinal epithelium, but we could not detect signals from pancreatic islets. Mouse CLC-7 (mCLC-7) was expressed in neurons in the medulla oblongata, Purkinje cells in the cerebellum, proximal tubules in the kidney, and hepatocytes in the liver. The distribution of mCLC-6 and mCLC-7 were similar in the lung, pancreas, and testis. mCLC-6 functionally complemented the gef1 phenotype of a yeast strain in which a single CLC channel (GEF1) had been disrupted by homologous recombination. In contrast, mCLC-7 did not complement this gef1 phenotype. This study identified the cell types that express mCLC-6 and mCLC-7 in the mouse tissues, and the complementation assay suggested that mCLC-6 functions as an intracellular chloride channel.

Animals↗

PubMed2001

Developmental expression of CLC-K1 in the postnatal rat kidney.

CLC-K1, a kidney-specific chloride channel, has been demonstrated to be involved in the urine concentration mechanism. Here, we investigated the developmental expression of CLC-K1 in the rat kidney. Using immunohistochemistry, we showed that CLC-K1 was not present in the thin ascending limb of Henle's loop during the early prenatal stages but was significantly expressed during the adult stage. CLC-K1 started to appear at day 5 and its expression increased during further development. In developing rats this increase coincided with the increase in the urine-concentrating capacity as the animals matured. We also investigated the expressions of other channels and transporters, including NKCC2, AQP-1, and AQP-2. NKCC2 was strongly expressed throughout the inner medulla in neonatal rat kidneys but was entirely undetectable at the adult stage. The decline in its expression took the form of a gradual recession from the inner medulla together with reciprocal increases in the expression of CLC-K1. AQP-1 was weakly expressed in the inner medulla during early development and showed a rapid increase in expression at a later stage. The collecting duct cells significantly expressed AQP-2 even at birth and maintained its expression throughout the development. These results suggest that CLC-K1 expression is one of the major determinants of the urine-concentrating capacity of the developing rat kidney.

Animals↗

PubMed2001

Jejunal carcinoid tumor mimicking leiomyosarcoma: preoperative diagnosis by endoscopic biopsy.

Primary carcinoid tumor of the jejunum is rare, and is an unusual cause of massive gastrointestinal bleeding. A case of primary jejunal carcinoid tumor in a 39-year-old woman who presented with massive hematochezia is described. Both upper and lower gastrointestinal endoscopies showed no abnormalities. An abdominal computed tomographic scan, small-bowel barium contrast studies, and small-bowel endoscopy showed a subserosal mass, of 5 x 4 cm, with a cavity suggesting central necrosis, and a deep mucosal ulceration, located in the proximal jejunum. Although these clinical presentations were strongly suggestive of a leiomyosarcoma, histologic examination of biopsy samples obtained by enteroscopy confirmed the diagnosis of jejunal carcinoid tumor. The patient underwent radical jejunal resection and recovered uneventfully. In spite of the large size of the tumor, there was one solitary lymph node metastasis, but no evidence of liver metastases. This kind of jejunal carcinoid tumor, presenting with massive gastrointestinal bleeding and a subserosal bulky growth mimicking a leiomyosarcoma, has not been reported previously. Moreover, this is a rare case of a jejunal carcinoid which was diagnosed preoperatively by small bowel-endoscopic biopsy.

Adult↗

PubMed2001

Microsatellite instability of colorectal cancer and adenoma in synchronous multiple colorectal cancer patients with associated extracolonic malignancies.

We examined microsatellite instability (MSI) in nonfamilial multiple synchronous colorectal cancer (multiple CC) patients. We divided the patients into two groups, those with and without extracolonic primary malignancies, and compared the frequency of MSI between the two groups. A colectomy was performed in 52 multiple CC patients between 1985 and 1998. Of them, 10 patients had extracolonic malignancies, while the other 42 patients did not. The MSI frequency was higher in the patients with extracolonic malignancies than in those without extracolonic malignancies, although it was not statistically significant (40% vs 19%, P = 0.21). Regarding the lesions, MSI frequency of cancers was higher in the multiple CC with extracolonic malignancies than in those without extracolonic malignancies (33% vs 13%, P = 0.033). From our results, there was statistically no difference in the existence of extracolonic malignancies between the patients with at least one MSI-positive cancer and those patients without any MSI-positive cancers. On the other hand, there was a significant correlation between MSI-positivity and the existence of extracolonic malignancies.

Adenoma↗