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Biomedical subjects

A Sasaki

Publications and source records attributed to A Sasaki.

At least 127 records · Page 7Linked to original sources
PubMed1999

'Small worlds' and the evolution of virulence: infection occurs locally and at a distance.

Why are some discases more virulent than others? Vector-borne diseases such as malaria and water-borne diseases such as cholera are generally more virulent than diseases spread by direct contagion. One factor that characterizes both vector- and water-borne diseases is their ability to spread over long distances, thus causing infection of susceptible individuals distant from the infected individual. Here we show that this ability of the pathogen to infect distant individuals in a spatially structured host population leads to the evolution of a more virulent pathogen. We use a lattice model in which reproduction is local but infection can vary between completely local to completely global. With completely global infection the evolutionarily stable strategy (ESS) is the same as in mean-field models while a lower virulence is predicted as infection becomes more local. There is characteristically a period of relatively moderate increase in virulence followed by a more rapid rise with increasing proportions of global infection as we move beyond a 'critical connectivity'. In the light of recent work emphasizing the existence of 'small world' networks in human populations, our results suggests that if the world is getting 'smaller'--as populations become more connected--diseases may evolve higher virulence.

Animals↗
PubMed1999

The GABA(B) receptor antagonist CGP36742 improves learned helplessness in rats.

Effects of 3-aminopropyl-n-butyl-phosphinic acid (CGP36742), a GABA(B) receptor antagonist, in the learned helplessness paradigm were examined in rats in comparison with those of imipramine and endo-8-methyl-8-azabicyclo[3,2,1]oct-3-ol indol-3-yl-carboxylate hydrochloride (ICS205-930). Rats were treated with CGP36742, imipramine or ICS205-930 for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks increased escape failures in the escape test. CGP36742, imipramine and ICS205-930 dose-dependently improved the escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of CGP36742, imipramine and ICS205-930. Although the action of imipramine and ICS205-930 was attenuated by 1-(m-chlorophenyl)-biguanide (mCPBG), mCPBG failed to influence the CGP36742 action. Therefore, it is suggested that CGP36742 may have an antidepressant profile and that the mechanisms of CGP36742 in antidepressant action may be different from those of imipramine and ICS205-930.

Analysis of Variance↗
PubMed1999

SOCS3 is essential in the regulation of fetal liver erythropoiesis.

SOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12-16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis.

Animals↗
PubMed1999

Identification of natural antigenic peptides of a human gastric signet ring cell carcinoma recognized by HLA-A31-restricted cytotoxic T lymphocytes.

Peptides of human melanomas recognized by CD8+ CTLs have been identified, but the nature of those of nonmelanoma tumors remains to be elucidated. Previously, we established a gastric signet ring cell carcinoma HST-2 and HLA-A31 (A*31012)-restricted autologous CTL clone, TcHST-2. In the present study, we determined the natural antigenic peptides of HST-2 cells. The purified preparation of acid-extracted Ags was submitted to the peptide sequencer, and one peptide, designated F4.2 (Tyr-Ser-Trp-Met-Asp-Ile-Ser-Cys-Trp-Ile), appeared to be immunogenic. To confirm the antigenicity of F4.2 further, we constructed an expression minigene vector (pF4.2ss) coding adenovirus E3, a 19-kDa protein signal sequence plus F4.2. An introduction of pF4.2ss minigene to HST-2 and HLA-A31(+) allogeneic tumor cells clearly enhanced and induced the TcHST-2 reactivity, respectively. Furthermore, when synthetic peptides of F4.2 C-terminal-deleted peptides were pulsed to HST-2 cells, F4.2-9 (nonamers), but not F4.2-8 or F4.2-7 (octamer or heptamer, respectively), enhanced the reactivity of TcHST-2, suggesting that the N-terminal ninth Trp might be a T cell epitope. This was confirmed by lack of antigenicity when using synthetic substituted peptides as well as minigenes coding F4.2 variant peptides with Ala or Arg at the ninth position of F4.2. Meanwhile, it was indicated that the sixth position Ile was critically important for the binding to HLA-A31 molecules. Thus, our data indicate that F4.2 may work as an HLA-A31-restricted natural antigenic peptide recognized by CTLs.

Amino Acid Sequence↗
PubMed1999

The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop.

The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. However, compared with other kinases, little is known about cellular regulators of the JAKs. We have recently identified a JAK-binding protein (JAB) that inhibits JAK signaling in cells. In the studies presented here we demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity. Binding to the phosphorylated activation loop requires the JAB SH2 domain and an additional N-terminal 12 amino acids (extended SH2 subdomain) containing two residues (Ile68 and Leu75) that are conserved in JAB-related proteins. An additional N-terminal 12-amino-acid region (kinase inhibitory region) of JAB also contributes to high-affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors.

Amino Acid Sequence↗
PubMed1999

APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis.

Previously we cloned a novel adaptor protein, APS (adaptor molecules containing PH and SH2 domains) which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here we report that APS was expressed in some human osteosarcoma cell lines, markedly so in SaOS-2 cells, and was tyrosine-phosphorylated in response to several growth factors, including platelet derived growth factor (PDGF), insulin-like growth factor (IGF), and granulocyte-macrophage colony stimulating factor (GM-CSF). Ectopic expression of the wild type APS, but not C-terminal truncated APS, in NIH3T3 fibroblasts suppressed PDGF-induced MAP kinase (Erk2) activation, c-fos and c-myc induction as well as cell proliferation. In vitro binding experiments suggest that APS bound to the beta type PDGF receptor, mainly via phosphotyrosine 1021 (pY1021). Indeed, tyrosine phosphorylation of PLC-gamma, which has been demonstrated to bind to pY1021, but not that of PI3 kinase and associated proteins, was reduced in APS transformants. PDGF induced phosphorylation of the tyrosine residue of APS close to the C-terminal end. In vitro and in vivo binding experiments indicate that the tyrosine phosphorylated C-terminal region of APS bound to c-Cbl, which has been shown to be a negative regulator of tyrosine kinases. Since coexpression of c-Cbl with wild type APS, but not C-terminal truncated APS, synergistically inhibited PDGF-induced c-fos promoter activation, c-Cbl could be a mechanism of inhibitory action of APS on PDGF receptor signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Immunohistochemical expression of cytokeratins in intrahepatic cholangiocarcinoma and metastatic adenocarcinoma of the liver.

BACKGROUND AND OBJECTIVES: This study was designed to identify a difference in immunostaining that might help to distinguish between primary and metastatic liver neoplasms. METHODS: We examined immunohistochemical expression of cytokeratins (CKs) 7, 8, 19, and 20 in 12 intrahepatic cholangiocarcinomas (ICCs; 9 of the mass-forming and 3 of the infiltrating type), 25 metastatic colorectal carcinomas (MCCs), and 7 metastatic gastric carcinomas (MGCs) of the liver. RESULTS: CKs 7 and 19 were expressed in all ICCs of infiltrating type, while each was seen in 7/9 (77.8%) of mass-forming type. CK 7-positive/CK 20-negative was seen in 9/12 (75.0%) of ICCs and in none of the 25 MCCs, while CK 7-negative/CK 20-positive was seen in 1/12 (8.3%) of ICCs and 20/25 (80.0%) of MCCs. No differences were observed between MGCs and ICCs. CONCLUSIONS: These results suggest that immunohistochemical staining for both CKs 7 and 20 is useful for the differential diagnosis of ICCs and MCCs, whereas phenotypic expression of CKs appears to be different between mass-forming and infiltrating types of ICCs.

Adenocarcinoma↗
PubMed1999

Intranuclear inclusions of meningioma associated with abnormal cytoskeletal protein expression.

We describe a case of meningothelial meningioma with a large number of intranuclear inclusions. Morphologically, these are divided into cytoplasmic inclusions and nuclear vacuoles. The cytoplasmic inclusion has a limiting membrane with cell organelles and filaments. Inclusions of this type are generally eosinophilic, like the cytoplasm. However, there are many inclusions that are more eosinophilic than the cytoplasm or that have a ground-glass appearance. Some of them may contain fine or coarse granules. On the other hand, the nuclear vacuole lacks a limiting membrane and appears empty. In most of the inclusions of this type, there is a faintly basophilic substance in the margin. Generally, the cytoplasmic inclusions are as immunopositive as cytoplasm with vimentin, but some of these cytoplasmic inclusions are more reactive. Under the electron microscope, abnormal aggregation of intermediate filaments is recognized in the cytoplasmic inclusions. It is considered that a strong reaction of cytoplasmic inclusions with vimentin immunostaining is due to abnormal aggregation of intermediate filaments. The present study distinctly demonstrates abnormal localization of intermediate filaments in the cytoplasmic inclusions, and it is suggested that the cytoskeleton participates in the evolution of the cytoplasmic inclusions.

Aged↗
PubMed1999

Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese.

Neonatal hyperbilirubinemia, which is prevalent among Asian peoples, has been considered as a physiological phenomenon, and its metabolic basis has not been clearly explained. Gilbert syndrome is a common inherited disease of unconjugated hyperbilirubinemia due to decreased bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT), and its role in neonatal jaundice has recently been considered. We have previously reported that the Gly71Arg mutation of the B-UGT gene associated with Gilbert syndrome is prevalent in Japanese, Korean, and Chinese populations and was more frequently detected in neonates with severe hyperbilirubinemia than in control subjects. We have studied 159 Japanese full-term neonates, evaluating the relationship between the B-UGT genotype and the severity of jaundice, as assessed with a transcutaneous bilirubinometer. The gene frequency of the Gly71Arg mutation in these neonates was 0.19, and neonates carrying the Gly71Arg mutation had significantly increased bilirubin levels on days 2-4, manifested in a gene dose-dependent manner. The frequency of the Gly71Arg mutation was 0.47 in the neonates who required phototherapy (i.e., those with more severe hyperbilirubinemia), significantly higher than 0.16 in the neonates who did not require the therapy. The gene frequency of the TA repeat promoter polymorphism, the (TA)7 mutation, was 0.07, and neonates carrying this mutation did not have an increase in bilirubin. These results suggested that the Gly71Arg mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese.

Base Sequence↗
PubMed1999

Implantation of a mechanical valve within a flexible mitral annular ring.

The implantation of a mechanical valve within the orifice of a mitral Duran flexible annular ring is presented. Exact orifice matches of the former ring and the new mechanical valve prosthesis (Advancing The Standard [ATS]; ATS Medical Inc, Minneapolis, MN) can be obtained using a standard mitral type ATS valve, when the size of the former Duran ring is larger than 31 mm. If ring dehiscence is not noted at reoperation after mitral valve repair, this procedure can be simply performed in patients with late mitral valve dysfunction requiring valve replacement.

Heart Valve Prosthesis Implantation↗
PubMed1999

Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats.

Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by either potentiating or mimicking insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of glucosamine on insulin action that may play an important role in hyperglycemia-induced insulin resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp was performed during the last 120 minutes. Pretreatment with troglitazone or D-chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic insulin resistance. In contrast, HGO failed to increase during glucosamine infusion in rats pretreated with troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic insulin resistance. D-Chiroinositol pretreatment had no effect on the glucosamine-induced increase in HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR, indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats, glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D-chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol, partially blocked the glucosamine-induced hepatic insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to hexosamine-induced peripheral insulin resistance.

Animals↗
PubMed1999

Microalbuminuria is closely related to diabetic macroangiopathy.

To investigate whether urinary excretion of transferrin (uTf) and albumin (uAlb) is related to diabetic macroangiopathy, we compared the levels of uTf and uAlb between ischemic heart disease (IHD) group and non-IHD group in patients with non-insulin-dependent diabetes mellitus. The patients (n = 102) without macroproteinuria were enrolled in the present study. Firstly, we divided the subjects into the two groups, IHD group (n = 16) and non-IHD group (n = 86), according to findings of ischemic changes on electrocardiogram. The levels of uTf and uAlb in IHD group were 3.9 +/- 0.9 and 40.6 +/- 9.7 (mean +/- S.E.M.) mg/g Creatinine, respectively. These values were significantly (P < 0.01) higher than those of non-IHD group (1.8 +/- 0.2 for uTf and 19.6 +/- 1.8 for uAlb). There was no significance in the levels of HbA1c, blood pressure, plasma lipids, and diabetic duration between the two groups. Secondly, we divided the subjects by the levels of uTf and uAlb. The frequency of IHD in the group (n = 22, 36.4%) with microalbuminuria and microtransferrinuria was significantly (P <0.03) higher than those (n = 38, 10.5%) with normoalbuninuria and microtransferrinuria, and also significantly (P < 0.02) higher than those (n = 42, 9.5%) with normoalbuminuria and normotransferrinuria. We concluded that the measurement of uAlb is important when approaching diabetic macroangiopathy.

Aged↗
PubMed1999

Carcinoma of the gallbladder associated with anomalous junction of the pancreaticobiliary duct in adults.

BACKGROUND: Anomalous junction of the pancreaticobiliary duct (AJPBD) is a congenital anomaly in which the junction is located outside the sphincter of Oddi. A high incidence of gallbladder carcinoma (GBC) has been reported in adult patients with AJPBD. STUDY DESIGN: Fourteen adult patients with AJPBD and 50 with GBC not associated with AJPBD were reviewed retrospectively to identify the clinical characteristics of AJPBD accompanied by GBC and to clarify the differences in clinicopathologic features between GBC associated with AJPBD and GBC without AJPBD. RESULTS: Among the 14 patients with AJPBD, there were five fusiform, four cystic, and two cylindric dilatations of the biliary tract and three nondilated bile ducts. Nine (64%) of 14 patients had GBC, five with fusiform dilatations, two with cylindric dilatations, and two with nondilated bile ducts. No patient with cystic dilatation had GBC. There were two stage I cancers, four stage II, two stage III, and one stage IVB. One patient with stage IVB GBC died of recurrence 8 months after operation. The remaining 8 patients were well without signs of recurrence from 8 to 72 months after operation. The frequency of grossly polypoid or histologically papillary adenocarcinoma was higher in GBC patients with AJPBD than in those without AJPBD (p < 0.01). The proportion of disease-free survivors was greater among GBC patients with AJPBD than among those without AJPBD (p < 0.05). CONCLUSIONS: AJPBD with noncystic dilatation or without dilatation appears to be an important risk factor for GBC. In this limited series, patients with GBC accompanied by AJPBD have had relatively favorable outcomes.

Adult↗
PubMed1999

Effects of bisphosphonate on experimental jaw metastasis model in nude mice.

The mechanism of osteolysis associated with metastatic cancer of the jaws is essentially osteoclast-mediated. Therefore, it is likely that potent osteoclastic bone resorption inhibitors such as bisphosphonates would be efficacious for the treatment of jaw metastasis. We examined the effects of a third generation bisphosphonate, YM175, in a nude mice jaw metastasis model with intracardiac injection of a human breast cancer cell line, MDA-MB-231. The metastatic lesions in untreated mice were radiographically observed at the body and angle of the mandible. Histology of the mandible of untreated mice revealed that most of the bone marrow cavities had been occupied by the metastatic tumor with active osteoclasts along the trabecular bone. The experimental group showed that YM175 markedly reduced the size of tumor and the number of osteoclasts. These results suggest that YM175 may suppress metastasis formation and tumor growth in jaw through inhibition of osteoclastic bone resorption.

Animals↗
PubMed1999

APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl.

We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl. Forced expression of APS in an erythropoietin (EPO)-dependent hematopoietic cell line resulted in reduced activation of STAT5 but not cell proliferation in response to EPO. APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain. Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Influences of vertical occlusal discrepancies on condylar responses and craniofacial growth in growing rats.

The present study was conducted to investigate the influence of vertical occlusal discrepancies on condylar remodeling and the subsequent craniofacial growth in growing rats. Thirty 4-week-old male Wistar strain rats were used. A 1-mm-thick metal plate was bonded onto the occlusal surface of the maxillary molars to increase posterior dentoalveolar height. During the early phase of the experiment, the thickness of the proliferative and maturative/hypertrophic zones in the anterior and superior portions of the condyle was significantly smaller in the experimental group than in the controls. The number of TRAP-positive cells was significantly greater in the experimental group than in the controls. At the end of the experiment, decreased ramus height and a large gonial angle were found in the experimental group. Changes in the intra-articular environment associated with vertical occlusal discrepancies may influence condylar and craniofacial growth in growing individuals, although some adaptive response of the condyle may be induced if growth potential remains.

Acid Phosphatase↗
PubMed1999

Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain.

BACKGROUND: The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. We have recently identified the JAK-binding protein, JAB that inhibits various cytokine-dependent JAK signalling pathways. JAB inhibits JAK2 tyrosine kinase activity by binding to the kinase domain (JH1 domain) through the N-terminal kinase inhibitory region (KIR) and the SH2 domain. The SH2 domain of JAB has been shown to bind to the phosphorylated Y1007 in the activation loop of JH1. We also identified another JAK-binding protein, CIS3 (cytokine-inducible SH2-protein 3, or SOCS3) that inhibits signalling of various cytokines. However, the mechanism of JAK signal inhibition by CIS3 has not been clarified. RESULTS: We showed that endogenous CIS3 bound to JAK2 in intact cells. The CIS3-SH2 domain bound to the phosphorylated Y1007 of JH1, and inhibited tyrosine kinase activity through the N-terminal KIR. Therefore, CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism. However, we found that the affinity of the SH2 domain of CIS3 to Y1007 was weaker than that of JAB. In contrast, the KIR of CIS3 showed stronger potential for both binding to JH1 and inhibition of JAK kinase activity than that of JAB. Consistent with this notion, chimeras containing CIS3-KIR and JAB-SH2 domain inhibited JAK2 kinase activity more efficiently than the wild-type CIS3 or JAB. CONCLUSION: CIS3 inhibits JAK2 kinase activity by binding to the activation loop through the SH2 domain, and KIR is necessary for kinase inhibition. Although the inhibitory mechanism by CIS3 is similar to that by JAB, the contributions of the SH2 domain and KIR for binding are different between JAB and CIS3. Our study defined the inhibitory mechanism of CIS3 and provides a useful information for creating a novel tyrosine kinase inhibitor.

Amino Acid Sequence↗