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Biomedical subjects

Y Shima

Publications and source records attributed to Y Shima.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mechanism of sodium load-induced hypertension in non-insulin dependent diabetes mellitus model rats: defective dopaminergic system to inhibit Na-K-ATPase activity in renal epithelial cells.

Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10(-5) M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting.

Animals↗
PubMed2001

Selective growth inhibition by sangivamycin of human umbilical vein endothelial cells.

In the course of our screening for selective growth inhibitors of human umbilical vein endothelial cells (HUVECs), we isolated sangivamycin from the culture filtrate of Streptomyces. It inhibited the growth of HUVECs at approximately 30 times lower concentration than that needed to inhibit the growth of WI-38 human fibroblasts. Structurally-related nucleosides, such as toyocamycin, tubercidin, and formycins A and B, did not show the differential inhibition. Although sangivamycin is known to inhibit protein kinase C, other protein kinase C inhibitors did not inhibit the growth of HUVECs selectively. Sangivamycin effectively inhibited S-phase induction in HUVECs, like TNP-470 and LLnL, known selective inhibitors. However, unlike them sangivamycin did not induce p21 expression. On the other hand, sangivamycin was found to inhibit DNA synthesis selectively in HUVECs. Thus, sangivamycin was shown to be a new selective growth inhibitor of HUVECs acting on DNA synthesis.

Antibiotics, Antineoplastic↗
PubMed2001

Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells.

OBJECTIVE: Inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha are produced in great quantities in inflamed rheumatoid joints. However, little is known about the pathogenic significance of each cytokine in the proliferative synovitis and destruction of bone and joint. We investigated the role of cytokine receptor signals transduced into cells at the foci of rheumatoid inflammation. METHODS: Synovial fluid (SF) cells from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were examined for the activation of a group of cytokine receptor signaling molecules, signal transducers and activators of transcription (STAT). RESULTS: DNA binding of STAT1 in SF cells was observed in 8 out of 14 patients with RA, but in none of the 10 patients with OA studied, and this was prevented by preincubation of these cells with neutralizing anti-IL-6 antibody. IL-6 activated both STAT1 and STAT3 in normal peripheral blood (PB) leukocytes, and preferentially STAT1 in rheumatoid SF cells. Moreover, STAT1 activation in rheumatoid SF cells appeared to be continuous, in contrast to the transient activation in normal PB leukocytes. CONCLUSION: STAT1 and STAT3 are differentially regulated in response to IL-6 in different cell types. The continuous STAT1 activation may be of pathogenic significance in the progression and persistence of RA.

Adult↗
PubMed2000

Ku86 variant expression and function in multiple myeloma cells is associated with increased sensitivity to DNA damage.

Ku is a heterodimer of Ku70 and Ku86 that binds to double-stranded DNA breaks (DSBs), activates the catalytic subunit (DNA-PKcs) when DNA is bound, and is essential in DSB repair and V(D)J recombination. Given that abnormalities in Ig gene rearrangement and DNA damage repair are hallmarks of multiple myeloma (MM) cells, we have characterized Ku expression and function in human MM cells. Tumor cells (CD38(+)CD45RA(-)) from 12 of 14 (86%) patients preferentially express a 69-kDa variant of Ku86 (Ku86v). Immunoblotting of whole cell extracts (WCE) from MM patients shows reactivity with Abs targeting Ku86 N terminus (S10B1) but no reactivity with Abs targeting Ku86 C terminus (111), suggesting that Ku86v has a truncated C terminus. EMSA confirmed a truncated C terminus in Ku86v and further demonstrated that Ku86v in MM cells had decreased Ku-DNA end binding activity. Ku86 forms complexes with DNA-PKcs and activates kinase activity, but Ku86v neither binds DNA-PKcs nor activates kinase activity. Furthermore, MM cells with Ku86v have increased sensitivity to irradiation, mitomycin C, and bleomycin compared with patient MM cells or normal bone marrow donor cells with Ku86. Therefore, this study suggests that Ku86v in MM cells may account for decreased DNA repair and increased sensitivity to radiation and chemotherapeutic agents, whereas Ku86 in MM cells confers resistance to DNA damaging agents. Coupled with a recent report that Ku86 activity correlates with resistance to radiation and chemotherapy, these results have implications for the potential role of Ku86 as a novel therapeutic target.

Antigens, Nuclear↗
PubMed2000

Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.

Antineoplastic Agents↗
PubMed2000

Elevated soluble MUC1 levels and decreased anti-MUC1 antibody levels in patients with multiple myeloma.

Soluble MUC1 (sMUC1) levels are elevated in many MUC1(+) cancers. We and others have shown that MUC1 is expressed on multiple myeloma (MM) plasma cells and B cells. In this study, we measured sMUC1 levels in bone marrow (BM) plasma from 71 MM patients and 21 healthy donors (HDs), and in peripheral blood (PB) plasma from 42 MM patients and 13 HDs using an immunoassay that detects the CA27.29 epitope of MUC1. sMUC1 levels were found to be significantly greater (mean 31.76 U/mL, range 5.69 to 142.48 U/mL) in MM patient BM plasma versus HD BM plasma (mean 9.68 U/mL, range 0.65 to 39.83 U/mL) (P <. 001). Importantly, BM plasma sMUC1 levels were related to tumor burden because sMUC1 levels were significantly higher for MM patients with active disease (34.62 U/mL, range 5.69 to 142.48 U/mL) versus MM patients with minimal residual disease (16.16 U/mL, range 5.7 to 56.68 U/mL) (P =.0026). sMUC1 levels were also elevated in the PB plasma of MM patients (32.79 U/mL, range 4.15 to 148.84 U/mL) versus HDs (18.47 U/mL, range 8.84 to 42.49) (P =.0052). Lastly, circulating immunglobulin M (IgM) and IgG antibodies to MUC1 were measured in 114 MM patients and 31 HDs, because natural antibodies to MUC1 have been detected in patients with other MUC1-bearing malignancies. These studies demonstrated lower levels of circulating IgM (P <.001) and IgG (P =.078) antibodies to MUC1 in MM patients compared with HDs. Our data therefore show that in MM patients, sMUC1 levels are elevated and correlate with disease burden, whereas anti-MUC1 antibody levels are decreased.

Autoantibodies↗
PubMed2000

SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells.

Our previous studies have shown that activation of a related adhesion focal tyrosine kinase (RAFTK) (also known as Pyk2) is required for dexamethasone (Dex)-induced apoptosis in multiple myeloma (MM) cells and that human interleukin-6 (IL-6), a known growth and survival factor for MM cells, blocks both RAFTK activation and apoptosis induced by Dex. However, the mechanism whereby IL-6 inhibits Dex-induced apoptosis is undefined. In this study, we demonstrate that protein-tyrosine phosphatase SHP2 mediates this protective effect. We show that IL-6 triggers selective activation of SHP2 and its association with RAFTK in Dex-treated MM cells. SHP2 interacts with RAFTK through a region other than its Src homology 2 domains. We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM.

Apoptosis↗
PubMed2000

Isolation and characterization of human multiple myeloma cell enriched populations.

We developed a simple and rapid method to enrich tumor cells within bone marrow (BM) aspirates from patients with multiple myeloma (MM). Thirty patients with a median of 50% (8-85%) MM cells by morphology and 55% (6--85%) MM cells identified by CD38+CD45-cell surface phenotype were studied. BM mononuclear cells (BMMCs) were isolated by Ficoll Hypaque sedimentation and incubated with a cocktail of mouse monoclonal antibodies (mAbs) directed against CD3 (T cells); CD11b and CD14 (monocytes); CD33 (myeloid cells), CD45 and CD45RA (leucocyte common antigen); CD32 as well as glycophorin A. After the addition of anti-mouse Fc Ig-coated immunomagnetic beads, mAb-bound cells were removed in a magnetic field. The residual cell populations were enriched for MM cells, evidenced by >95% plasma cell morphology and >95% CD38+CD45RA-cell surface phenotype. Since this method requires only two short incubations, cell losses were minimal and the yield of MM cells was therefore high (>95%). Viability of the MM-cell enriched fractions was 99%, and these cells were functional in assays of proliferation, cell cycle analysis and immunoglobulin secretion. This immunomagnetic bead depletion method therefore permits the ready isolation of homogeneous populations of patient MM cells for use in both cellular and molecular studies.

Bone Marrow Cells↗
PubMed2000

CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines.

It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status.

3T3 Cells↗
PubMed2000

Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy.

Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease. (Blood. 2000;95:56-61)

Adult↗
PubMed2000

Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients.

We herein describe the development and validation of the Cancer Fatigue Scale (CFS) for assessment of fatigue in cancer patients. We designed this scale specifically to reflect the nature of fatigue experienced by cancer patients, by using factor analysis; the CFS is a 15-item scale composed of 3 subscales (physical, affective, and cognitive subscales). Three hundred seven cancer patients participated in the validation phase. Construct validity, confirmed by repeating factor analysis, was good. Convergent validity, confirmed by a correlation between CFS and a visual analogue scale for fatigue, was also shown to be good (r = 0.67, P < 0.001). The CFS had good stability (average test-retest reliability r = 0.69, P < 0.001) and good internal consistency (Cronbach's alpha coefficient for all 15 items = 0.88). The present study indicates that the CFS is a brief, valid, and feasible measure of fatigue for use with cancer patients.

Adolescent↗
PubMed2000

Construction and characterization of phage libraries displaying artificial proteins with random sequences.

Three phage libraries, PL1, PL2, and PL3, displaying artificial proteins with random sequences were constructed. The artificial proteins, which are model of ancestral proteins, are derivatives of the 25 kinds of random proteins with about 140 amino acid residues produced via random mutagenesis and combinatorial recombination. The random proteins were displayed on the surface of filamentous bacteriophage as fusion protein with the pIII coat protein at an estimated average number on the phage particles in PL1, PL2, and PL3 of 0.32, 0.32, and 0.08, respectively. Each library was shown to express 10(5) to 10(6) kinds of random proteins. With the phage libraries displaying long random peptides, we now have an effective selection system to observe in vitro evolution of new functional proteins from artificial proteins with random sequences.

Journal Article↗
PubMed2000

Diagnosis and management of cystic pancreatic tumours with mucin production.

BACKGROUND: To aid selection of the most appropriate treatment for intraductal tumours (IDTs) and mucinous cystic tumours (MCTs) of the pancreas, this study describes the clinical and diagnostic features of these tumours and compares the clinicodiagnostic features of malignant and benign tumours and hyperplasia. METHODS: The clinical features of 28 IDTs (four cases of hyperplasia, six adenomas and 18 adenocarcinomas) and six MCTs (four adenomas and two adenocarcinomas) were studied. RESULTS: An IDT was found in 24 men and four women with a mean age of 64.5 years, whereas all patients with an MCT were women, with a mean age of 50.8 years. Twenty IDTs were located in the pancreatic head, whereas all MCTs were in the pancreatic body-tail. The mean size of IDTs was smaller than that of MCTs (4.4 versus 7.7 cm). The mean size of hyperplastic lesions, adenomas and adenocarcinomas in IDTs were 1.7, 2.9 and 5.4 cm respectively. Hyperplastic IDT lesions were smaller than 2 cm without either mural nodules or dilatation of the main pancreatic duct. IDTs larger than 3 cm with mural nodules and mucin secretion from an enlarged papilla orifice and dilatation of the main pancreatic duct were often adenocarcinomas. CONCLUSION: Although follow-up of intraductal hyperplasia is a reasonable approach, other types of IDT and MCT require surgical treatment.

Adenocarcinoma↗
PubMed2000

Continuous monitoring of nitric oxide release induced by cholecystokinin from the choledochal sphincter in guinea pigs.

BACKGROUND/AIMS: Many in vitro studies in the choledochoduodenal junction of the guinea pig have shown that cholecystokinin (CCK) contracts the sphincter of Oddi (SO). This study, using the choledochal sphincter of the guinea pig as the SO, evaluates the hypothesis that effects of CCK on the SO were mediated by nitric oxide (NO). METHODS: Spontaneous motility and effects of CCK on the choledochal sphincter were recorded using a constant-perfusion technique, and direct measurement of NO release using a specific NO sensor was performed at the same time. RESULTS: CCK-8 decreased the phasic wave amplitude of the choledochal sphincter, and increased NO release. N(G)-L-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase, increased the spontaneous motility and converted the CCK-induced inhibitory response into an excitatory response. L-NAME also reduced NO release and abolished the increase of NO that had been caused by CCK-8. These effects were reduced by treatment with L-arginine (L-Arg). L-Arg application enhanced NO release, and recovered the increase of NO by CCK-8. CONCLUSION: These studies demonstrate that CCK relaxes the choledochal sphincter and this relaxant response is mediated by NO.

Animals↗
PubMed2000

Clinicopathological analysis of premature infants treated with artificial surfactant.

OBJECTIVE: Our aim was to obtain new information about the relationship between infant responses to surfactant replacement therapy and histopathological changes in vital organs. STUDY DESIGN: To accomplish this, the autopsy findings and clinical backgrounds of 41 very low birth weight infants (gestational week 25.6 +/- 2.3; birth weight 806.4 +/- 251.6g) who had died after receiving surfactant replacement therapy were reviewed, and those who responded to therapy were compared with those who did not. Responders were infants in whom the required FiO(2) declined by > 20% or mean airway pressure declined by > 20% within six hours of instilling surfactant (n=18); non-responders were infants who did not meet those criteria (n=23). RESULT: Gestational age, birth weight and time at treatment were similar in responders and non-responders, but survival was significantly longer in responders. The incidences of hyaline membrane disease, pulmonary interstitial emphysema, hemorrhagic necrosis and parenchymal degeneration of the liver and kidney were all higher in non-responders, whereas the incidences of bronchopulmonary dysplasia and pneumonia were higher in responders. Prior to treatment, acidosis and hypothermia were significantly more severe in non-responders, and perinatal complications, such as fetal distress and intrauterine infection, were observed more often in non-responders. Substantial degradation of vital organs had already occurred during the early post-natal or intrauterine life of the non-responders, which would be expected to interfere with the clinical response to instilled surfactant. CONCLUSION: It is anticipated that in the future improved monitoring of immature fetuses will be indispensable to improve intrauterine fetal management and to achieve better control over the timing and mode of delivery.

Gestational Age↗
PubMed2000

Diverse regulations of albumin gene expression by hepatocyte growth factor in HepG2 human hepatoma cells and primary culture of rat hepatocytes.

The effects of HGF on albumin gene expression in HepG2 human hepatoma cells and rat hepatocytes were investigated. HGF reduced the levels of albumin mRNA in HepG2 cells but the level was augmented in rat hepatocytes. By the transfection assay, HGF stimulated albumin promoter activity but repressed alpha-fetoprotein (AFP) enhancer activity regulating both AFP and albumin promoters in HepG2 cells. In contrast, HGF stimulated albumin promoter and AFP enhancer activities in rat hepatocytes. These results suggest that HGF elicits diverse responses of albumin gene expression in HepG2 cells and rat hepatocytes through the different biological actions on AFP enhancer in these cells.

Albumins↗