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H Saji

Publications and source records attributed to H Saji.

At least 55 records · Page 3Linked to original sources
PubMed1999

The integrity of the disulfide bond in a cyclic somatostatin analog during 99mTc complexation reactions.

Recent development of a variety of thiol-free chelating agents has facilitated the design of 99mTc-labeled somatostatin analogs suitable for receptor imaging of somatostatin-positive tumors. However, it remains ambiguous whether the disulfide bonds in cyclic peptides are stable during 99mTc complexation reactions, and contradictory results have been reported regarding the integrity of disulfide bonds in cyclic somatostatin analogs. To estimate the stability of the disulfide bond in a synthetic somatostatin analog at low peptide concentrations, [125I]I-RC-160, in which radioiodine was incorporated into the 3-Tyr residue, was synthesized and the integrity of the disulfide bond of the peptide was investigated in the presence of reducing agents such as ascorbic acid, dithionite, and stannous ions. The disulfide bond in [125I]I-RC-160 remained stable in the presence of ascorbic acid in boiling water. The disulfide bond was also stable when treated with stannous ions at concentrations sufficient to reduce 99mTc for complexation with a thiol-free chelating agent, bis(hydroxamamide) analog when the 99mTc complexation reaction was performed at room temperature. However, the disulfide bond of [125I]I-RC-160 was slightly cleaved in the presence of a small amount of stannous ions when the reaction was performed in boiling water. Treatment of [125I]I-RC-160 with dithionite in boiling water markedly reduced the disulfide bond of the parental peptide. These findings indicated that synthetic somatostatin analogs may be labeled with 99mTc with stannous ions as the reducing agent without impairing their structure after conjugation of thiol-free chelating agents that provide 99mTc chelates under mild reaction conditions.

Ascorbic Acid↗
PubMed1999

A novel immunoscintigraphy technique using metabolizable linker with angiotensin II treatment.

Immunoscintigraphy is a tumour imaging technique that can have specificity, but high background radioactivity makes it difficult to obtain tumour imaging soon after the injection of radioconjugate. The aim of this study is to see whether clear tumour images can be obtained soon after injection of a radiolabelled reagent using a new linker with antibody fragments (Fab), in conditions of induced hypertension in mice. Fab fragments of a murine monoclonal antibody against human osteosarcoma were labelled with radioiodinated 3'-iodohippuryl N-epsilon-maleoyl-L-lysine (HML) and were injected intravenously to tumour-bearing mice. Angiotensin II was administered for 4 h before and for 1 h after the injection of radiolabelled Fab. Kidney uptake of 125I-labelled-HML-Fab was much lower than that of 125I-labelled-Fab radioiodinated by the chloramine-T method, and the radioactivity of tumour was increased approximately two-fold by angiotensin II treatment at 3 h after injection, indicating high tumour-to-normal tissue ratios. A clear tumour image was obtained with 131I-labelled-HML-Fab at 3 h post-injection. The use of HML as a radiolabelling reagent, combined with angiotensin II treatment, efficiently improved tumour targeting and enabled the imaging of tumours. These results suggest the feasibility of PET scan using antibody fragment labelled with 18F-fluorine substitute for radioiodine.

Angiotensin II↗
PubMed1999

In-vivo evaluation of indium-111-diethylenetriaminepentaacetic acid-labelling for determining the sites and rates of protein catabolism in mice.

Pharmacokinetic analyses of protein pharmaceuticals are of prime importance for their clinical application. Because many proteins have pharmacological activity at low concentrations, radiolabelling of proteins is widely used to identify the sites and determine the rates of protein catabolism in-vivo due to the high sensitivity of detection of radioactivity. Recently, a metallic radionuclide, (111)In, has been used to trace the pharmacokinetics of proteins of interest after conjugation of the proteins with diethylenetriaminepentaacetic acid (DTPA). In this study, galactosyl-neoglycoalbumin (NGA) was reacted with the cyclic dianhydride of DTPA and labelled with (111)In to estimate the validity of this radiolabelling procedure for pharmacokinetic analyses. For comparison, we also evaluated direct radioiodination, because directly-radioiodinated proteins are widely used to assess the pharmacokinetics of proteins of interest. The hepatic radioactivity profile after intravenous injection of [131I]NGA or [(111)In]DTPA-NGA into mice was analysed pharmacokinetically, and the first-order rate constant representing the elimination of the respective radiometabolite from hepatic parenchymal cells was determined. The results indicated that direct radioiodination is inappropriate for pursuing the pharmacokinetics of the proteins, because of rapid elimination of the radioactivity from the sites of protein catabolism. These findings also implied that the [(111)In]DTPA label could be used to identify the catabolic sites and determine the rates of catabolism of proteins with relatively short biological half-lives, although characterization of radiolabelled species at the sites of accumulation would be required for accurate determination of the catabolic sites of proteins.

Albumins↗
PubMed1999

Endogenous interleukin-12: relationship with angiogenic factors, hormone receptors and nodal status in human breast carcinoma.

Interleukin-12 (IL-12) is known to be a key cytokine for regulating immune response, but it is also known to provide some other biological function including inhibition of angiogenesis. We have determined using an enzymatic immunoassay the endogenous levels of IL-12 in 390 cytosols of primary breast cancers previously tested also for the angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). The concentration of IL-12 ranged from 0 to 7.6 ng/mg protein, and 124 (31.8%) out of 390 cancers showed a detectable dose (>0.1 ng/ml). There was no statistical association of IL-12 levels with tumor size and menopausal status. IL-12 levels tended to be higher in the tumors of node-positive patients as compared to those of node-negative ones (t-test, p=0.082). In addition, IL-12 levels were inversely associated with hormone receptor status, particularly progesterone receptor expression (p=0.0013). There was a significant inverse association between IL-12 and TP concentration (p=0.0007). The proportion of tumors with detectable levels of IL-12 and low levels of either VEGF or TP was higher among the patients with node-negative as compared to those with node-positive disease. On the contrary, the proportion of tumors with no detectable IL-12 and high levels of either VEGF or TP was higher in node-positive versus node-negative cancers. In conclusion, our study evaluated the balance between pro-angiogenic factors (TP and VEGF) and IL-12, as a detectable naturally occurring inhibitor of angiogenesis, in the same series of node-negative and node-positive breast cancers. Further studies are warranted to investigate the biological and clinical significance of the co-determination of pro and contra angiogenic factors in human breast carcinoma.

Adult↗
PubMed1999

Significance of thymidine phosphorylase as a marker of protumor monocytes in breast cancer.

Tumor-associated monocytic cells (TAMs) are a major component of the stroma responsible for tumor formation. TAMs generate various kinds of mediators for their function, one of which is thymidine phosphorylase (TP). TP is an angiogenic enzyme that is known to be up-regulated in tumor tissues. Here, we focused on the clinical implication of TP expression in TAMs by studying 229 primary breast carcinoma tissues. Immunohistochemical analysis demonstrated that monocytic TP+ tumors had a significantly worse prognosis than did monocytic TP- tumors (P < 0.01, log-rank test). A multivariate analysis confirmed that monocytic TP status provided an independent prognostic value (P < 0.0001). Furthermore, of interest was that monocytic TP status could categorize the CD68+ patients, who had an extensive accumulation of CD68+ TAMs, into two subgroups with strikingly contrasting prognoses: a good prognostic monocytic TP- group and a poor prognostic monocytic TP+ group. This indicates that there are both antitumor and protumor types of TAM. Subanalysis showed that microvessel density was significantly increased in CD68+/monocytic TP+ tumors compared with CD68+/monocytic TP- tumors. Experimentally, TAMs are known to function in diverse manners, antitumor and protumor; however, little is known about clinically recognizable markers to characterize the TAMs in histological sections. TP might be such a marker, which would be useful for identifying the character of TAMs, particularly the protumor phenotype.

Adult↗
PubMed1999

Targeted delivery of radiolabeled imaging and therapeutic agents: bifunctional radiopharmaceuticals.

Clinical application of radioactive diagnostic and therapeutic agents constitutes one of the great advances in noninvasive medicine, nuclear medicine. The radioactive agents used in the nuclear medical field are called "radiopharmaceuticals," and are required to exhibit high and specific localization of radioactivity into target tissue. Among radionuclides used in radiopharmaceuticals, radiometals such as 99mTc and (111)In have received much attention because of their nuclear physical characteristics and widespread availability. However, since these metallic elements are not constituents of bioactive molecules, they cannot simply replace common constituent atoms in biologically interesting compounds. Thus, demand for biospecific radiopharmaceuticals constitutes a great challenge in rational design of biologically active molecules labeled with metallic radionuclides, and evolves into a generation of bifunctional radiopharmaceuticals. Molecules contain both a biologically active site and a chelating group for binding the metallic radionuclide in which attachment of a chelating group does not affect the inherent biospecificity of the mother compound. This paper describes recent progress in research of macro- and small-molecular bifunctional radiopharmaceuticals for targeted diagnosis and therapy.

Animals↗
PubMed1999

Typing for human platelet alloantigens.

Antibodies to platelet alloantigens, and sometimes to isoantigens, induce severe clinical problems such as neonatal alloimmune thrombocytopenia (NAIT), post-transfusion purpura (PTP) and refractoriness to platelet transfusions (PTR). For example, NAIT affects approximately 1 in 5,000 live births. It is essential, therefore, to screen pregnant women for platelet antibodies in order to save babies' lives. Almost 40 years ago, two platelet alloantigen systems were discovered using relatively simple methods, namely the platelet agglutination test and the complement fixation test. However, these methods were not sensitive enough to identify all antibodies in mothers and patients, even in those with severe clinical problems. Tremendous effort has been devoted to establish more sensitive and reliable methods. In recent years, excellent new serological and immunochemical methods have been established and several new platelet antigen systems have been discovered. Simultaneously, newly developed molecular genetic techniques have been introduced for the typing and analysis of human platelet alloantigen systems. These methods allow DNA typing for cases in which serological typing is not available. In this article, the history of studies on human platelet alloantigen systems and isoantigens, the nomenclature of platelet alloantigen systems and their alleles, the present status of antibody detection and typing techniques and, finally, ethnic variations in platelet antigen profiles are reviewed.

Alleles↗
PubMed1998

HLA-DRB1 and tumor necrosis factor gene polymorphisms in Japanese patients with multiple sclerosis.

We studied genetic polymorphisms in the tumor necrosis factor (TNF) region as well as HLA-DRB1 of 42 patients with Western-type multiple sclerosis (MS) and 38 with Asian-type MS in Japan. The sex ratio (Female:Male) was significantly higher in Asian than in Western type MS (3.8 vs. 1.3, P = 0.038). The frequency of HLA-DRB1 * 1501 allele in the Western-type MS group increased significantly compared with the control group, while Asian-type MS and control groups showed similar distribution in the frequencies of HLA-DRB1 alleles. No significant differences existed in the TNF region, however, including TNF-a microsatellite alleles. The results suggest that MS in Asians may present two different clinical and immunogenetic manifestations.

Adult↗
PubMed1998

Evidence that CD31, CD49b, and CD62L are immunodominant minor histocompatibility antigens in HLA identical sibling bone marrow transplants.

Despite complete matching of siblings for the HLA loci, after bone marrow transplantation (BMT), approximately 20% develop graft-versus-host disease (GVHD). This is presumably due to incompatibility of minor histocompatibility antigens (mHa). We investigated the polymorphisms of 14 adhesion molecules (CD2, CD28, CD31, CD34, CD36, CD42, CD44, CD48, CD49b, CD54, CD62L, CD86, CD102, and CD106) in Japanese subjects and their association with the occurrence of GVHD after allogeneic HLA identical BMT. Six molecules (CD2, CD31, CD42, CD49b, CD54, and CD62L), which were found to be polymorphic, were then examined in 118 HLA identical sibling donors and recipients who had undergone BMT. Association of the incompatibility of the polymorphic molecules with the presence or absence of GVHD was examined. In these six, we observed a significant correlation between acute GVHD and the compatibility of CD31 (codons 563/670) (Pcorrected = .018), and CD31 (codons 563/670) + CD62L (Pcorrected = .018) in patients with the HLA-B44-like superfamily. In patients with the HLA-A3-like superfamily, the compatibility of CD62L (Pcorrected = .03) and CD62L + CD49b (P = . 004, Pcorrected = .078) was associated with acute GVHD. Therefore, CD31, CD49b, and CD62L might be candidates for immunodominant mHa.

Adolescent↗
PubMed1998

Genetic contribution of the tumor necrosis factor region in Guillain-Barré syndrome.

We studied genetic polymorphisms in the tumor necrosis factor (TNF) region in 81 Japanese patients with Guillain-Barré syndrome (GBS) and 85 controls. A significantly higher frequency of the 100-base pair (bp) (TNFa2) allele of the TNFa microsatellite marker, which is associated with high TNF alpha production, existed in Campylobacter jejuni-positive (Cj+) GBS patients than in controls, suggesting the involvement of a genetic predisposition to high TNF alpha secretion in the development of C. jejuni-related GBS.

Alleles↗
PubMed1998

One-way donor-recipient HLA-matching as a risk factor for graft-versus-host disease in living-related liver transplantation.

Although one-way matching between an HLA-homozygous donor and a haploidentical recipient is a recognized risk factor in transfusion-associated graft-versus-host disease (GVHD), its impact in living-related liver transplantation (LRLT) has so far not been investigated. We present a case of fatal acute GVHD in our LRLT program that was attributed to one-way HLA matching between donor and recipient. Although the disappearance of donor cells in peripheral blood was suggested by genetic analysis, severe septicemia led to a fatal outcome. We further reviewed 280 LRLT cases and correlated one-way HLA matching with outcome. A total of 8 out of 280 donors (2.9%) and 11 out of 278 recipients (4.0%) were completely HLA homozygous in our LRLT program. Complete one-way HLA matching linked to GVHD was observed in four cases, including the present case. Although other contributing factors also need to be clarified, one-way HLA matching is a definite risk factor for GVHD in LRLT. We advocate caution before proceeding with one-way HLA donor-recipient combinations.

Fatal Outcome↗
PubMed1998

Hemolytic reaction due to graft-versus-host (GVH) antibody production after liver transplantation from living donors: report of two cases.

Among 27 patients who received minor ABO-incompatible partial liver transplantations and 19 who received major ABO-incompatible partial liver transplantations from living donors, 2 developed hemolytic anemia within 2 weeks after transplantation. These 2 patients had received livers from their living fathers whose blood type was ABO-incompatible. B-to-A transplantation was performed in patient 1 and O-to-B transplantation was performed in patient 2. Anti-A IgM and IgG were detected in the serum of patient 1, and anti-B IgM and IgG were detected in the serum of patient 2. These antibodies were eluted from the red blood cells of the patients. The coexistence of donor-specific DNA in the peripheral blood of the patients proved that they had chimerism, and graft-versus-host antibody production due to passenger B lymphocytes in the donor's liver was subsequently confirmed.

ABO Blood-Group System↗
PubMed1998

Pharmacokinetic models to evaluate radiolabeling reagents for protein radiopharmaceuticals.

Pharmacokinetic models were constructed to further estimate the hepatic radioactivity levels derived from bifunctional chelating agents used for radiolabeling of proteins. Both galactosyl-neoglycoalbumin (NGA) and mannosyl-neoglycoalbumin (NMA) were labeled with (111)In using two benzyl-EDTA derivatives. Time-activity profiles for the liver with gallbladder, intestine, and blood after administration of (111)In-labeled NGAs in mice were simultaneously fitted to a multi-compartment model, and the first-order rate constants representing the disappearance from parenchymal cells were obtained. Similarly, a model composed of the blood and liver compartment was constructed, and the disappearance rate constants from nonparenchymal cells were calculated from the biodistribution studies following administrations of (111)In-labeled NMAs. Fitting curves showed good agreements with the experimental data. Each rate constant clearly distinguished the elimination rate of the respective radiometabolite from the liver cells. Thus, quantitative estimations of radiolabeling reagents were performed only by animal biodistribution studies, and the present pharmacokinetic analyses would be useful for screening of newly designed reagents for protein radiopharmaceuticals.

Albumins↗
PubMed1998

Evaluation of [1-11C]octanoate as a new radiopharmaceutical for assessing liver function using positron emission tomography.

[1-11C]Octanoate was evaluated as a new radiopharmaceutical for the evaluation of liver function using positron emission tomography (PET). In biodistribution studies with normal mice, [1-11C]octanoate was rapidly taken up by the liver. [1-11C]Octanoate in the liver was present in the parenchymal cells and was predominantly metabolized via beta-oxidation followed by its rapid clearance. In the CCl4-treated mice, [1-11C]octanoate showed significantly slower hepatic clearance than that in the controls. In PET studies using rats, the time-radioactivity curves in the liver showed a two-phase decrease, and compared with the normal rat, the CCl4-treated rat showed a slower hepatic half-clearance time for the first phase, which is related to beta-oxidation metabolism. A preliminary PET study of [1-11C]octanoate metabolism in a normal volunteer was consistent with these animal studies. The present study showed that metabolism of [1-11C]octanoate in the liver was influenced by beta-oxidation, and it is advantageous to use [1-11C]octanoate clinically as a regional liver-function diagnostic agent in conjunction with PET.

Acetates↗
PubMed1998

Tc(V)-DMS tumor localization mechanism: a pH-sensitive Tc(V)-DMS-enhanced target/nontarget ratio by glucose-mediated acidosis.

Since the conception of the pentavalent technetium polynuclear complex of dimercaptosuccinic acid, Tc(V)-DMS, a great number of papers published on its clinical applicability forced us to question "how tumor tissue appropriates the Tc(V)-DMS." Preliminary in vitro studies with Ehrlich ascites tumor cells (EATC) indicated the pH-sensitive character of this tumor agent. From this finding and the well-established notion that malignant tumors are more acidic than normal tissue, the in vivo correlation of Tc(V)-DMS accumulation in tumor tissue with its tissue acidification was considered of interest. The systemic lowering of tumor tissue pH by the stimulation of aerobic glycolysis has been well reported. In the present paper, the response of Tc(V)-DMS tumor accumulation to acidification induced by the glucose administration was explored in EATC-bearing mice. Measurement of tumor tissue pH was carried out by direct microelectrode technique and by histochemical umbelliferone technique in tumor tissue excised from EATC bearing mice. The regional acidity distribution is correlated with the regional radioactivity distribution registered by autoradiography. Evidence related to the pH sensitiveness of Tc(V)-DMS in response to glycolytic acidification was gathered; the pH measurement and the in vivo biodistribution of the double-tracer macroautoradiography with C-14 deoxyglucose (C-14-DG) demonstrated that the regional tissue distribution of Tc(V)-DMS was superimposed to that of C-14-DG. The glucose interventional modality offers the premier foundation for the interpretation of Tc(V)-DMS accumulation in diagnostic studies of malignant tumors.

Acidosis↗
PubMed1998

pH sensitive properties of Tc(V)-DMS: analytical and in vitro cellular studies.

Numerous clinical studies with the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] seem to indicate its new role in nuclear oncology. Thus, we questioned what properties of the Tc(V)-DMS molecule associate with its tumoral tissue accumulation. Because studies have reported tumor tissue to be more acidic than normal tissue, acidification might be related to the Tc(V)-DMS localization in tumor tissue. Thus, in the present study, a working hypothesis drew to test the acidification as a plausible factor, and various analytical methods and an in vitro cellular system using Ehrlich ascites tumor cells (EATC) implemented. Analytical methodologies demonstrated the decrease of the overall negative charge of the Tc(V)-DMS molecule, promoted by the acidification of the analytical medium and the sample dilution. In the in vitro cellular experiment, acidification alone showed no effect on the radioactivity accumulation in EATC; nevertheless, if accompanied by a pre-dilution of the Tc(V)-DMS sample added into the cell incubation media, cellular radioactivity accumulation was observed. Thus, acidification as a mediator for the Tc(V)-DMS accumulation in tumoral cells, concurrently with dilution as the promoter of the process, constituted the foundation for discerning the working hypothesis.

Acetic Acid↗
PubMed1998

HLA-DRB1 alleles contribute to determining the prognosis of Japanese diabetes mellitus positive for antibodies to glutamate decarboxylase.

Diabetes mellitus positive for antibodies to glutamate decarboxylase is heterogeneous as far as the degree of impairment of endogenous insulin release, though antibodies to glutamate decarboxylase are the most useful marker for future insulin deficiency. To investigate what determines the prognosis of diabetes mellitus positive for antibodies to glutamate decarboxylase, we measured HLA-DRB1 alleles in three groups: 77 cases of insulin-dependent diabetes mellitus (IDDM), 44 of non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure of oral hypoglycemic therapy, and 22 of NIDDM well controlled by diet and/or sulfonylurea agents. The proportion of susceptible and resistant alleles to IDDM determined the degree of insulin deficiency, and comparison of IDDM to NIDDM well controlled by diet and/or sulfonylurea agents revealed significant differences in DRB1*0405 (P < 0.05; RR = 2.82 and RR = 0.89, respectively) and DRB1*1502 (P < 0.001; RR = 0.02 and RR = 2.19, respectively). This study revealed that HLA-DRB1 alleles contribute to determining the prognosis of Japanese diabetes mellitus positive for antibodies to glutamate decarboxylase.

Adolescent↗