[Results of molecular screening of anti-cancer agents. 8. Results of screening of possible anti-cancer agents in Japan].
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Antineoplastic Agents↗
Biomedical subjects
S Uehara
Publications and source records attributed to S Uehara.
Complete androgen insensitivity in a 47,XXY patient with uniparental disomy for the X chromosome.
We describe a unique patient with complete androgen insensitivity syndrome and a 47,XXY karyotype. Androgen receptor assay using cultured pubic skin fibroblasts showed no androgen-binding capacity. Sequence analysis of the androgen receptor gene demonstrated two nonsense mutations, one in exon D and one in exon E. Microsatellite marker analysis showed that the patient is homozygous for all five Xq loci examined. The results suggest that the long-arms of the two X chromosomes are identical, i.e., uniparental isodisomy at least for Xq, and carry the same mutations in the androgen receptor gene. This explains how complete androgen insensitivity syndrome occurred in this 47,XXY individual.
Adult↗
IL-5 induces IgG1 isotype switch recombination in mouse CD38-activated sIgD-positive B lymphocytes.
Mouse B cells express CD38, whose ligation by anti-CD38 Ab induces their proliferation and protection from apoptosis. We previously showed that stimulation of mouse splenic B cells with IL-5 together with CS/2, an anti-mouse CD38 mAb, induces production of IgG1 and IgM. Here we examined the role of IL-5 and CS/2 in the expression of germline gamma1 transcripts and the generation of reciprocal products forming DNA circles as byproducts of mu-gamma1 switch recombination. By itself, CS/2 induced significant expression of germline gamma1 transcripts in splenic naive B cells, whereas IL-5 neither induced nor enhanced germline gamma1 expression. Increased cellular content of reciprocal product, which is characteristic of mu-gamma1 recombination, was not observed after culturing B cells with CS/2, but increased reciprocal product, along with high levels of lgG1 secretion, was found when B cells were cultured with CS/2 plus IL-5. Although IL-4 did not, by itself, induce mu-gamma1 recombination in B cells stimulated with CS/2, in conjunction with CS/2 plus IL-5, IL-4 dramatically enhanced sterile gamma1 transcription and IgG1 production. These results demonstrate that CD38 ligation induces only germline gamma1 transcription and that IL-5 promotes both mu-gamma1 switch recombination and lgG1 secretion in an IL-4-independent manner.
ADP-ribosyl Cyclase↗
Comparison of survival rates of patients with nasopharyngeal carcinoma treated with radiotherapy, 5-fluorouracil and vitamin A ("FAR" therapy) vs FAR therapy plus adjunctive cisplatin and peplomycin chemotherapy.
The overall survival rate (OSR) of 36 patients with nasopharyngeal carcinomas (NPC) treated at Kyushu University hospital between 1983 to 1992 was analyzed. As primary treatment, 16 patients received a combination therapy of 5-fluorouracil, vitamin A, and radiation (FAR therapy); two patients received radiotherapy only; 18 patients received FAR therapy plus adjunctive systemic chemotherapy consisting of cisplatin and peplomycin. The radiation dose to the nasopharynx was 6000 to 7050 cGy while that to the neck was 4000-6000 cGy. The 5-year OSR of all the patients was 49%. Histological type (moderately differentiated squamous cell carcinoma) and patient age (> or = 55) were found to be significant prognostic factors for a worse OSR. Although survival decreased with increasing T stage, no significant difference was observed. The 5-year OSR of the patients treated with FAR therapy was 53% and was 51% with FAR therapy plus chemotherapy. Compared to FAR therapy alone, adjunctive chemotherapy did not increase OSR of the patients with NPC.
Adult↗
Hepatocellular carcinoma complicated by gastrointestinal hemorrhage caused by direct tumor invasion of stomach.
A 65-year-old man with multiple hepatocellular carcinoma (HCC) underwent intra-hepato-arterial chemotherapy (IHAC) through an implantable port over a period of 10 months after transcatheter arterial embolization (TAE) had been performed three times. TAE was performed twice more, and radiotherapy (total dose, 30 Gy; given over a 3-week period) was given for progressive disease in the lateral segment of the liver. Three months after the radiotherapy had finished, the patient suddenly developed melena. Diagnostic imaging revealed gastrointestinal (GI) hemorrhage from HCC invading the stomach, and total gastrectomy and lateral segmentectomy of the liver were performed because the bleeding could not be controlled. The resected specimen disclosed a centrally necrotic tumor that had invaded the lesser gastric curvature and perforated into the lumen. Pathology examination revealed that the HCC had expansively invaded the gastric mucosa, resulting in exposure in the lumen. The possible mechanisms of direct GI invasion by HCC are briefly discussed, with a review of the literature. GI bleeding secondary to involvement by HCC is rare. The enteric radiation injury seems to have been largely responsible for the GI bleeding in this patient.
Aged↗
Process of carboxylation of glutamic acid residues in the gla domain of human des-gamma-carboxyprothrombin.
In the absence of vitamin K (VK) or in the presence of VK antagonists, hepatic VK-dependent carboxylase activity is inhibited and des-gamma-carboxyprothrombin (DCP) is released into the blood. We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6). The process of Glu carboxylation seemed to proceed three-dimensionally from inside to outside the molecule.
Adult↗
Serologic study of human parvovirus B19 infection in pregnancy in Japan.
OBJECTIVES: To clarify the relationship between hydrops fetalis and parvovirus outbreaks in the community, seroprevalence of B19 antibody among women of childbearing age, and adverse effects of intrauterine B19 infection. METHODS: Sera were collected from 168 cases of hydrops fetalis which were diagnosed between 1987 and 1997 in Miyagi prefecture, Japan, from 232 healthy pregnant women in 1987 and 277 healthy pregnant women in 1997 in Miyagi, and from 48 women infected with B19 during pregnancy. The sera were examined for B19 IgG and IgM antibodies by enzyme-linked immunosorbent assay and for B19 DNA by polymerase chain reaction. The number of cases of erythema infectiosum in Miyagi had been monitored each month. RESULTS: Thirteen of the 168 cases of hydrops fetalis were found to be caused by intrauterine B19 infection and 12 of the 13 cases clustered in two periods of outbreaks of erythema infectiosum in the community. The positive rates of B19 IgG antibody between 1987 and 1997 were significantly different: 33% in 1987 and 46% in 1997. Nine of the 48 women infected during pregnancy showed adverse effects of the fetus: eight hydrops fetalis and one early abortion with positive B19 DNA. The fetal death rate (>12 weeks of gestation) among them was 15% (7/48), far higher than the calculated 1% among the general population. The nine mothers with adverse fetal outcomes had contact with the infectious source at the 16 weeks of gestation or earlier. CONCLUSIONS: These data clearly showed a relationship between hydrops fetalis and parvovirus outbreaks in the community, and it may be important to follow the seroprevalence for an extrapolated period time to predict occurrence of hydrops fetalis caused by B19. Also the data indicated that the gestational week infection occurred is the most important determinant of an adverse effect to the fetus as described previously.
Adolescent↗
Parvovirus B19 infection induces apoptosis of erythroid cells in vitro and in vivo.
OBJECTIVE: intrauterine parvovirus B19 infection is related to non-immune hydrops fetalis, the pathogenesis of which is based on the strict tropism of B19 for erythroid precursor cells and the massive destruction of the infected erythroid cells, although the mechanism of beta19-induced cytotoxicity has not been studied in detail. The purpose of this study is to provide empirical evidence that beta19 induces apoptosis of erythroid cells both in vitro and ill vivo. METHODS: we analysed culture cells infected in vitro by B19 and tissues of nine cases of hydrops fetalis caused by B19 intrauterine infection by histological and biological methods. RESULTS: cells infected iil vitro by B19 showed nuclear changes characteristic of apoptosis by light microscopic examination and DNA extracted from the infected cells was fragmented. Electron microscopic examination showed the nuclei of infected cells contained crescent-shaped clumps of heterochromatin with increased density and double staining with anti-B1 9 antibody and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) confirmed apoptosis of individual cells. Tissues of cases of hydrops fetalis caused by B19 contained erythroid cells with nuclear inclusions and characteristic nuclear changes of apoptosis by light microscopy. The double-staining confirmed apoptosis of erythroid cells in the tissues. Immunohistochemical analysis with antibodies against cellular factors involved in apoptosis showed that caspase3, p53 and p21 were positive in infected cells.
Apoptosis↗
SRY mutation and tumor formation on the gonads of XP pure gonadal dysgenesis patients.
We report three patients with XY pure gonadal dysgenesis. Two of these patients developed gonadoblastoma and associated dysgerminoma. Molecular analyses were undertaken to investigate the relationship between the formation of these tumors and Y chromosome aberrations. Deletion analyses were performed by polymerase chain reaction (PCR) amplification of Y chromosome-specific DNA sequences (PABY, SRY, DYS250, DYS254, and DYZ1). A cryptic deletion of the short arm of the Y chromosome that included the PABY, SRY, DYS250, and DYS254 loci was observed in one of the patients (22-years-old) with an associated tumor. In the other two patients who did not demonstrate such a deletion, the sequence of the SRY open reading frame was determined by the dideoxynucleotide method. Two nucleotide substitutions followed by a seven nucleotide deletion were observed in the 3' end of HMG (high mobility group)-box in the other patient (15-years-old) with an associated tumor. The patient (22-years-old) without an associated tumor did not have the cryptic deletion or mutation of SRY. A Y chromosome specific sequence (DYZ1) was demonstrated by PCR amplification of microdissected tumor tissues from these two patients. These results suggest that SRY may play a role in the formation of gonadal tumors, especially dysgerminoma.
Adolescent↗
IgG1 production by sIgD+ splenic B cells and peritoneal B-1 cells in response to IL-5 and CD38 ligation.
CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induces proliferation, IL-5 receptor alpha chain expression and tyrosine phosphorylation of Bruton's tyrosine kinase. Furthermore, stimulation of splenic B cells with IL-5 together with CS/2 induces Blimp-1 expression and differentiation into Ig-producing cells. Here we examined the role of IL-5 in IgG1 and IgA production by B cells isolated from the spleen and peritoneal cavity. CD38 recognized by CS/2 was expressed in the follicular mantle B cells surrounding the germinal center, sIgD+ splenic B cells and peritoneal B cells. IL-5 induced IgG1 production in splenic sIgD+ B cells stimulated with CS/2, while it was ineffective to induce IgA production. Among the various cytokines tested, only IL-5 had a synergistic effect on IgG1 production with CS/2. IL-5 could induce the generation of S micro-Sgamma1 reciprocal recombination DNA products in CS/2-stimulated B cells. IL-4 was ineffective to induce either micro-gamma1 switch recombination or IgG1 secretion with CS/2, demonstrating that IL-5 promotes both micro-gamma1 switch recombination and IgG1 secretion in an IL-4-independent manner. The peritoneal B-2 cells exhibited both IgG1 and IgA production in response to IL-5 plus CS/2, while B-1 cells produced IgG1. These results imply that the pattern of differentiation to Ig-producing cells seen with peritoneal B cells is not identical to the pattern seen with splenic B cells and that peritoneal B-2 cells contain precursors of IgA-producing cells responding to IL-5 plus CS/2.
ADP-ribosyl Cyclase↗
Risk of recurrence of fetal chromosomal aberrations: analysis of trisomy 21, trisomy 18, trisomy 13, and 45,X in 1,076 Japanese mothers.
OBJECTIVE: To evaluate the risk of recurrence of fetal chromosomal aberrations in women who had offspring with numeric chromosomal abnormalities. SUBJECTS AND METHODS: This collaborative study consisted of 1,076 Japanese women with a history of offspring with trisomy-21, -18, -13, or 45,X. Second-trimester amniocenteses were performed, resulting in 1,248 fetal karyotypes that were analyzed with reference to prior offspring karyotypes and maternal age. RESULTS: Of the 842 women with trisomy-21 offspring, 10 conceived another such fetus. In 2 women with 3 or more such offspring, parental mosaicism of trisomy-21 was suspected. The incidence of recurrence of trisomy-21 increased with age, and significantly exceeded the incidence of trisomy-21 fetuses in the general population. None of the 170 women with trisomy-18 offspring, and none of the 46 women with trisomy-13 offspring, had another such fetus. Of the 18 women with 45,X offspring, 1 with mos 45,X/46,XX had another such fetus. CONCLUSIONS: The risk of recurrence of trisomy-21 is affected by maternal age and parental germline mosaicism. The risk of recurrence of trisomy-18 or -13 appears to be much lower than that of trisomy-21. Women who give birth to more than 1 offspring with 45,X should be examined for mos 45,X/46,XX.
Adult↗
Transforming growth factor-beta isoforms and receptors in endometriotic cysts of the human ovary.
PROBLEM: The present study examined the presence and cellular distribution of transforming growth factor-beta1, 2, and 3 isoforms and their type I and II receptors in endometriotic cysts of the ovary, relative to their presence in normal endometrial tissue. METHOD OF STUDY: Thirteen control samples of normal endometrium in the proliferative phase and 11 ovarian endometriotic cysts were examined by immunohistochemistry for transforming growth factor-beta1, 2, and 3 isoforms and their type I and II receptors. RESULTS: Immunoreactivity for all ligands and receptors was detected in both normal endometrium and endometriotic cysts. Isoform-specific differences in immunostaining were not detected. Expression of all ligands and receptors was significantly increased in epithelial cells of endometriotic cysts compared with those of normal endometrium. On the other hand, stromal cells in normal endometrium and endometriotic cysts were only faintly immunostained. Inflammatory cells infiltrating among endometriotic stromal cells contained the highest immunostaining intensity for all ligands and receptors. We identified nearly all inflammatory cells as macrophages using a specific antibody. CONCLUSIONS: These findings suggest that macrophages in endometriotic tissue are a major source of transforming growth factor-beta, which may be an important regulator of cell proliferation in endometriotic cysts through paracrine and autocrine actions.
Activin Receptors, Type I↗
[Influence of dexamethasone on the clinical course of bacterial meningitis in children. Especially on secondary fever. Experiences in 27 institutions].
Of pediatric patients with purulent meningitis seen at the institutions listed in the title page of this paper between 1986 and 1994, 93 patients treated with antibiotics and dexamethasone (DXM) were compared with 91 patients treated with antibiotics alone. The patients receiving antibiotics with dexamethasone achieved overall improvement in inflammatory symptoms and signs and cerebrospinal fluid findings and became afebrile significantly earlier than those receiving antibiotics alone. However, some of the patients became febrile again. The secondary fever rate for the DXM group was much higher than that for the antibiotic alone group (p < 0.0001). In most of the rebounded cases, the body temperature rose above 38 degrees C and remained elevated for 2-4 days. Cerebrospinal fluid (CSF) was cultured daily in 54 and 32 patients receiving antibiotics with and without DXM, respectively. Although this study was not a controlled study in a strict sense, these patients compared. In both groups, the CSF became mostly culture-negative within 48 hours. In a few patients receiving DXM, however, it became culture-negative after 72 hours or longer. DXM caused an adverse effect in a patient with meningitis caused by Streptococcus pneumoniae. The adverse effect was mild gastrointestinal bleeding, which recovered spontaneously. From the findings described above, the use of DXM combined with antibiotic therapy was considered to accelerate the relief from fever and improvement of inflammatory symptoms and signs and CSF findings. The body temperature rose again in more than half of the patients receiving DXM, but fell to normal spontaneously without treatment. The elevation doubtlessly could not be distinguished from recurrence of the meningitis itself or complications. It seems to be likely that no treatment but careful observation is required even if the fever recurs as far as the CSF findings showed favorable progress with excelluent general conditions. When DXM is given, it is essential that CSF tests and culture are repeated during the early stages and the progress is monitored carefully.
Anti-Bacterial Agents↗
Molecular epidemiological study of Haemophilus influenzae serotype b strains obtained from children with meningitis in Japan.
We report an epidemiological study of 30 Haemophilus influenzae serotype b (Hib) strains derived from the cerebrospinal fluid of children with meningitis. The Hib strains were biotyped, tested for beta-lactamase production, and genotyped by long PCR-ribotyping, random amplified polymorphic DNA (RAPD) analysis, and genomic DNA restriction fragment length polymorphism (RFLP) analysis by pulsed-field gel electrophoresis (PFGE). The phenotypic study characterized 22 of the strains (73%) as biotype I. A genotypic study using long PCR-ribotyping with HaeIII restriction digestion showed no polymorphisms among these 30 Hib strains, but RAPD analysis with two sets of primers demonstrated two distinctive subtypes: one typical of the strains of biotype group II and the second characteristic of the strains of biotype groups I and IV. Each RAPD group was subtyped into several genotypic groups by PFGE-RFLP with SmaI digestion. The genotyping of clinically isolated Hib strains may help to elucidate transmission routes in community infections, endemicity, and the reasons for vaccine failure.
Child, Preschool↗
Point mutations in the steroid-binding domain of the androgen receptor gene of five Japanese patients with androgen insensitivity syndrome.
We analyzed the androgen receptor (AR) gene in five Japanese patients diagnosed with androgen insensitivity syndrome (AIS). All AR genes from the five patients had single-nucleotide substitutions, which introduced a premature termination codon in three patients (Gln640, Arg752, and Gln640 and Trp751), and a single amino acid substitution in two patients (Arg831 to Gln, and Leu812 to Phe). All the mutations occurred in the steroid-binding domain, comprising exons D through G. The three patients with the premature termination codon(s) and the one patient with Arg831Gln were clinically diagnosed as having complete AIS, while the patient with Leu812Phe had a partial form of AIS. Pubic skin fibroblasts from four of the five patients did not show detectable androgen binding. These data on mutations that have not been reported previously, provide valuable information for the further characterization of structural and functional relationships in the steroid-binding domain of the AR protein.
Adult↗
In vivo and in vitro positive interference by cefpirome in measurement of serum creatinine by the Jaffe method.
We report the case of an 81-year-old female patient with diverticulitis of the colon, whose symptoms were relieved by intravenous administration of cefpirome. However, her serum creatinine levels were falsely increased by the Jaffe method when serum samples were drawn after intravenous administration of cefpirome. The serum creatinine level in the same sample was within the normal range by the enzymatic method in the automated analyzer. In vitro experiment demonstrated dose-dependent positive interference of the creatinine level with cefpirome. These results indicate that we should be aware of the positive interfering effect of cefpirome when we measure serum creatinine by the Jaffe method, and that the enzymatic method should be widely used to measure serum creatinine levels to eliminate false reactions due to certain chemicals.
Aged↗
[Accuracy, precision and clinically acceptable level of complete blood cell count by an automated multichannel hematology analyzer].
Measurement of complete blood cell count (CBC) is one of the essential laboratory tests. In this study, the accuracy of CBC was high, when measured by six different automated blood cell counters, including SE-9000/RAM-1, CELL-DYN 4000, ADVIA 120, VEGA RETIC-LC141 or GEN*S. The correlations of CBC counts among these instruments were also good. In contrast, the accuracy in abnormal samples depended on matching the instrument and type of clinical conditions. Internal quality control of automated multichannel hematology analyzers was recommended by the NCCLS H26-A in 1996. However, actual external quality control of the CBC count was poorly understood. We surveyed three samples from healthy volunteers for CBC values in 1997. Among six different instruments, the inter-assay of the red blood cell count (RBC), hemoglobin, hematocrit and MCV was fairly good, shown as < 4.2%, < 3.0%, < 4.4% and < 3.4%, respectively. In contrast, the inter-assay of the white blood cell count (WBC) and platelet (PLT) was not good, shown as < 11.4% and < 9.6%, respectively. The clinically acceptable levels for the blood cell count were reported to be 4% for RBC, 3% for hemoglobin, 4% for MCV, 5% for WBC and 7% for PLT, by JCCLS in 1994. The clinically acceptable CBC by hematologists at Keio University resembled those by councilors of The Japanese Society of Clinical Hematology, whereas, residents at Keio University and general physicians required more precise clinical CBC counts. These results indicate that a larger study is needed to clarify the accuracy, clinically acceptable level, and performance of different automated blood cell counters.
Blood Cell Count↗
Comparison and assessment of electron cross sections for Monte Carlo track structure codes.
The purpose of this study was to make an intercomparison and assessment of cross sections for electrons in water used in electron track structure codes. This study is intended to shed light on the extent to which the differences between the input data and physical and chemical assumptions influence the outcome in biophysical modeling of radiation effects. Ionization cross sections and spectra of secondary electrons were calculated by various theories. The analyses were carried out for water vapor cross sections, as these are more abundant and readily available. All suitable published experimental total ionization cross sections were fitted by an appropriate function and used for generation of electron tracks. Three sets of compiled data were used for comparison of total excitation cross sections and mean excitation energy. The tracks generated by a Monte Carlo track code, using various combinations of cross sections, were compared in terms of radial distributions of interactions and point kernels. The spectrum of secondary electrons emitted by the ionization process was found to be the factor that has the most influence on these quantities. A different set of cross sections for excitation and elastic scattering did not affect the electron track structure as much as did ionization cross sections. It is concluded that all codes, using different cross sections and in different phase, currently used for biophysical modeling exhibit close similarities for energy deposition in larger size targets while appreciable differences are observed in B-DNA-size targets. We recommend fitted functions to all available suitable experimental data for the total ionization and elastic cross sections. We conclude that most codes produce tracks in reasonable agreement with the macroscopic quantities such as total stopping power and total yield of strand breaks. However, we predict differences in frequencies of clustering in tracks from the different models.
DNA Damage↗