[A case of IIa + IIb-like advanced gallbladder cancer: usefulness of endoscopic double contrast cholecystography].
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Adenocarcinoma, Papillary↗
Biomedical subjects
H Inoue
Publications and source records attributed to H Inoue.
[Positional cloning of the gene(WFS1) for Wolfram syndrome].
Wolfram syndrome(DIDMOAD syndrome) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset, insulin-requiring diabetes mellitus and optic atrophy. Other symptoms including diabetes insipidus, neurosensory deafness, urinary tract and neurological abnormalities are often accompanied. In patients, beta-cells are selectively lost from their pancreatic islets of Langerhans. The gene was previously mapped to 4p16.1. By haplotype analysis and recombination mapping in 5 families, we localized the gene within a region less than 250 kb on chromosome 6p. In the region, we identified a novel gene(WFS1) encoding a putative transmembrane protein. Mutations were identified in all affected members of the families and these mutations were associated with disease phenotype. This finding was further confirmed by other investigators and to date, more than 50 mutations were identified in the WFS1 gene from the patients with Wolfram syndrome. The WFS1 gene encodes a protein of 100.3 kDa with 9 to 10 putative transmembrane domains. The protein appears to be important in the survival and maintenance of normal pancreatic beta-cells and neurons. Physiological function of the WFS1 protein and mechanisms by which defective WFS1 lead to the development of Wolfram syndrome need to be clarified.
Cell Survival↗
[Metastatic bladder tumor disseminated lymphogenously from gastric cancer: a case report].
A 59-year-old man was referred to our clinic with a complaint of frequent urination, voiding pain, and macroscopic hematuria. He had undergone total gastrectomy for mucinous adenocarcinoma, 21 months earlier. Pelvic computed tomography revealed a thick bladder wall all around. There were no other metastatic sites except for paraaortic lymph nodes. Transurethral resection of the bladder tumor was performed. The specimen showed signet ring cell carcinoma and revealed the same pathological findings as the primary gastric cancer. We diagnosed him with metastastic bladder tumor lymphogenously disseminated from gastric cancer. Such lymphogenous metastases from gastric cancer at the entire bladder wall without other apparent lesions have rarely been reported in the Japanese literature.
Adenocarcinoma, Mucinous↗
c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads.
Smads are intracellular signaling mediators of the transforming growth factor-beta (TGF-beta) superfamily that regulates a wide variety of biological processes. Among them, Smads 2 and 3 are activated specifically by TGF-beta. We identified c-Ski as a Smad2 interacting protein. c-Ski is the cellular homologue of the v-ski oncogene product and has been shown to repress transcription by recruiting histone deacetylase (HDAC). Smad2/3 interacts with c-Ski through its C-terminal MH2 domain in a TGF-beta-dependent manner. c-Ski contains two distinct Smad-binding sites with different binding properties. c-Ski strongly inhibits transactivation of various reporter genes by TGF-beta. c-Ski is incorporated in the Smad DNA binding complex, interferes with the interaction of Smad3 with a transcriptional co-activator, p300, and in turn recruits HDAC. c-Ski is thus a transcriptional co-repressor that links Smads to HDAC in TGF-beta signaling.
Acetyltransferases↗
Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro.
p70 S6 kinase alpha (p70alpha) is activated in vivo through a multisite phosphorylation in response to mitogens if a sufficient supply of amino acids is available or to high concentrations of amino acids per se. The immunosuppressant drug rapamycin inhibits p70alpha activation in a manner that can be overcome by coexpression of p70alpha with a rapamycin-resistant mutant of the mammalian target of rapamycin (mTOR) but only if the mTOR kinase domain is intact. We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate, the 40 S ribosomal protein S6. Moreover, sequential phosphorylation of p70alpha by mTOR and 3-phosphoinositide-dependent protein kinase 1 in vitro resulted in a synergistic stimulation of p70alpha activity to levels similar to that attained by serum stimulation in vivo. These results indicate that mTOR is likely to function as a direct activator of p70 in vivo, although the relative contribution of mTOR-catalyzed p70 phosphorylation in each of the many circumstances that engender p70 activation remains to be defined.
3-Phosphoinositide-Dependent Protein Kinases↗
Is the left atrium the only embolic source in ischemic stroke patients with nonvalvular atrial fibrillation?
Embolic sources were investigated in 74 ischemic stroke patients with nonvalvular atrial fibrillation using transesophageal echocardiography. In patients without left atrial spontaneous echo contrast, 78% had some embolic sources other than left atrial thrombus or spontaneous echo contrast, suggesting that these embolic sources play an important role in patients with nonvalvular atrial fibrillation.
Aged↗
Targeted disruption of the gene encoding the proteolipid subunit of mouse vacuolar H(+)-ATPase leads to early embryonic lethality.
Vacuolar H(+)-ATPase (V-ATPase) is responsible for acidification of intracellular compartments in eukaryotic cells. Its 16-kDa subunit (proteolipid, PL16) plays a central role in V-ATPase function, forming the principal channel via which protons are translocated. To elucidate physiological roles of V-ATPase in mammalian cell function and embryogenesis, we attempted to generate a PL16 null mutant mouse by gene-targeting. Mice heterozygous (PL16(+/-)) for the proteolipid mutation were intercrossed and their offspring were classified according to genotype. There were no homozygous (PL16(-/-)) pups among 69 neonates examined, but a few PL16(-/-) embryos were found during the pre-implantation stages of embryonic development, up to day 3.5 post-coitum. These results suggested that PL16 (and hence V-ATPase) may play an essential role in cell proliferation and viability during early embryogenesis. PL16(+/-) mice were indistinguishable from their wild-type littermates and displayed no discernible abnormalities, although the PL16 mRNA level in PL16(+/-) mice decreased to about one-half of wild-type levels.
Animals↗
Construction of Epstein-Barr virus-based expression vector containing mini-oriP.
Epstein-Barr virus (EBV)-based vectors are extrachromosomal vectors carrying a replicational origin, oriP (about 2200 bp) and a replication initiation factor (EBNA-1) which are sufficient for autonomous replication. Because one disadvantage of these vectors is their large sizes, we examined the effect of partial deletion of oriP on the effectiveness of the EBV-based vectors, using an enhanced green fluorescent protein (EGFP) as a reporter to monitor gene expression. Results indicated that 954 bp-deleted mini-oriP is useful in primate cells since the vector showed high efficiency of stable transfection, a high ratio of EGFP-positive cells, and high recovery of intact plasmid DNA from transfected cells.
Animals↗
Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2.
Human breast cancer cell line Hs578T was stably transfected with cDNA for cyclooxygenase-1 or -2. When the cells overexpressing cyclooxygenase-1 or -2 were stimulated with concanavalin A, the processing of matrix metalloproteinase-2 was observed with the aid of gelatin zymography. This processing was not seen in mock-transfected and original cells which did not express detectable cyclooxygenase activity. Furthermore, Northern blotting showed 8-13 fold induction of membrane-type 1 matrix metalloproteinase which processed matrix metalloproteinase-2 in the cells expressing cyclooxygenases. These findings suggest that both isoforms of cyclooxygenase mediate the processing of matrix metalloproteinase-2 through induction of membrane-type I metalloproteinase in breast cancer cells.
Breast Neoplasms↗
Cationic porphyrins bearing diazolium rings: synthesis and their interaction with calf thymus DNA.
Two novel cationic porphyrins bearing five-membered rings at the meso-positions, meso-tetrakis(1,3-dimethylimidazolium-2-yl)porphyrin (H2TDMImP) and meso-tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrin (H2TDMPzP), have been synthesized. These two compounds interact with calf thymus DNA (CTDNA) in different binding modes from that of mesotetrakis(N-methylpyridinium-4-yl)porphyrin (H2TMPyP). H2TDMImP outside binds to the minor groove of CTDNA while H2TDMPzP intercalates into CTDNA. These two novel cationic porphyrins strongly bind to CTDNA even at high ionic strength and the binding constant of H2TDMPzP to CTDNA is comparable to that of H2TMPyP. The binding of H2TDMImP to CTDNA is enthalpically driven. The favorable free energy changes in binding of H2TDMPzP to CTDNA come from the large negative enthalpy changes accompanied by small positive entropy changes.
Animals↗
Regulation of cyclooxygenase-2 by interferon gamma and transforming growth factor alpha in normal human epidermal keratinocytes and squamous carcinoma cells. Role of mitogen-activated protein kinases.
Treatment of normal human epidermal keratinocytes (NHEK) with interferon-gamma (IFN-gamma) causes a 9-fold increase in the level of cyclooxygenase-2 (COX-2) mRNA expression. Nuclear run-off assays indicate that this induction is at least partly due to increased transcription. Activation of the epidermal growth factor receptor (EGFR) signaling pathway due to the enhanced transforming growth factor alpha (TGFalpha) expression plays an important role in the induction of COX-2 by IFN-gamma. This is supported by the ability of TGFalpha to rapidly induce COX-2 and the inhibition of the IFN-gamma-mediated COX-2 mRNA induction by an EGFR antibody and EGFR-selective kinase inhibitors. Deletion and mutation analysis indicates the importance of the proximal cAMP-response element/ATF site in the transcriptional control of this gene by TGFalpha. The increase in COX-2 mRNA by TGFalpha requires activation of both the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways. Inhibition of p38 MAPK decreases the stability of COX-2 mRNA, while inhibition of MAPK/ERK kinase (MEK) does not. These results suggest that the p38 MAPK signaling pathway controls COX-2 at the level of mRNA stability, while the ERK signaling pathway regulates COX-2 at the level of transcription. In contrast to NHEK, IFN-gamma and TGFalpha are not very effective in inducing TGFalpha or COX-2 expression in several squamous carcinoma cell lines, indicating alterations in both IFN-gamma and TGFalpha response pathways.
Amphiregulin↗
Recovery from exercise-induced desaturation in the paraspinal muscles in idiopathic scoliosis.
STUDY DESIGN: A study using near-infrared light spectroscopy to measure recovery from exercise-induced desaturation in the paraspinal muscles of patients with idiopathic scoliosis. OBJECTIVES: To measure oxygenation of the paraspinal muscles and obtain differences between the convex and concave sides. SUMMARY OF BACKGROUND DATA: Authors of previous studies have reported that some patients experience pain on the convex side of the paraspinal muscles. The muscles on the convex side are more stretched and stressed than those on the concave side. The current authors investigated the degree of stress by measuring oxygenation and blood volume changes. METHODS: Paraspinal muscle spectral properties at L3 were investigated using near-infrared light spectroscopy. Thirty-six patients (8 men and 28 women) underwent this procedure. To assess a level of peripheral adaptations to exercise, the half-time of Oxyhemoglobin/Myoglobin recovery was measured, which indicates the recovery from energy deficit after exercise. RESULTS: The average half-time recovery on the convex side was 3.38 seconds (range, 1.5-5.5 seconds), whereas that on the concave side was 1.51 seconds (range, 0.7-4.0 seconds). The average difference between the convex side and the concave side was 1.87 seconds (range, 0.9-3.5 seconds). CONCLUSIONS: Half-time recovery on the convex side in the patients with idiopathic scoliosis was slower than that in healthy adults (P < 0.05). Half-time recovery on the concave side in such patients was faster than that on the convex side (P < 0.01). The authors consider half-time recovery an indication of back muscle stress.
Adult↗
Imaging assessment of the responses of osteosarcoma patients to preoperative chemotherapy: angiography compared with thallium-201 scintigraphy.
BACKGROUND: Assessment of the responses of osteosarcoma patients to preoperative chemotherapy is of clinical importance. The purpose of this study was to estimate the accuracy of angiography and thallium-201 scintigraphy, compared with histology, in assessing the responses of patients with osteosarcoma to preoperative chemotherapy. METHODS: Nineteen patients with osteosarcoma who were diagnosed between 1992 and 1997 were studied. The findings of angiography and thallium-201 scintigraphy before and after preoperative chemotherapy were compared with the percentage of necrosis of tumor cells and the response grade as determined histologically. Quantitative analysis of the isotopic uptake by thallium-201 scintigraphy before and after chemotherapy, defined as the alteration ratio, was correlated with the percentage of tumor necrosis. RESULTS: Angiography yielded a sensitivity of 88%, a specificity of 73%, and a predictive accuracy of positive test of 70%, whereas thallium-201 scintigraphy achieved 88%, 100%, and 100%, respectively. Both angiographic and scintigraphic assessment showed a significant correlation with response grade as determined histologically (P < 0.05 and P < 0.0003, respectively). The alteration ratio of thallium-201 scintigraphy showed a strong, highly significant correlation with the percentage of tumor necrosis (P < 0.0001). CONCLUSIONS: A change in the tumor uptake of thallium-201 scintigraphy after preoperative chemotherapy can predict the tumor necrosis in osteosarcoma precisely. Thallium scintigraphy is a noninvasive technique and seems to be more useful than angiography in assessing the response of osteosarcoma to preoperative chemotherapy.
Adolescent↗
Suppression of anchorage-independent growth of human cancer cell lines by the drs gene.
We have previously reported that the drs gene, whose mRNA expression is downregulated by retroviral oncogenes such as v-src and v-K-ras, has the ability to suppress transformation by v-src in a rat cell line F2408. We have now isolated a human homolog of this gene (h-drs) and found that the expression of h-drs mRNA is markedly downregulated in a variety of human cancer cell lines including those of the colon, bladder, and ovary. To investigate the function of the drs gene as a tumor suppressor in human cancer cells, we constructed recombinant amphotropic retrovirus containing the drs gene, introduced this virus into human cancer cell lines whose drs expression was downregulated and found that drs has the ability to suppress anchorage-independent growth of these cells without disturbing cell proliferation. Analyses with deletion mutants of the drs gene revealed that both the C-terminal region inside the transmembrane domain and three consensus repeats in the N-terminal region are essential for the suppression of anchorage-independent growth of the cells. We also found that the G1-S progression of the cell cycle and expression of cyclin A mRNA were significantly suppressed in T24 cells expressing the drs gene under non-adhesion culture conditions. In contrast, the expression of cyclin D and E and the phosphorylation of Rb protein were not affected by ectopic expression of the drs gene, suggesting that an Rb-independent downregulation of cyclin A is involved in the suppression of anchorage-independent growth by means of the drs gene.
Amino Acid Sequence↗
Circadian variation of idiopathic ventricular tachycardia originating from right ventricular outflow tract.
We determined circadian variation of isolated ventricular premature complexes (VPCs), 2 to 4 consecutive VPCs, and ventricular tachycardia (5 consecutive VPCs) originating from the right ventricular outflow tract in patients without apparent structural heart diseases. There was apparent circadian variation with 2 prominent peaks for these ventricular arrhythmias, and blockade abolished ventricular tachycardia and attenuated the circadian variation of consecutive VPCs.
Adult↗
Cancer-specific chromosome alterations in the constitutive fragile region FRA3B.
We have sequenced 870 kilobases of the FHIT/FRA3B locus, from FHIT intron 3 to intron 7. The locus is AT rich (61.5%) and Alu poor (6. 2%), and it apparently does not harbor other genes. In a detailed analysis of the 308-kilobase region between FHIT exon 5 and the telomeric end of intron 3, a region known to encompass a human papillomavirus-16 integration site and two clusters of aphidicolin-induced chromosome 3p14.2 breakpoints, we have precisely mapped 10 deletion and translocation endpoints in cancer-derived cell lines relative to positions of specific repetitive elements, regions of high genome flexibility and aphidicolin-induced breakpoints. Conclusions are (i) that aphidicolin-induced breakpoint clusters fall close to high-flexibility sequences, suggesting that these sequences contribute directly to aphidicolin-induced fragility; (ii) that 9 of the 10 FHIT allelic deletions in cancer cell lines resulted in loss of exons, with 7 deletion endpoints near long interspersed nuclear elements or long terminal repeat elements; and (iii) that cancer-specific deletions encompass multiple high-flexibility genomic regions, suggesting that fragile breaks may occur at these regions, whereas repair of the breaks involves homologous pairing of flanking sequences with concomitant deletion of the damaged fragile sequence.
Acid Anhydride Hydrolases↗
The combination of polymorphisms within interferon-gamma receptor 1 and receptor 2 associated with the risk of systemic lupus erythematosus.
Genetic factors seem to play a significant role in susceptibility to systemic lupus erythematosus (SLE). We previously described the amino acid polymorphism (Val14Met) within the IFN-gamma receptor 1 (IFN-gammaRI), and that the frequency of the Metl4 allele in SLE patients was significantly higher than that of the healthy control population [Tanaka et al. (1999) Immunogenetics 49, 266-271]. We also found an amino acid polymorphism (Gln64Arg) within IFN-gamma receptor 2 (IFN-gammaR2). Since the IFN-gamma receptor is a complex consisting of IFN-gammaR1 and IFN-gammaR2, we searched for the particular combination of two kinds of amino acid polymorphisms found within the IFN-gamma receptor which plays a prominent role in susceptibility to SLE. The greatest risk of the development of SLE was detected in the individuals who had the combination of IFNGR1 Met14/Val14 genotype and IFNGR2 Gln64/Gln64 genotype.
Adolescent↗
Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver.
Bisphenol A, an environmental oestrogenic chemical, was found to conjugate highly with glucuronic acid in male rat liver microsomes studied in vitro. In the various isoforms tested (1A1, 1A3, 1A5, 1A6, 1A7 and 2B1), glucuronidation of bisphenol A and of diethylstilboestrol, a synthetic crystalline compound possessing oestrogenic activity and known to be glucuronidated by liver microsomes, was catalysed by an isoform of UDP-glucuronosyltransferase (UGT), namely UGT2B1, which glucuronidates some endogenous androgens. UGT activity towards bisphenol A in liver microsomes and in UGT2B1 expressed in yeast AH22 cells (22.9 and 0.58 nmol/min per mg of microsomal proteins respectively) was higher than that towards diethylstilboestrol (75.0 and 4.66 pmol/min per mg of microsomal proteins respectively). UGT activities towards both bisphenol A and diethylstilboestrol were distributed mainly in the liver but were also observed at substantial levels in the kidney and testis. Northern blot analysis disclosed the presence of UGT2B1 solely in the liver, and about 65% of the male rat liver microsomal UGT activities towards bisphenol A were absorbed by the anti-UGT2B1 antibody. These results indicate that bisphenol A, in male rat liver, is glucuronidated by UGT2B1, an isoform of UGT.
Amino Acid Sequence↗