[Superficial siderosis of the central nervous system].
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Brain Diseases, Metabolic↗
Biomedical subjects
K Yamazaki
Publications and source records attributed to K Yamazaki.
Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance.
E-cadherin, a calcium-dependent cell-cell adhesion molecule, plays a key role in the maintenance of tissue integrity. The function of this molecule is partly mediated by alpha-/beta-/gamma-catenin. Loss or dysfunction of E-cadherin is associated with an invasive phenotype. We analyzed the expression of E-cadherin and beta-catenin in human lung cancer to determine the relationship to clinicopathological factors and prognosis. E-cadherin and beta-catenin expressions were evaluated in 331 lung cancer tissues in a immunohistochemical analysis. Reduced E-cadherin expression was evident in 138 (42%), and reduced beta-catenin expression was noted in 122 (37%). Reduced E-cadherin expression significantly correlated with lymph nodes metastasis (P = 0.0199). E-cadherin expression significantly correlated with increasing histological differentiation (P = 0.0403). Although reduced E-cadherin did not correlate with the prognosis (P = 0.0652), reduced beta-catenin expression did significantly correlate with a poor prognosis (P = 0.0001). When both were reduced, there was a significant unfavorable prognosis compared with either the reduced expression (P = 0.0493) and preserved expression (P = 0.0003). Multivariate analysis showed a significantly lower survival rate for patients with reduced beta-catenin (P < 0.0001). We interpret these data to mean that dysfunction of the cell-cell adhesion molecule has a role in the progression of lung cancer and that analysis of E-cadherin and beta-catenin expression can provide clinically important evidence on which to base treatment.
Adenocarcinoma↗
Pulmonary metastasis with an endobronchial growth pattern: report of a case.
We herein report a case of a pulmonary metastatic tumor with an endobronchial growth pattern. A 75-year-old female was operated on for pulmonary metastasis which originated from a malignant melanoma of the upper gum. Computed tomography (CT) of the chest demonstrated a solitary mass in right S6 region and a preoperative bronchoscopic examination revealed an endobronchial tumor in rtB6b. A retrospective analysis of the chest CT showed a thickened bronchial wall extending to the entrance of rtB6b. Therefore, not a wedge resection but a segmentectomy (rtS6) was performed. When the surgical margin is determined, we should therefore keep in mind the possibility of an endobronchial growth pattern if only a solitary mass is recognized on the CT, even though pulmonary metastatic tumors showing an endobronchial growth pattern is uncommon.
Aged↗
Thymoma arising in a thymic cyst.
We present a case of thymoma arising in the wall of the thymic cyst. A 77-year-old asymptomatic woman demonstrated an approximately 3.5 cm sized cystic mass in the left anterior mediastinum in the CT scan. The tumor was extirpated by a total thymectomy. Histologically, the cyst wall was lined by low cuboidal cells, but a markedly thickened wall was observed at the upper site of the mass, which was found to be thymoma. These findings may suggest that the thymoma originated from the wall of the thymic cyst.
Aged↗
Light-induced reactivation of movement in degenerated sperm of echiuroid, oyster and sea urchin.
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Acyl Coenzyme A↗
[Polyarthralgia as the initial manifestation of isolated ACTH deficiency].
A 57-year-old man, employed as a taxi driver, noticed arthralgia of his fingers beginning in May 1999. He was unable to work due to the arthralgia and the accompanying general malaise and anorexia, and was thus admitted to a local hospital in July 1999. Since a diagnosis of rheumatic disease was suspected due to elevated inflammatory reactions and joint symptoms, he was referred to our hospital in September 1999. Although no joint swelling was observed, severe tenderness was present in both the fingers and wrists. His grasping power had decreased markedly and fever was intermittently observed. All autoantibodies aside from antinuclear antibody were negative. Given that hyponatremia (126 mEq/l) and fasting hypoglycemia were demonstrated, an endocrinological examination, in particular for hypopituitary-adrenal function, was performed. Both plasma and urinary cortisol concentrations were very low, and an associated low concentration of plasma ACTH (6.0 pg/ml) was noted. The ACTH circadian rhythm was absent and there was no response to the administration of corticotropin releasing hormone. All other pituitary hormones were secreted at normal levels and brain MRI revealed a normal appearance of a pituitary gland. Based on these findings, the patient was diagnosed as having isolated ACTH deficiency. Arthralgia and general malaise both improved soon after replacement of glucocorticoid, and CRP levels were normalized. Isolated ACTH deficiency should be considered in the differential diagnosis of patients suffering from polyarthralgia, given that fever and increased inflammatory reactions occasionally develop and that rheumatic symptoms are also present, as in the present case.
Adrenocorticotropic Hormone↗
Giant-cell fibroblastoma: a case report emphasising the presence of hyperplastic subplasmalemmal linear densities in continuity with granular matrices in the extracellular space.
The histological, immunohistochemical and ultrastructural features of a case of giant-cell fibroblastoma from the soft tissues of the chest wall in a 48-year-old female are described with special reference to the cell surface and matrix. Subplasmalemmal linear densities (SLDs) characterised cell surfaces, and exhibited excessive development of the dense external component: foci of identical dense material were present in the matrix. The nature of these dense foci, both the external component of the SLD and those free in the extracellular space, was investigated by light microscope immunostaining for fibronectin, laminin and collagen IV. All three proteins stained vessels. There was weaker but positive staining for tumour cell surfaces and matrix, consistent with the widely dispersed nature of the dense foci. Given their fine structural appearance, these dense foci can be referred to as granular matrices. Given also that the matrix protein immunostaining pattern is consistent with the distribution of these granular matrices as observed by electron microscopy, they may be provisionally interpreted as a kind of basement-membrane-related granular matrix. The presence of these proteins emphasises the point that, while giant-cell fibroblastoma fibroblasts lack a lamina, they nevertheless bear basement-membrane-related proteins organised, however, in a non-laminate fashion. The observations reinforce the need to qualify immunostaining results by ultrastructural investigation in order to understand the organisation of immuno-detected proteins and are discussed in terms of their diagnostic and possible biological significance.
Basement Membrane↗
Basement-membrane-related peri-vascular matrices not organised as a basal lamina: distribution in malignant tumours and benign lesions.
Peri-vascular matrices having a finely textured granular substructure have been identified in 27 human lesions: these were mostly malignancies but included benign tumours and reactive processes. The matrices were defined as stromal components surrounding endothelium and pericytes, and lying between vessels and adjacent lesional cells. They were identified as having a finely textured, uniform and moderately dense substructure, and differed from a conventional basal lamina expected at these sites by the absence of the typical lamina densa/lamina lucida configuration. By light microscope immunohistochemistry, vessels stained positively for laminin and collagen IV, two of the main proteins characterising a conventional basal lamina. The present observations emphasise the following. 1) The proteins laminin and collagen IV can be found in peri-vascular locations which have a finely textured granular substructure, and which have clearly defined ultrastructural differences from a conventional basal lamina. 2) While conventional light microscope immunohistochemistry demonstrates the presence and cellular location of proteins, electron microscopy is helpful for giving information on their physical organisation. 3) Peri-vascular granular matrices have a widespread distribution in malignant tumours but also exist in benign tumours and reactive lesions. This paper briefly discusses the possible functions of these matrices as modulators of cell biological processes.
Basement Membrane↗
Cyclopentenosine, major trifunctional crosslinking amino acid isolated from acid hydrolysate of elastin.
A trifunctional crosslinking amino acid named cyclopentenosine (CP) was isolated from the hydrolysate of bovine nuchal ligament elastin. CP and its derivatives were identified by spectroscopic methods. CP was found to consist of a 2-cyclopenten-1-one structure and its imine-enamine tautomers with enantiomers in H(2)O. A model reaction for the formation of the CP crosslink using model compounds for allysine (propanal) and lysine (n-butylamine) demonstrated that CP is composed of 2-cyclopenten-1-one and alpha, beta, gamma, delta-unsaturated aldehyde derived from three allysine residues. An ion-paired high-performance liquid chromatographic method for the determination of CP was developed. Among various bovine tissues the nuchal ligament had the highest concentration of CP. The age-related changes in the concentration of CP were examined in the aorta from rat (short-lived species) and bovine (long-lived species). The CP content was very low in the newborn rat but increased markedly with growth. After maturity, the CP content remained nearly the same or slightly decreased. In bovine aorta, the CP content scarcely changed from 7 months to 16 years.
Aging↗
Cutting edge: tumor secreted heat shock-fusion protein elicits CD8 cells for rejection.
The endoplasmic reticulum resident heat shock protein gp96 chaperons peptides, including those derived from tumor Ags, on their way to presentation by MHC class I. Replacement of the endoplasmic reticulum retention signal of gp96 with the Fc portion of murine IgG1 generated a secretory form of gp96, gp96-Ig. Tumor cells secreting gp96-Ig exhibited decreased tumorigenicity and increased immunogenicity in vivo and were rejected after initial growth. Rejection required CD8 T cells during the priming and effector phase. CD4 T cells were not required for rejection in either phase. Carrageenan, a compound known to inactivate macrophages in vivo, did not diminish CD8-mediated tumor rejection. Therefore, immunization with tumors secreting gp96-Ig generates efficient tumor-rejecting CD8 CTL without requirement for CD4 or macrophage help. In contrast, immunization with purified, tumor-derived gp96 or with irradiated tumor cells requires both.
Animals↗
Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor.
Characterization of mammalian homologues of Drosophila transient receptor potential protein (TRP) is an important clue to understand molecular mechanisms underlying Ca(2+) influx activated in response to stimulation of G(q) protein-coupled receptors in vertebrate cells. Here we have isolated cDNA encoding a novel seventh mammalian TRP homologue, TRP7, from mouse brain. TRP7 showed abundant RNA expression in the heart, lung, and eye and moderate expression in the brain, spleen, and testis. TRP7 recombinantly expressed in human embryonic kidney cells exhibited distinctive functional features, compared with other TRP homologues. Basal influx activity accompanied by reduction in Ca(2+) release from internal stores was characteristic of TRP7-expressing cells but was by far less significant in cells expressing TRP3, which is structurally the closest to TRP7 in the TRP family. TRP7 induced Ca(2+) influx in response to ATP receptor stimulation at ATP concentrations lower than those necessary for activation of TRP3 and for Ca(2+) release from the intracellular store, which suggests that the TRP7 channel is activated independently of Ca(2+) release. In fact, TRP7 expression did not affect capacitative Ca(2+) entry induced by thapsigargin, whereas TRP7 greatly potentiated Mn(2+) influx induced by diacylglycerols without involvement of protein kinase C. Nystatin-perforated and conventional whole-cell patch clamp recordings from TRP7-expressing cells demonstrated the constitutively activated and ATP-enhanced inward cation currents, both of which were initially blocked and then subsequently facilitated by extracellular Ca(2+) at a physiological concentration. Impairment of TRP7 currents by internal perfusion of the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid revealed an essential role of intracellular Ca(2+) in activation of TRP7, and their potent activation by the diacylglycerol analogue suggests that the TRP7 channel is a new member of diacylglycerol-activated cation channels. Relative permeabilities indicate that TRP7 is slightly selective to divalent cations. Thus, our findings reveal an interesting correspondence of TRP7 to the background and receptor stimulation-induced cation currents in various native systems.
Amino Acid Sequence↗
Small cell lung carcinomas express shared and private tumor antigens presented by HLA-A1 or HLA-A2.
Tumor-derived peptides presented by MHC class I molecules are targets for tumor rejection by CD8+ CTLs. MHC-restricted CD8+ CTLs are required also for the identification and characterization of tumor antigens that will be useful for immune therapy. For many human solid tumors, however, tumor antigens remain undefined because of the difficulty of generating MHC-restricted, tumor-specific CTLs required for their analysis. CD8+ CTL responses are modulated by CD4+ helper T cells and by antigen-presenting cells. In this study, highly purified CD8+ T cells were mixed with tumor cells in primary cultures in the absence of any other cells to reduce the complexity of CTL generation. Tumor cells were transfected with HLA-A1 or HLA-A2 and used to stimulate partly matched HLA-A1- or HLA-A2-positive CD8+ T cells. Partial MHC class I matching of tumor and CD8+ T cells and omission of other cells in primary culture was highly effective in generating MHC class I-restricted CTL to poorly immunogenic small cell lung carcinomas (SCLCs). Cytotoxicity was further enhanced by cotransfection of tumor cells with B7.1 (CD80). ICAM-1 (CD54) was not as effective as costimulation. SCLC cells presented tumor-specific peptides with HLA-A1 and HLA-A2 and were lysed by A1- or A2-restricted CD8+ CTLs. A1- and A2-restricted CD8+ CTLs detected shared tumor antigens on unrelated SCLC tumor lines in addition to private antigens. The use of direct antigen presentation by MHC class I-transfected tumors to MHC class I-matched CD8+ T cells is an effective way to generate MHC class I-restricted CTLs toward poorly immunogenic tumors in vitro, permitting the molecular identification of their tumor antigens.
Animals↗
Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel.
We synthesized a novel anticancer agent MS-247 (2-[[N-[1-methyl-2-[5-[N-[4-[N,N-bis(2-chloroethyl) amino] phenyl]] carbamoyl]-1H-benzimidazol-2-yl] pyrrol-4-yl] carbamoyl] ethyldimethylsulfonium di-p-toluenesulfonate) that has a netropsin-like moiety and an alkylating residue in the structure. We evaluated antitumor activity of MS-247 using a human cancer cell line panel coupled with a drug sensitivity database and subsequently using human cancer xenografts. The average MS-247 concentration required for 50% growth inhibition against a panel of 39 cell lines was 0.71 microM. The COMPARE analysis revealed that the differential growth inhibition pattern of MS-247 significantly correlated with those of camptothecin analogues and anthracyclins, indicating that MS-247 and the two drug groups might have similar modes of action. MS-247 exhibited remarkable antitumor activity against various xenografts. A single i.v. injection of MS-247 significantly inhibited the growth of all 17 xenografts tested, which included lung, colon, stomach, breast, and ovarian cancers. In many cases, MS-247 was more efficacious than cisplatin, Adriamycin, 5-fluorouracil, cyclophosphamide, VP-16, and vincristine and was almost comparable with paclitaxel and CPT-11; these are the most clinically promising drugs at present. MS-247 was noticeably more effective than paclitaxel (in HCT-15) and CPT-11 (in A549, HBC-4, and SK-OV-3). The toxicity of MS-247, indicated by body weight loss, was reversible within 10 days after administration. The MS-247 mode of action showed DNA binding activity at the site where Hoechst 33342 bound, inhibited topoisomerases I and II (as expected by the COMPARE analysis) blocked the cell cycle at the G2-M phase, and induced apoptosis. These results indicate that MS-247 is a promising new anticancer drug candidate to be developed further toward clinical trials.
Animals↗
Cloning and chromosomal mapping of mouse ADAM11, ADAM22 and ADAM23.
A cellular disintegrin, also called MDC and ADAM is a recently discovered gene family that encodes protein with disintegrin-like and metalloprotease-like domains. We have reported the identification of human cDNAs encoding novel ADAM family proteins that we named MDC2 and MDC3 because of their structural similarity to the MDC (Sagane, K. et al., 1998. Biochem. J. 334, 93-98). The Human Gene Nomenclature Committee assigned the gene symbols ADAM11 for the MDC, ADAM22 for the MDC2 and ADAM23 for the MDC3. Here we report the isolation of three novel murine cDNAs encoding the proteins closely related to the human ADAM11, ADAM22 and ADAM23. Their chromosomal locations in the mouse were identified by interspecies backcross mapping. The loci of these murine ADAM genes were in good accordance with the location of each human ortholog, ADAM11, ADAM22 and ADAM23. These findings suggest that three murine cDNAs that we have isolated are the murine ADAM11, ADAM22 and ADAM23 cDNAs. Northern blot analysis shows that all of these three murine ADAMs were highly expressed in the mouse brain. The structures of these ADAM proteins strongly suggest that they could function as integrin receptors. The implications of the cellular disintegrins in neural development are discussed.
ADAM Proteins↗
Differential responses to parathyroid hormone-related protein (PTHrP) deficiency in the various craniofacial cartilages.
PTHrP null mutant mice exhibit skeletal abnormalities both in the craniofacial region and limbs. In the growth plate cartilage of the null mutant, a diminished number of proliferating chondrocytes and accelerated chondrocytic differentiation are observed. In order to examine the effect of PTHrP deficiency on the craniofacial morphology and highlight the differential feature of the composing cartilages, we examined the various cartilages in the craniofacial region of neonatal PTHrP deficient mice. The major part of the cartilaginous anterior cranial base appeared to be normal in the homozygous PTHrP deficient mice. However, acceleration of chondrocytic differentiation and endochondral bone formation was observed in the posterior part of the anterior cranial base and in the cranial base synchondroses. Ectopic bone formation was observed in the soft tissue-running mid-portion of the Meckel's cartilage, where the cartilage degenerates and converts to ligament in the course of normal development. The zonal structure of the mandibular condylar cartilage was scarcely affected, but the whole condyle was reduced in size. These results suggest the effect of PTHrP deficiency varies widely between the craniofacial cartilages, according to the differential features of each cartilage.
Animals↗
Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease.
To investigate the significance of nitric oxide (NO)-mediated neuron death in aging and Alzheimer's disease (AD), the 3-nitrotyrosine concentration in the cerebrospinal fluid (CSF) was investigated in neurologically normal controls and patients with AD. The 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio significantly increased with advancing age, whereas the tyrosine concentration was unaltered. In patients with AD, the 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio increased significantly (>six-fold) compared with controls of similar age, and increased significantly with decreasing cognitive functions, whereas the tyrosine concentration did not change. These findings suggest that an activation of tyrosine nitration, increase in nitrated tyrosine-containing proteins, and/or its degradation may be involved in brain aging and play an important role in the pathogenesis of AD.
Aged↗
cDNA cloning of mouse tumor necrosis factor-alpha converting enzyme (TACE) and partial analysis of its promoter.
Tumor necrosis factor-alpha (TNFalpha) is a cytokine that induces pleiotropic inflammatory reactions. Soluble TNFalpha is released from its membrane-bound precursor by TNFalpha converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17). We have recently cloned the mouse TACE complete cDNA and the 5' flanking promoter region of the gene. Two versions of the mouse TACE cDNA having a coding region of 2541bp were obtained: one was about 4.1kb and the other was 4.4kb in length, in which only the length of the 3' UTR was different. Rapid amplification of 5' cDNA ends suggested that there were multiple transcriptional start sites. From the coding sequence, 827 amino acids were deduced which were 91.9 % identical to those of human TACE. Northern blot analysis indicated that the major transcript was approx. 4.4kb product in the mouse. The mouse TACE mRNA was ubiquitously expressed, and was particularly high in the lung. The proximal promoter contained multiple AP2 and Sp1 transcription factor binding sites and included a GC box and a CCAAT box, but lacked a consensus TATA box. Reporter gene analysis using RAW264.7 cells showed that the fragment at nt -290 to -1 from the translation start site has a strong promoter activity, and appeared to be essential for transcription of the mouse TACE mRNA. Finally, we found that the mouse TACE promoter at nt -2304 to -1 also worked in NIH3T3, 3T3L1 and C6 cell lines.
3' Untranslated Regions↗
Mechanism of ubiquitous expression of mouse uncoupling protein 2 mRNA: control by cis-acting DNA element in 5'-flanking region.
Uncoupling protein (UCP) 2 is a member of the uncoupling-protein family, and it appears to function as an uncoupler of oxidative phosphorylation. To identify cis-acting regulatory elements controlling this gene's expression, we cloned an approx. 6.2-kb region upstream from the translation-initiation site of the mouse UCP2 gene and analysed its transcription activity using chimaeric mouse UCP2 promoter-placental-alkaline-phosphatase (PLAP) reporter-gene constructs. Sequence analysis showed that the 5'-flanking region of the mouse UCP2 gene was not similar to those of mouse UCP1 or UCP3. For the mouse UCP2, the region near the transcription-initiation site lacked the typical TATA box, but was GC-rich, resulting in presence of several potential specificity protein 1 (Sp-1), activator protein (AP)-1 and AP-2 binding sites. The putative regulatory motifs for muscle-regulatory protein (MyoD), brown-fat regulatory element, CCAAT box, cAMP-response element and Y box were also found in the mouse UCP2 promoter region by computer-assisted analysis. From the results of Northern-blot analysis and transient expression assay, we found that the mouse UCP2 gene responded to the cAMP-dependent protein kinase alpha-catalytic subunit signal activation at the transcription level. Additionally, deletion analysis of the UCP2 promoter-PLAP constructs indicated that the minimal region exhibiting the promoter activity was located between nt -33 and +100, and that a strong enhancer was present within 601 bp of the 5'-promoter region. In particular, the region from nt -233 to -34 significantly induced PLAP activity in the cell lines derived from various tissues and in the primary culture cells of rat brown adipose tissue, suggesting that this region is most important for the ubiquitous expression of mouse UCP2 mRNA. Furthermore, it was shown that two silencer elements were involved in the mouse UCP2 gene; one was located between nt -2746 and -602, and the other was identified in intron 1. These regions deprived the enhancer of the ability to induce PLAP activity. This study shows a fundamental role for positive and negative cis-acting DNA elements in regulating the basal and cAMP-induced transcription activity of the mouse UCP2 gene.
3T3 Cells↗