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Biomedical subjects

M Shoji

Publications and source records attributed to M Shoji.

At least 127 records · Page 7Linked to original sources
PubMed1998

Active cyclin A-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas.

Expression of cyclins A and E and cyclin-dependent kinase 2 (CDK2) was examined immunohistochemically in 190 cases of human lung carcinoma. Cyclin A and CDK2 were expressed in the majority of squamous cell carcinomas, small cell carcinomas, and large cell carcinomas, but in significantly fewer cases of adenocarcinomas. Cyclin E was expressed in a minority of all subtypes. In particular, well differentiated cells in squamous cell carcinoma stained positively for cyclin E; in contrast, cyclin A was expressed in the nonkeratinized proliferating areas of the tumor nests. Immunoblotting revealed that all these proteins were expressed at higher levels in tumor tissues than in adjacent normal tissues. Immunoprecipitation also revealed higher levels of cyclin A and cyclin E associated with CDK2 in tumor tissues. Furthermore, tumor tissues which exhibited higher cyclin A and CDK2 expression also had higher CDK2 kinase activity. However, cyclin E-associated kinase activity was barely detectable even in tumor samples exhibiting higher cyclin E expression. Consistent with these data, elevated expression of cyclin A correlated to shorter survival periods in contrast to expression of cyclin E, which correlated to longer survival periods. These results suggest that in human lung carcinomas, elevated expression of active cyclin A-CDK2 complexes with associated higher CDK2 kinase activity is critical for promoting cell cycle progression and unrestrained proliferation of tumor cells and can be a predictive marker for patients' prognosis. On the other hand, immunohistochemical detection of cyclin E-CDK2 reflects accumulation of inactive forms of protein complexes, implying differentiation or senescence of the tumor and the better prognosis.

Adenocarcinoma↗
PubMed1998

Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is defined as a poorly differentiated and high-grade neuroendocrine tumor that is morphologically and biologically between atypical carcinoid and small cell lung carcinoma (SCLC). During a survey concerning bcl-2 protein expression in the subtypes of lung cancer, we noticed that two previously diagnosed non-SCLCs met the criteria for LCNEC. Because LCNEC is a newly recognized clinicopathologic entity and because all reported cases have been retrieved from the so-called "neuroendocrine tumor file," we suspected that LCNEC had been underdiagnosed. In the present study, we histologically reviewed 766 surgically resected lung cancers and were able to diagnose 22 (2.87%) LCNECs with the neuroendocrine features subsequently confirmed by immunostaining for multiple neuroendocrine markers. Each case stained positively for at least three general neuroendocrine markers, and 12 (54.5%) also were positive for neuroendocrine hormones. Histologically, most LCNECs showed a marked decrease in or a loss of organoid architecture and could be mistaken for poorly differentiated adenocarcinoma or squamous cell carcinoma. Because our LCNECs are the first to be identified by retrospective review of routinely diagnosed lung cancers, and 18 had been classified as non-SCLC, they may represent cases relatively difficult to diagnose. The present study shows that the most difficult diagnostic factor of LCNEC is the recognition of its light microscopic neuroendocrine features, and LCNEC must be distinguished not only from atypical carcinoid or SCLC, but also from common non-SCLC. Histologically, when an organoid architecture is subtle or absent, the rosettelike structure becomes the best marker for the recognition of neuroendocrine differentiation. Clinically, the prognosis for our LCNECs was significantly worse than that for stage-comparable non-SCLCs (p = 0.046).

Aged↗
PubMed1998

Effects of endothelin-induced nitric oxide on venous circulation and renal water-electrolyte handling.

To assess the interaction of endothelin (ET) with nitric oxide (NO) and the effects on venous circulation and handling of renal water and electrolytes, ET (1.0 ng/kg/min) or saline was administered with or without three doses (0.27, 2.7 and 27 ng/kg/min for 40 min) of N omega-nitro-L-arginine methyl ester (L-NAME), and NO synthase inhibitor, in anesthetized dogs. ET increased total peripheral resistance (TPR), pulmonary capillary wedge pressure (PCWP), urine flow (UF), and urinary K excretion (UKV), and decreased cardiac output (CO), urinary osmolality (Uosm), renal plasma flow (RPF), and glomerular filtration rate (GFR). L-NAME increased blood pressure (BP), TPR, PCWP, right atrial pressure (RAP), and mean circulatory filling pressure (MCFP), and decreased CO, RPF, and GFR, ET plus L-NAME markedly increased TPR, resistance to venous return, and plasma atrial natriuretic peptide (ANP), but not BP and MCFP, and curtailed the ET-induced responses in UF, UKV, and Uosm. Plasma aldosterone (ALD) was decreased in all groups, but plasma vasopressin (AVP) and renin activity (PRA) were not altered in any group. These results indicate that ET-induced NO formation might mitigate increases in venous as well as arterial vascular resistance and changes in renal handling of water and electrolytes, and might also play an inhibitory role in ANP release but not in PRA or AVP and ALD release.

Animals↗
PubMed1998

A morphological and morphometrical study of the retina in aging SAM mice.

We investigated whether neuronal cell loss occurred as a part of normal aging of the retina in the Senescence-Accelerated Mouse, strains SAMP1 and SAMR1, and in the BALB/c mouse. All three strains showed age-related atrophy of the retina after histologically normal development. Morphometrical study revealed the following facts. The rate of loss of photoreceptor cells in the peripheral retina was greater than in the central retina in all three strains. In the central retina, the rate of loss of photoreceptor cells was greater in the SAMP1 and SAMR1 mice than in the BALB/c mice. In the peripheral retinal, the SAMR1 and SAMP1 strains had fewer cells than the BALB/c strain at all ages, but the rate of loss of these cells did not differ among the three strains. The rate of loss of ganglion cells did not differ between the peripheral and central retinas in the three strains. The SAMR1 and SAMP1 strains had fewer ganglion cells in the peripheral retina than the BALB/c strain at all ages. Because the rate of age-related loss of these cells in SAMP1 mice was not accelerated, and they were short-lived, SAMP1 mice did not show marked age-related loss. On the contrary, the SAMR1 mice showed a marked loss of photoreceptor cells and ganglion cells late in life because of their longer life span, and we propose that this strain is a suitable animal model for the study of mechanisms of age-related loss of neuronal cells in the retina.

Aging↗
PubMed1998

Synthesis of pyridinium dinitrobenzyl sulfates and potassium (dinitrobenzyl beta-D-glucopyranosid)uronates.

Sulfates and glucuronides of 2,4-dinitrobenzyl alcohol 1a and 2,6-dinitrobenzyl alcohol 1b, which are major or putative metabolites of 2,4-dinitrotoluene (2,4-DNT) and 2,6-dinitrotoluene (2,6-DNT), were synthesized from 1a and 1b by reaction with pyridinium sulfonate and methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl)uronate bromide 3, respectively, as their pyridinium salts (2a, 2b) and potassium salts (6a, 6b). These conjugates are important for the study of the carcinogenicity of 2,4-DNT and 2,6-DNT.

Benzyl Alcohols↗
PubMed1998

Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

Blood Coagulation↗
PubMed1998

[Endothelial nitric oxide synthase gene polymorphism and hypertension].

Nitric oxide (NO) is produced by endothelial cells and serves as a potent vasodilator. Several lines of evidence have shown that NO plays an important role in the regulation of blood pressure and regional blood flow. Endothelial NO synthase (eNOS) gene polymorphisms exhibit a positive association in myocardial infarction and smoking-dependent risk of coronary artery disease. However, the relationship between eNOS gene polymorphisms and hypertension is controversial. To examine the possible involvement of the eNOS gene in the genetic basis for hypertension, we identified genotypes for 2 eNOS gene polymorphisms in 166 hypertensive and 174 normotensive populations in Aomori prefecture, in northern Japan. The specific genotypes for Glu298Asp missense variant and variable numbers of tandem repeats in intron 4 (eNOS 4b/4a) were isolated using allele specific gene amplification and restriction fragment length polymorphism. The 298Asp variant was significantly correlated to hypertension in these groups (odds ratio, 1.8; 95% confidence interval, 1.1-3.2). The allelic frequencies of 298Asp for Glu298 in hypertensive patients were significantly higher than those in normotensive subjects (0.136 vs 0.083, p < 0.05). However, disequilibrium of eNOS4b/4a was absent between these 2 groups. These results suggest that Glu298Asp is a genetic susceptibility factor for hypertension.

Aged↗
PubMed1997

Analysis of the McLeod syndrome gene in three patients with neuroacanthocytosis.

McLeod syndrome is a rare X-linked disorder involving neurological defects and acanthocytosis. We examined the XK gene in three patients with neuroacanthocytosis, one of whom had cardiomyopathy, and his symptoms were very similar to those of McLeod syndrome. We found two new transversions (C to G at codon 204 and G to C at codon 205) in exon 3 in all those cases. However, the transversion at codon 205 was found in all 70 Japanese normal subjects and four non-Japanese (two Caucasian males, one Chinese female and one Micronesian female) and that at codon 204 was also detected in all 14 normal Japanese males and the four non-Japanese. These findings suggest that they are not the cause of McLeod syndrome, but normal polymorphisms which have not been reported. Moreover, there is a possibility that patients with neuroacanthocytosis similar to McLeod syndrome exist without the XK gene abnormalities.

Acanthocytes↗
PubMed1997

Lysosomal generation of amyloid beta protein species in transgenic mice.

Soluble amyloid beta protein (A beta)1-40 and highly amyloidogenic A beta 1-42/43 were immunocytochemically labeled in lysosomes of acinar cells and macrophages in the pancreas of transgenic mice systemically expressing a C-terminal fragment of the A beta precursor. A beta 1-42/43 and long A beta species extending their C-termini were detected in the detergent-insoluble fraction. Immunoreactivity of cathepsin D was markedly increased in lysosomes filled with A beta fibrils. These findings indicated that A beta 1-40, A beta 1-42, A beta 1-43 and longer A beta species were generated in the lysosomes of the transgenic pancreas, and suggested that the activation of cathepsin D, a candidate gamma-secretase, leads to acceleration of A beta amyloid formation.

Amyloid beta-Protein Precursor↗
PubMed1997

Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemical, immunohistochemical and ultrastructural study.

To better understand the characteristics of amyloid deposition in the choroid plexus, we examined autopsied brain by routine histology, immunohistochemistry, and electron microscopy in three group of patients: primary systemic amyloidosis (n = 7), cerebral amyloid angiopathy (CAA, n = 6), and controls (n = 3). Three of the CAA patients had Alzheimer's disease. Congophilic, birefringent amyloid deposits of the choroid plexus were seen in six of the seven cases of systemic light chain amyloidosis. Immunohistochemistry revealed that the deposited amyloids had reactivity for immunoglobulin light chain and amyloid P component. Accumulation of macrophages labeled with monoclonal antibodies against CD 68 and major histocompatibility complex class II antigens were observed around the massive amyloid deposits. The presence of approximately 10 nm amyloid fibrils along the epithelial basement membrane as well as in the vascular walls was ascertained by electron microscopy. In CAA, Congo red-positive amyloid deposits were consistently present in meningeal blood vessels and were often found in senile plaques of the cerebral parenchyma; congophilic amyloid deposits were absent in the choroid plexus. Choroid plexus epithelial cells exhibited immunostaining for beta amyloid precursor protein (APP) with N-terminal- and C-terminal-specific antibodies; in particular, consistent staining was obtained for the latter antibody. Immunoreactivity for amyloid beta protein (A beta) with monoclonal antibodies (6E10, 4G8) was often found in choroid plexus epithelial cells. These findings suggest that amyloid deposition of the choroid plexus depends on the major component protein in amyloidosis, and that the choroid plexus may produce APP and A beta protein although A beta amyloidosis is not evident in the choroid plexus.

Aged↗
PubMed1997

Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.

To investigate the pathomechanism of amyloid beta protein (A beta) deposition in brains with Alzheimer's disease (AD), cerebrospinal fluid (CSF) levels of A beta species (CSF-A beta) with different carboxy termini, i.e. A betaX-40 and A betaX-42(43) as well as A beta1-40 and A beta1-42(43), were measured in patients with AD and age-matched controls without dementia (CTR) using sandwich enzyme-linked immunosorbent assays (ELISAs). The present study revealed that both CSF-A betaX-42(43) and A beta1-42(43) levels were significantly lower in the AD patients (P<0.005) than in the CTR group, whereas neither CSF-A betaX-40 nor CSF-A beta1-40 levels showed any differences between the two groups. In addition, although there was no difference between the ratios of A betaX-40 to A beta1-40 in the AD and CTR groups, the ratios of A betaX-42(43) to A beta1-42(43) were increased in the AD group compared with those in the CTR group (P<0.05). Therefore, it can be assumed that the ratios of amino terminal truncations and/or modifications of CSF-A beta42(43) with carboxy termini ending at residue 42(43) were more increased in the AD group than in the CTR group. Increased adsorption of A beta42(43) to A beta deposition in AD brains, decreased secretion of A beta42(43) to CSF and/or increased clearance of A beta42(43) from CSF might explain the diminished levels of A beta42(43) in the CSF of AD patients. In addition, CSF-A beta42(43) could reflect increased amino terminal truncations and/or modifications of A beta42(43) in AD brains.

Aged↗
PubMed1997

Cell cycle control with minimal participation of Cdk2 in a murine fibrosarcoma clone cultured in protein-free medium.

The differences in the protein expression of cyclins, cyclin-dependent kinases (cdks), and their inhibitors and cdk kinase activities were examined in serum dependent (SD) and independent (PF) clones of the murine fibrosarcoma cell line, Gc-4. The expression of cyclin A in SD was minimal in contrast to PF. Furthermore, cdk2 kinase activity in PF was remarkably lower than that in SD, yet the G1/S transition in PF appeared normal. PF was also resistant against the selective inhibitor of cdk2, butyrolactone I. These findings suggest that tumor cell proliferation and tumor progression can be promoted by the activation of a molecule(s) downstream of cdk2.

4-Butyrolactone↗
PubMed1997

Reduction of plasma glutamyl aminopeptidase activity in sporadic Alzheimer's disease.

Previously, we hypothesized that aminopeptidase-catalyzed proteolysis may limit the rate of beta-amyloid catabolism in brain and that reduction of a certain aminopeptidase activity may lead to deposition of peptidic metabolites represented by beta-amyloid and thus to Alzheimer's disease (AD). To explore this possibility in clinical situations and to seek a possible biochemical marker for the disease, we quantitated four classes of aminopeptidase activities in cerebrospinal fluids and heparinized plasma from sporadic AD patients and agematched controls collected in two independent medical institutions. We found that only plasma glutamyl aminopeptidase activity was significantly and consistently lower in AD patients. Although the mechanism leading to such a biochemical change in plasma remains to be elucidated, the results provide support for the aminopeptidase hypothesis and indicate that the enzyme activity may potentially be used as a diagnostic/ predictive marker for AD.

Aged↗
PubMed1997

Genotype analysis of prepro-vasopressin signal peptide in vasopressin-producing and -non-producing lung tumors.

A polymorphism in the nucleic acid sequence encoding the signal peptide of the human prepro-vasopressin (AVP) has been reported in an AVP producing small cell lung carcinoma (SCLC) cell line. The difference predicts expression in tumor cells of a variant signal peptide with Pro for Leu 11. To clarify whether this difference is required for AVP secretion from SCLC cells and/or reflects increased mutagenesis in malignant tumors, the exon encoding the signal peptide of prepro-AVP in two AVP producing SCLC and 9 non-producing lung tumors was amplified using polymerase chain reaction. The variant sequence was neither found by direct sequencing nor by restriction enzyme analysis. These results suggest that similar to the hypothalamus the normal signal peptide is functional in tumor cells and that the variant signal peptide is not a prerequisite for AVP secretion from SCLC cells.

Animals↗
PubMed1997

The Wilms tumor protein is persistently associated with the nuclear matrix throughout the cell cycle.

In order to investigate the subnuclear interactions of the WT1 gene product, nuclear fractionation analyses were performed with human osteosarcoma HOS and myelogenous leukemia K562 cells. The WT1 protein was tightly associated with the nucleus and was resistant to high-salt or detergent extraction and DNase I digestion. Both the expression level and stability of WT1 and its resistance to high salt and DNase I treatments remained constant during the cell cycle. In addition, human WT1 ectopically expressed in mouse NIH3T3 cells was also resistant to these treatments. These results suggest that WT1 functions in tight association with the nuclear matrix.

3T3 Cells↗