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1.
Eur J Clin Invest ; 39(5): 359-67, 2009 May.
Article in English | MEDLINE | ID: mdl-19371267

ABSTRACT

BACKGROUND: Endothelial progenitor cells (EPCs) play an important role in the maintenance of vascular integrity. Lipid lowering therapy (LLT) with statins may contribute to biologically relevant activities including the proliferation of endothelial cells. The physiological role of microRNA (miR)-221/222, a newly discovered class of small RNA, is closely linked to the proliferation of endothelial cells. We therefore investigated whether LLT with statins might affect miR-221/222 expression in EPCs obtained from patients with coronary artery disease (CAD). MATERIALS AND METHODS: This study included 44 patients with stable CAD and 22 subjects without CAD (non-CAD). Patients with CAD were randomized to 12 months of LLT with atorvastatin (10 mg day(-1)) or pravastatin (10 mg day(-1)). EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Levels of miR-221/222 in EPCs were measured by real-time RT-PCR. RESULTS: Levels of miR-221/222 were significantly higher in the CAD group than in the non-CAD group (P < 0.01). Levels of miR-221/222 were weakly negatively correlated with EPC number in the CAD group. After 12 months of therapy, changes in lipid profiles were greater in the atorvastatin group than in the pravastatin group. LLT with atorvastatin markedly increased EPC numbers and decreased miR-221/222 levels (all P < 0.05), whereas LLT with pravastatin did not change EPC numbers or miR-221/222 levels. CONCLUSIONS: This study demonstrates that LLT with atorvastatin increases EPC numbers and decreases miR-221/222 levels in patients with CAD, possibly contributing to the beneficial effects of LLT with atorvastatin in this disorder.


Subject(s)
Anticholesteremic Agents/therapeutic use , Coronary Artery Disease/drug therapy , Endothelial Cells/drug effects , MicroRNAs/drug effects , Stem Cells/drug effects , Aged , Atorvastatin , Endothelial Cells/metabolism , Female , Heptanoic Acids/therapeutic use , Humans , Male , MicroRNAs/metabolism , Middle Aged , Pravastatin/therapeutic use , Prospective Studies , Pyrroles/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Single-Blind Method , Statistics as Topic , Stem Cells/metabolism
2.
J Clin Pathol ; 59(3): 328-30, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16505288

ABSTRACT

OBJECTIVE: Aberrant expression of maspin protein related to DNA hypomethylation in the promoter region is frequently observed in gallbladder carcinomas, whereas the non-tumorous gallbladder epithelium is maspin negative. We investigated maspin expression in non-tumorous gallbladder epithelium in patients with cholelithiasis. METHODS: An immunohistochemical study of maspin expression was performed in 69 patients with cholelithiasis and 30 patients with gastric cancer without cholelithiasis. RESULTS: Immunoreactivity for maspin was observed in focal and patchy regions of the gallbladder epithelium. Positive immunoreactivity for maspin was significantly associated with the presence of intestinal metaplasia in patients with cholelithiasis (p<0.05). CONCLUSION: The high incidence of aberrant maspin expression in both intestinal metaplasia and carcinoma of the gallbladder supports the assumption that intestinal metaplasia of the gallbladder may predispose to gallbladder carcinoma.


Subject(s)
Biomarkers, Tumor/analysis , Cholelithiasis/chemistry , Gallbladder/chemistry , Serpins/analysis , Adult , Case-Control Studies , Cholelithiasis/pathology , Disease Progression , Endothelium/chemistry , Endothelium/pathology , Female , Gallbladder/pathology , Genes, Tumor Suppressor , Humans , Immunohistochemistry/methods , Intestinal Mucosa/pathology , Male , Metaplasia , Middle Aged , Stomach Neoplasms/chemistry
3.
Dis Esophagus ; 19(1): 48-52, 2006.
Article in English | MEDLINE | ID: mdl-16364045

ABSTRACT

Most esophageal carcinosarcomas are diagnosed as so-called carcinosarcoma, in which individual elements may be derived from a single common ancestor cell, and there have been a few reports describing true carcinosarcoma originating from two individual stem cells. We describe a case of esophageal carcinosarcoma exhibiting neoplastic osteoid formation. Immunoreactivity for vimentin and p53 was limited to only the sarcomatous component and was absent in the carcinomatous component. Furthermore, a point mutation in exon 7 of the p53 gene was observed only in the sarcomatous component. Both sarcoma and carcinoma cells distinctively metastasized to different lymph nodes. These observations led us to diagnose the esophageal tumor as a true carcinosarcoma.


Subject(s)
Carcinosarcoma/genetics , Carcinosarcoma/pathology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Genes, p53 , Point Mutation , Carcinosarcoma/surgery , DNA, Neoplasm/genetics , Esophageal Neoplasms/surgery , Fatal Outcome , Genes, p53/genetics , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/radiotherapy
4.
Br J Cancer ; 92(6): 1130-6, 2005 Mar 28.
Article in English | MEDLINE | ID: mdl-15770218

ABSTRACT

To seek for a candidate gene that would regulate tumour progression and metastasis in gastric cancer, we investigated gene expression profiles by using DNA microarray. Tumour tissue and adjacent normal tissue were obtained from 21 patients with gastric cancer and then examined for their gene expression profiles by the Gene Chip Human U95Av2 array, which includes 12 000 human genes and EST sequences. A total of 25 genes were upregulated and two genes were downregulated by at least four-fold in the tumour tissue. In a further analysis according to lymph node metastasis, the expressed levels of maspin, as well as carcinoembryonic antigen and nonspecific crossreacting antigen were significantly higher in tumours with lymph node metastasis than in those without it. Maspin expression in 85 gastric cancer patients was further investigated by using immunohistochemistry. Maspin expression was not observed in normal gastric epithelia without intestinal metaplasia. In contrast, maspin was expressed in 74 of 85 tumour tissues. There was a significant correlation between the incidence of maspin-positive tumour staining and lymph node metastasis. These results suggest that maspin has a potential role for tumour metastasis in gastric cancer.


Subject(s)
Gene Expression Profiling , Serpins/genetics , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , DNA Methylation , Female , Genes, Tumor Suppressor , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic , Serpins/analysis , Stomach Neoplasms/pathology
5.
Gut ; 53(7): 1001-9, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15194652

ABSTRACT

BACKGROUND AND AIM: Significant telomere shortening of hepatocytes is associated with replicative senescence and a non-dividing state in chronic liver disease, resulting in end stage liver failure and/or development of hepatocellular carcinoma. To prevent critical telomere shortening in hepatocytes, we have focused on oestrogen dependent transactivation of the human telomerase reverse transcriptase (hTERT) gene as a form of telomerase therapy in chronic liver disease. METHODS: We examined expression of hTERT mRNA and its protein, and telomerase activity (TA) in three human normal hepatic cell lines (Hc-cells, h-Nheps, and WRL-68) before and after treatment with 17beta-oestradiol. The effects of exogenous oestradiol administration were examined in a carbon tetrachloride (CCl(4)) induced model of liver fibrosis in rats. RESULTS: Expression of hTERT mRNA and its protein was upregulated by oestradiol treatment. Telomere length decreased in Hc-cells and h-Nheps with accumulated passages whereas with long term oestradiol exposure it was greater than without oestradiol. The incidence of beta-galactosidase positive cells, indicating a state of senescence, decreased significantly in oestradiol treated cells in comparison with non-treated cells (p<0.05). TA in both male and female rats with CCl(4) induced liver fibrosis was significantly higher with oestradiol administration than without (p<0.05). Long term oestradiol administration markedly rescued the hepatic telomere from extensive shortening in both male and female rats. CONCLUSION: These results suggest that oestradiol acts as a positive modulator of the hTERT gene in the liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.


Subject(s)
Cellular Senescence/drug effects , Estradiol/pharmacology , Hepatocytes/drug effects , Liver Cirrhosis, Experimental/pathology , Telomere/drug effects , Animals , Carbon Tetrachloride , Cell Line , DNA-Binding Proteins , Estrogen Receptor alpha , Female , Gene Expression Regulation/drug effects , Hepatocytes/metabolism , Humans , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/genetics , Male , RNA, Messenger/genetics , Rats , Rats, Inbred F344 , Receptors, Estrogen/metabolism , Telomerase/genetics , Telomerase/metabolism , beta-Galactosidase/metabolism
6.
Br J Surg ; 91(4): 435-43, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15048743

ABSTRACT

BACKGROUND: A sensitive method for detecting minimal residual disease in the peritoneal cavity by quantifying carcinoembryonic antigen (CEA) mRNA using real-time quantitative reverse transcription-polymerase chain reaction (RQ-RT-PCR) was developed. The clinical value of the method for predicting peritoneal recurrence in patients with gastric cancer was evaluated. METHOD: A total of 195 patients with gastric cancer and 20 with asymptomatic cholecystolithiasis were included in the study. CEA mRNA expression in peritoneal washings (p-CEA mRNA) was measured by RQ-RT-PCR and normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The cut-off level of p-CEA mRNA for gastric cancer was determined by examining p-CEA mRNA levels in patients with asymptomatic cholecystolithiasis. RESULTS: Fifty-five (28.2 per cent) of the 195 patients were p-CEA mRNA positive. The rate of p-CEA mRNA positivity correlated significantly with clinicopathological factors. In 163 patients who underwent curative surgery, overall survival and disease-free survival were significantly poorer in p-CEA mRNA-positive patients than in p-CEA mRNA-negative patients (P < 0.001). Cox regression analysis revealed that only p-CEA mRNA was a significant independent prognostic factor (P = 0.034). Multivariate logistic regression analysis showed that p-CEA mRNA was a significant independent risk factor for peritoneal recurrence (P = 0.027). CONCLUSION: These results suggest that p-CEA mRNA is a reliable prognostic factor and predictor of peritoneal recurrence in gastric cancer.


Subject(s)
Carcinoembryonic Antigen/analysis , Peritoneal Neoplasms/diagnosis , Stomach Neoplasms/pathology , DNA, Complementary/analysis , Disease-Free Survival , Humans , Neoplasm, Residual/pathology , Peritoneal Neoplasms/chemistry , Peritoneal Neoplasms/secondary , Prognosis , RNA, Messenger/analysis , RNA, Neoplasm/analysis , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity , Tumor Cells, Cultured
7.
J Clin Pathol ; 56(12): 952-5, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14645357

ABSTRACT

AIMS: To develop immunoglobulin heavy chain variable (VH) gene probes that are shorter and more flexible in position for monitoring minimal residual disease (MRD) in childhood leukaemia (ALL), using minor groove binder (MGB) technology. METHODS: All VH germline sequences registered in the database were aligned and the consensus regions were determined. The reliability of the MGB probes was compared with non-MGB probes in all 24 cases of ALL. RESULTS: Ten MGB probes (16 to 18 mers) were designed that enabled all the germline sequences on the database to be analysed, whereas the conventional non-MGB probes (21 to 27 mers) did not allow the analysis of four of the VH1 and five of the VH3 germline sequences. The sequencing results in five of the 24 cases of ALL were not matched to the non-MGB probes. CONCLUSIONS: MGB technology allows shorter probes to be designed, enabling MRD to be detected in childhood ALL. This would provide a considerable reduction in cost for a large MRD study.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Oligonucleotide Probes , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Child , Consensus Sequence/genetics , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Humans , Neoplasm, Residual , Polymerase Chain Reaction/methods , Sequence Alignment
8.
J Clin Pathol ; 56(10): 778-9, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14514784

ABSTRACT

AIMS: To demonstrate the usefulness of polymerase chain reaction (PCR) methodology with both the FR2A/LJH/VLJH and the FR1c/LJH/VLJH primer sets for detecting monoclonal immunoglobulin heavy chain (IgH) gene rearrangement in B cell non-Hodgkin lymphomas (B-NHLs). METHODS: Eighty three patients with B-NHL were enrolled in this study. DNA was isolated from paraffin wax embedded sections and amplified by PCR to determine the sequences of the rearranged IgH gene. Each PCR product was subcloned. Cycle sequences and sequence analyses were done to determine the clone specific IgH variable region (VH) sequences. RESULTS: Clonal IgH gene rearrangements were detected in 45 cases with FR2a/JH/VLJH and in 14 of the remaining cases with FR1c/JH/VLJH. Most of the cases detectable with FR2a/JH/VLJH were derived from VH3 and VH4 families. Five of six cases in the VH1 family and one in the VH7 family were amplified with the FR1c/JH/VLJH primer set only. CONCLUSION: The detection rate of IgH rearrangement in B-NHLs can be increased by using both FR2A/LJH/VLJH and FR1c/LJH/VLJH, and these two primer sets are suitable for routine PCR methodology. Moreover, each primer set appears to be closely related to VH family specificity.


Subject(s)
Gene Rearrangement, B-Lymphocyte, Heavy Chain , Lymphoma, B-Cell/genetics , Clone Cells , Consensus Sequence , DNA Primers , Humans , Polymerase Chain Reaction/methods , Sensitivity and Specificity
9.
Br J Dermatol ; 147(5): 998-1002, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12410714

ABSTRACT

We present a patient with primary CD30+ cutaneous T-cell lymphoma whose histological and clinical features overlapped with those of granulomatous slack skin disease (GSSD). A 26-year-old woman had infiltrative erythema on the abdominal wall and an incurable ulcerative lesion on the left knee. Her skin progressively became atrophic and pendulous, showing a hyperpigmented appearance over almost the whole body. Histopathologically, a dense lymphoid cell infiltrate accompanying numerous macrophages and multinucleated giant cells (MGC) extended into the subcutaneous tissue. Most lymphoid cells were small and positive for T-cell markers. Some relatively large atypical cells were scattered in the lesion, most of which (60%) were positive for CD30. T-cell receptor-beta gene rearrangement was confirmed in the abdominal lesion. MGC infiltrated more dominantly into a deeeper layer of the skin with the elastic fibres there almost completely disappearing. Immunoreactivity for CD30 of MGC was negative and overexpression of elastolytic metalloproteinases was observed. The association between primary cutaneous CD30+ lym- phoproliferative disorders and GSSD has not previously been reported. Overexpression of elastolytic metalloproteinases in MGC contributes to the disappearance of the elastic fibres and enhances the severity of the clinical course.


Subject(s)
Granuloma/pathology , Ki-1 Antigen/analysis , Lymphoma, T-Cell, Cutaneous/pathology , Skin Neoplasms/pathology , Adult , Female , Granuloma/enzymology , Granuloma/immunology , Humans , Lymphoma, T-Cell, Cutaneous/enzymology , Lymphoma, T-Cell, Cutaneous/immunology , Skin Diseases/enzymology , Skin Diseases/immunology , Skin Diseases/pathology , Skin Neoplasms/enzymology , Skin Neoplasms/immunology
11.
Intern Med ; 40(2): 114-7, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11300142

ABSTRACT

A 58-year-old woman was admitted to our hospital because of renal dysfunction that continued to progress even after withdrawal of cefdinir, the presumed cause of acute renal failure. Renal histologic findings included interstitial fibrosis accompanied by moderate lymphocytic infiltration, and tubular atrophy with reduced numbers of epithelial cells. Mesangial cells and glomerular basement membranes were nearly normal. Scintigraphy with 67gallium disclosed diffuse abnormal accumulation in both kidneys. A lymphocyte stimulation test with cefdinir was positive. The patient was diagnosed with acute tubulointerstitial nephritis caused by cefdinir. Serum creatinine concentrations continued to rise after withdrawal of the drug, but steroid therapy was effective in normalizing renal function.


Subject(s)
Acute Kidney Injury/etiology , Anti-Infective Agents/adverse effects , Anti-Inflammatory Agents/therapeutic use , Cephalosporins/adverse effects , Methylprednisolone/therapeutic use , Nephritis, Interstitial/drug therapy , Prednisolone/therapeutic use , Acute Disease , Acute Kidney Injury/blood , Acute Kidney Injury/drug therapy , Anti-Infective Agents/therapeutic use , Biopsy , Bronchitis/drug therapy , C-Reactive Protein/analysis , Cefdinir , Cephalosporins/therapeutic use , Creatinine/blood , Disease Progression , Drug Therapy, Combination/therapeutic use , Famotidine/therapeutic use , Female , Histamine H2 Antagonists/therapeutic use , Humans , Kidney/diagnostic imaging , Kidney/pathology , Kidney Function Tests , Middle Aged , Nephritis, Interstitial/blood , Nephritis, Interstitial/chemically induced , Nephritis, Interstitial/diagnosis , Nephritis, Interstitial/pathology , Ofloxacin/therapeutic use , Radionuclide Imaging
12.
Dis Esophagus ; 14(3-4): 197-201, 2001.
Article in English | MEDLINE | ID: mdl-11869319

ABSTRACT

The objective of this study was to evaluate the therapeutic usefulness of chemoradiotherapy (CRT) followed by surgery in patients with clinically T4 (cT4) esophageal cancer involving adjacent organs such as the trachea, main bronchi, and large vessels. Thirty-seven patients with cT4 squamous cell carcinoma of the thoracic esophagus were enrolled in this study. The CRT regimen comprised cisplatin (70 mg/m2) on day 1, 5-fluorouracil (700 mg/m2) on days 1-4 and external irradiation (200 cGy/day, total 30 Gy) on either days 8-26 (sequential schedule, n=15) or days 1-19 (concurrent schedule, n022). Two courses of CRT were given. The results of CRT were complete response in nine patients, partial response in 19, no change in three (minor response in two), and progressive disease in six patients. The median response duration in all responders was 172 days (range: 56-2469, n=19). After CRT, 13 patients received surgery. In 12 of these patients, tumors were completely resected. Histopathologic examination of the resected specimen revealed a discrepancy between clinical response and histopathologic effect. The median duration of survival and the 1-, 2- and 5-year survival rates were 304 days (84-3155), 45%, 35% and 23% in all patients, respectively, 866 days (190-3155), 83%, 83% and 57% in the 13 patients whose tumors were resected, and 187 days (84--2630), 25%, 5% and 5% in the 24 patients whose tumors were not resected. Grade 3 toxicity, especially hematological reactions, was noted in 13.5% (5/37) of the patients. There was one toxicity-related death (sepsis). A good outcome may be obtained with CRT, followed by surgery when feasible. However, CRT can cause toxic reactions, and close monitoring of patients is required.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/therapy , Esophageal Neoplasms/therapy , Neoplasms, Multiple Primary/therapy , Aged , Biopsy, Needle , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cisplatin/administration & dosage , Combined Modality Therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophagectomy/methods , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms, Multiple Primary/mortality , Neoplasms, Multiple Primary/pathology , Radiation Dosage , Statistics, Nonparametric , Survival Analysis , Thorax , Treatment Outcome
13.
Cancer Res ; 60(17): 4761-6, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10987283

ABSTRACT

The mutational inactivation of a tumor suppressor gene, adenomatous polyposis coli (APC), results in the accumulation of cytoplasmic beta-catenin protein and the activation of T-cell factor (TCF)/lymphoid enhancer factor transcriptional factors. A colorectal carcinoma cell line, DLD-1, was engineered to suppress transactivation by the TCF4/beta-catenin complex in a dominant-negative manner under the strict control of the tetracycline regulatory system. A large-scale comparison of the expression profiles, using two-color fluorescence hybridization of cDNA microarray, led to the identification of MDR1 as a target gene of the TCF4/beta-catenin complex. Luciferase reporter and gel retardation assays revealed the TCF4/beta-catenin responsive elements in the promoter of the human MDR1 gene. Corresponding to the accumulation of beta-catenin, expression of the MDR1 gene product was steadily up-regulated in adenomas and adenocarcinomas of 10 patients with familial adenomatous polyposis. In combination with cell proliferative activities of c-myc and cyclin D1, MDR1 may initiate colorectal tumorigenesis by suppressing cell death pathways programmed in intestinal epithelial cells.


Subject(s)
Colorectal Neoplasms/genetics , Cytoskeletal Proteins/physiology , Genes, MDR/genetics , Trans-Activators , Transcription Factors/physiology , Transcriptional Activation/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/metabolism , Amino Acid Sequence , Colorectal Neoplasms/metabolism , Cytoskeletal Proteins/metabolism , Doxycycline/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Silencing , Genes, APC/genetics , Humans , Molecular Sequence Data , TCF Transcription Factors , Transcription Factor 7-Like 2 Protein , Transcription Factors/metabolism , Transfection , Tumor Cells, Cultured , beta Catenin
14.
Rinsho Byori ; 48(6): 521-6, 2000 Jun.
Article in Japanese | MEDLINE | ID: mdl-10897670

ABSTRACT

It has been suggested that SIRS are triggered by superfluous pro-inflammatory cytokine production, and that organ injury is caused by uncontrolled inflammatory responses. However, the results of clinical studies, on the usefulness of specific cytokine antagonists and anti-TNF antibodies for the treatment of septic shock, have been unsatisfactory. The reason for this might have been that when uncontrolled inflammatory reactions progressed locally, anti-inflammatory reactions were elevated in the circulated blood by way of CARS, thus the timing of administration and pharmacokinetics did not match clinical course. Recent research has shown that SIRS is always accompanied by CARS, and since it seems to do the amplitude of SIRS and CARS to each other so that there may be a deep valley, if there is a high mountain. We introduce the recent knowledge which indicates that SIRS is a preliminary alert for not only organ dysfunction but also immunosuppression after severe injury or major surgery.


Subject(s)
Stress, Physiological/etiology , Surgical Procedures, Operative/adverse effects , Systemic Inflammatory Response Syndrome/etiology , Cytokines/metabolism , Cytokines/physiology , Humans , Inflammation Mediators , Stress, Physiological/metabolism
15.
Jpn J Cancer Res ; 90(9): 993-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10551330

ABSTRACT

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and beta-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the beta-catenin gene were observed in any patient. One patient lacked beta-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic beta-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.


Subject(s)
Cadherins/genetics , Stomach Neoplasms/genetics , Trans-Activators , Adult , Base Sequence , Cadherins/analysis , Cell Adhesion , Cytoskeletal Proteins/analysis , Cytoskeletal Proteins/genetics , Female , Gene Deletion , Humans , Immunohistochemistry , Male , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Stomach Neoplasms/pathology , beta Catenin
16.
Eur J Cancer ; 35(2): 316-9, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10448277

ABSTRACT

The non-coding control region of mitochondrial DNA (mtDNA), containing the hypervariable regions HV1 and HV2 and the D-loop region, was screened for mutations in 45 gastric tumours (15 tumours each of adenoma, differentiated adenocarcinoma and undifferentiated carcinoma). We found mutations in two of the 45 tumours (4%); a 1 bp A deletion at nucleotide position 248 in a differentiated adenocarcinoma and a G to A transition at nucleotide position 16,129 in an adenoma. We also observed 10 polymorphisms, four of which were not previously recorded. Both mtDNA mutations were present in replication error negative (RER-) tumours. Short mono- or dinucleotide repeats in the control region, such as (C)7, (A)5 or (CA)5, were not altered regardless of nuclear genetic instability. In summary, mtDNA is mutated in a subset of benign and malignant gastric tumours, but, disruption of the mtDNA repair system appears not to be significantly involved in gastric tumours of Japanese patients.


Subject(s)
DNA, Mitochondrial/genetics , DNA, Neoplasm/genetics , Mutation/genetics , Stomach Neoplasms/genetics , DNA Repair , Humans , Japan , Locus Control Region , Polymerase Chain Reaction/methods , Polymorphism, Genetic
17.
Circulation ; 99(25): 3260-5, 1999 Jun 29.
Article in English | MEDLINE | ID: mdl-10385500

ABSTRACT

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-alpha-converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-alpha in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-alpha in myocardium and whether levels of TACE and TNF-alpha are related to clinical severity of DCM. METHODS AND RESULTS: Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-alpha and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase-polymerase chain reaction method. Expression of TNF-alpha and TACE proteins was determined by immunohistochemical analysis. TNF-alpha mRNA was expressed in DCM patients (TNF-alpha/GAPDH ratio 0.85+/-0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH ratio 2.52+/-0.59 vs 0.03+/-0.02, P<0.05). A positive correlation was found between TNF-alpha and TACE mRNA levels (r=0.779, P<0.001). TACE and TNF-alpha immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventricular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (>/=45 mm) showed significantly greater expression of TACE (P=0.02) and TNF-alpha (P=0. 001) than did the low LVESD subgroup (<45 mm). In addition, the DCM subgroup with lower LVEF (<40%) showed higher expression of TACE (P=0.006) and TNF-alpha (P=0.01) than did the subgroup with high LVEF (>/=40%). CONCLUSIONS: This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-alpha expression in both mRNA and protein levels in clinically advanced DCM.


Subject(s)
Cardiomyopathy, Dilated/blood , Metalloendopeptidases/blood , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , ADAM17 Protein , Adolescent , Adult , Aged , Cardiomyopathy, Dilated/enzymology , DNA Primers , Female , Gene Expression Regulation , Humans , Immunohistochemistry , Male , Metalloendopeptidases/genetics , Middle Aged , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction/methods , Severity of Illness Index , Tumor Necrosis Factor-alpha/genetics
18.
Genes Chromosomes Cancer ; 23(4): 317-22, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9824204

ABSTRACT

Frequent frameshift mutations of simple nucleotide repeats in the protein-encoding regions, as well as replication errors (RERs) at microsatellite loci, have recently been demonstrated in gastrointestinal tumors. These genetic instabilities have been considered indicative of an increased risk of accumulating mutations in cancer-associated genes and of developing multiple cancers. We studied frameshift (or insertion/deletion) mutations of simple nucleotide repeats in five genes (TGFbeta type II receptor [TGFbetaRII], E2F4, MSH2, MSH3, and MSH6) in 23 tumors from 12 patients who had synchronous cancers of the esophagus and other organs. Genetic instability at four microsatellite loci, as well as mutations in the TP53, APC, and KRAS2 genes, were also studied. No frameshift mutations were observed in the TGFbetaRII, MSH3, and MSH6 genes. RER and a deletion mutation of BAT26 in MSH2 were present in one (1/23; 4%) gastric cancer. This tumor also carried a deletion mutation in the serine (AGC) repeat of the E2F4 gene. Mutation screening of the TP53, APC, and KRAS2 genes revealed that the synchronous cancers did not carry the same mutations. Our results suggested that genetic instability, such as insertion/deletion mutations in simple nucleotide repeats, is not significantly associated with the development of multiple primary cancers of the esophagus and other organs, and that these synchronous cancers developed independently according to their different environmental factors.


Subject(s)
Esophageal Neoplasms/genetics , Frameshift Mutation/genetics , Multidrug Resistance-Associated Proteins , Neoplasms, Multiple Primary/genetics , Repetitive Sequences, Nucleic Acid/genetics , Colonic Neoplasms/genetics , DNA Mutational Analysis , DNA, Neoplasm/analysis , DNA-Binding Proteins/genetics , Humans , Kidney Neoplasms/genetics , Loss of Heterozygosity , Microsatellite Repeats , MutS Homolog 2 Protein , MutS Homolog 3 Protein , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/genetics , Thyroid Neoplasms/genetics
19.
Int J Cancer ; 77(4): 522-7, 1998 Aug 12.
Article in English | MEDLINE | ID: mdl-9679752

ABSTRACT

Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor-suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor-1 (IRF-1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF-1 is a transcriptional activator that shows tumor-suppressor activity in the mouse. In the present study, we examined the sequence of the IRF-1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF-1 locus. We identified a mis-sense mutation in the residual allele in one case. This mutated form of IRF-1 showed markedly reduced transcriptional activity. In addition, overexpression of wild-type IRF-1 induced cell-cycle arrest, whereas such activity was attenuated in the mutant IRF-1. These results suggest that the loss of functional IRF-1 is critical for the development of human gastric cancers.


Subject(s)
Chromosomes, Human, Pair 5/genetics , DNA-Binding Proteins/genetics , Genes, Tumor Suppressor/genetics , Loss of Heterozygosity , Phosphoproteins/genetics , Point Mutation , Stomach Neoplasms/genetics , 3T3 Cells , Animals , Cell Cycle/genetics , Humans , Interferon Regulatory Factor-1 , Mice , Stomach Neoplasms/pathology
20.
Gastroenterology ; 114(6): 1206-10, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9609757

ABSTRACT

BACKGROUND & AIMS: Tumor-suppressor genes found in inherited cancer predisposition syndromes are also responsible for sporadic cancers of the same type. Recently, the tylosis oesophageal cancer (TOC) gene locus has been mapped to 17q25 by linkage analyses of pedigrees with focal nonepidermolytic palmoplantar keratoderma associated with a high risk of esophageal cancer development. The aim of this study was to clarify whether the TOC locus is affected in sporadic esophageal cancers. METHODS: We investigated loss of heterozygosity (LOH) on 17q in 58 sporadic esophageal squamous cell carcinomas (ESCs) using 20 microsatellite markers focusing on the TOC locus. RESULTS: LOH on 17q was observed in 37 of 52 (71%) informative cases at one or more loci, 80% (33/37) of which included the TOC locus. The smallest common deleted region was at D17S1839 within the TOC locus. CONCLUSIONS: The constructed deletion map revealed that the TOC locus is commonly deleted in sporadic ESCs, suggesting that a tumor-suppressor gene responsible for ESC is contained within this locus.


Subject(s)
Carcinoma, Squamous Cell/genetics , Chromosome Mapping , Chromosomes, Human, Pair 17/genetics , Esophageal Neoplasms/genetics , Keratoderma, Palmoplantar, Diffuse/genetics , Gene Deletion , Humans , Loss of Heterozygosity/genetics , Microsatellite Repeats/genetics
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