Biomedical subjects

Takuya Moriya

Publications and source records attributed to Takuya Moriya.

At least 91 records · Page 5Linked to original sources

PubMed2003

Pulmonary mucinous cystadenocarcinoma: report of a case and review of the literature.

A case of primary mucinous cystadenocarcinoma of the lung is presented. The patient was a 42-year-old woman with a 5-cm left lung mass. Left lower lobectomy was performed and analysis of a frozen section revealed mucinous cystadenocarcinoma. The tumor was a fibrous, walled cyst containing abundant mucinous material. Sparse groups of malignant cells were microscopically observed in pools of mucin; thus, the tumor resembled mucinous cystadenocarcinoma that occurs in the ovary, appendix, or pancreas. The tumor we found is a very rare intrapulmonary neoplasm that is differentiated from a metastatic lesion and mucinous bronchoalveolar carcinoma by its very different clinical course and prognosis.

Adult↗

PubMed2003

Adrenal adenomas: relationship between histologic lipid-rich cells and CT attenuation number.

OBJECTIVE: To evaluate the relationship between lipid-rich cells of the adrenal adenoma and precontrast computed tomographic (CT) attenuation numbers in three clinical groups. MATERIALS AND METHODS: Thirty-five surgically resected adrenal adenomas were used. The clinical diagnoses of the patients included 13 cases of primary aldosteronism, 15 cases of Cushing's syndrome, and 7 non-functioning tumors. The number of lipid-rich clear cells was counted using a microscopic eyepiece grid that contained 100 squares. The results were expressed as the percentages of lipid-rich areas. RESULTS: There was a strong inverse linear relationship between the percentage of lipid-rich cells and the precontrast CT attenuation number (R(2)=0.724, P<0.0001). There were significantly more lipid-rich cells in the primary aldosteronism and non-functioning tumor cases compared to cases of Cushing's syndrome (P=0.007 and 0.015, respectively). The CT attenuation numbers of the primary aldosteronism cases were significantly lower than those of Cushing's syndrome (P=0.0052). Furthermore, the CT attenuation numbers of the non-functioning tumor cases were lower than those of Cushing's syndrome cases. CONCLUSION: We showed that adrenal adenomas in primary aldosteronism and non-functioning tumors contain significantly more lipid-rich cells than those in Cushing's syndrome. They also showed significantly lower attenuation than that in Cushing's syndrome on CT scans. Our results suggest that precontrast CT attenuation numbers may be helpful in the differentiation of adenomas from non-adenomatous lesions, which include malignancies.

Adenoma↗

PubMed2003

Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma.

Steroid sulfatase (STS) hydrolyzes inactive estrone sulfate (E1-S) to estrone (E1), while estrogen sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates estrogens to estrogen sulfates. They are considered to play important roles in the regulation of local estrogenic actions in various human tissues, however, their biological significance remains largely unknown. Therefore, we examined the expression of STS and EST in non-pathologic human tissues and breast carcinomas. STS expression was very weak except for the placenta, while EST expression was markedly detected in various tissues examined. In breast carcinoma tissues, STS and EST immunoreactivity was detected in carcinoma cells in 74 and 44% of cases, respectively, and was significantly associated with their mRNA levels and enzymatic activities. STS immunoreactivity was significantly correlated with the tumor size, and an increased risk of recurrence. EST immunoreactivity was inversely correlated with the tumor size or lymph node status. Moreover, EST immunoreactivity was significantly associated with a decreased risk of recurrence or improved prognosis. Our results suggest that EST is involved in protecting various peripheral tissues from excessive estrogenic effects. In the breast carcinoma, STS and EST are suggested to play important roles in the regulation of in situ estrogen production in the breast carcinomas.

Breast Neoplasms↗

PubMed2003

The correlation between the response to progestogen treatment and the expression of progesterone receptor B and 17beta-hydroxysteroid dehydrogenase type 2 in human endometrial carcinoma.

OBJECTIVE: In situ metabolism and synthesis of oestrogens are considered to play important roles in the pathogenesis and development of human endometrial endometrioid adenocarcinoma. Approximately 3-5% of patients with these neoplasms are under age 40, some of whom have been treated with progestogen alone as a primary therapy for both atypical endometrial hyperplasia and adenocarcinoma in order to preserve their fertility. Medroxyprogesterone acetate (MPA) has been used extensively in the treatment of both breast and endometrial disorders as an endocrine therapy. However, details of the alterations of in situ oestrogen metabolism following progestogen treatment have yet to be fully elucidated. DESIGN, PATIENTS AND MEASUREMENTS: In this study we examined the immunolocalization of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) types 1 and 2, oestrogen receptor (ER), progesterone receptor (PR)A + PRB, PRB, and Ki67 in progestogen-treated endometrial endometrioid adenocarcinoma (16 cases). We compared our findings both prior to and following treatment. These findings were then correlated with the treatment outcome of individual patients in order to elucidate factors associated with the response to treatment. RESULTS: 17beta-HSD type 2 immunoreactivity was detected in 8/16 cases examined, whereas 17beta-HSD type 1 immunoreactivity was undetected in all cases examined. 17beta-HSD type 2 positive immunostaining, PRA + PRB labelling index (LI), and PRB/PRA + PRB ratio were all significantly higher in cases responding to the treatment than in those not responding. There were no significant correlations between responsive and nonresponsive cases for positive 17beta-HSD type 1 immunostaining, Ki67 LI, ER LI and age. There were no significant differences in the positive immunostaining for 17beta-HSD types 1 and 2, Ki67 LI, ER LI, PRA + PRB LI, age and PRB/PRA + PRB ratio between specimens taken prior to and following progestogen treatment. CONCLUSION: These results suggest that in situ abundance of 17beta-HSD type 2 and PR, especially PRB, can predict the possible response of patients with endometrial carcinoma to progestogen treatment.

17-Hydroxysteroid Dehydrogenases↗

PubMed2003

Microinvasive ductal carcinoma (T1mic) of the breast. The clinicopathological profile and immunohistochemical features of 28 cases.

Microinvasive ductal carcinoma of the breast, namely ductal carcinoma in situ with microinvasion (T1mic) as defined by the American Joint Committee on Cancer (AJCC) Staging Manual, is a rare disease, although it is increasing because of widespread use of mammography. The aim of the present study was to describe the clinicopathological and immunohistochemical features of this entity. Twenty-eight patients who were diagnosed as T1mic from January 1997 to August 2002 were studied by using 3-5 mm-thick serial sections with hematoxylin-eosin staining. Immunohistochemical staining for the estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and HER-2 were performed. All 28 patients were female, with a mean age of 48.8 years. Twenty-six patients (93%) revealed mammographic abnormalities on routine examination. All foci of the invasions were measured using an ocular micrometer. Invasive foci consisted of isolated cells or cell clusters, or appeared as a tongue-like projection of tumor through the basement membrane of the duct of ductal carcinoma in situ (DCIS). The mean number of invasive foci was 3, and the mean size was 0.6 mm. We found that high nuclear grade and predominant comedo subtype of DCIS components were 57.1% and 46.4%, respectively. Twenty-four cases (86%) demonstrated necrosis of DCIS components. Microinvasion was often associated with periductal stromal reaction (71.5%) and/or a lymphocytic infiltration (78.6%). All patients, excluding two, received axillary resection (the mean number of lymph nodes examined per case was 12), and none had lymph node metastasis. The positive expression of ER and PR strongly related to low grade nuclei and non-comedo subtype; however, the positive expression of HER-2 and P53 related to high grade nuclei and comedo subtype (P<0.01). Ki-67 expression was significantly higher in the high grade nuclei group than in the low grade group (P<0.01). Our study suggested that high nuclear grade and comedo DCIS were more aggressive and more common with microinvasion, and that microinvasion is more likely to be multifocal.

Adult↗

PubMed2003

Medroxyprogesterone acetate decreases secretion of interleukin-6 and parathyroid hormone-related protein in a new anaplastic thyroid cancer cell line, KTC-2.

A new thyroid cancer cell line, KTC-2, was established from the malignant pleural effusion of a patient with recurrent thyroid cancer associated with anaplastic transformation from thyroid papillary cancer. Karyotype analysis showed a mode of 109 chromosomes. Subcutaneous cell injections produced small regressing tumors in athymic or severe combined immunodeficiency disorders (SCID) mice. Histologic examination showed anaplastic tumor cells surrounded by prominent mononuclear cells. An expression of thyroglobulin, thyroid transcription factor-1, and PAX-8 but not thyroid peroxidase and thyrotropin (TSH) receptor was detected. Biochemical analysis revealed secretion of interleukin (IL)-6, parathyroid hormone-related protein (PTHrP), and granulocyte-macrophage colony-stimulating factor. All the cytokines are known to induce paraneoplastic syndromes in patients with anaplastic thyroid cancer. Our previous studies revealed that medroxyprogesterone acetate (MPA) reduces secretion of IL-6 and PTHrP from human breast cancer cells. To investigate the regulatory mechanisms of secretion of these cytokines, MPA was administered to the KTC-2 cells. MPA dose-dependently decreased the secretion and mRNA expression of IL-6 and PTHrP. Expression of androgen receptor and glucocorticoid receptor (GR) but not progesterone receptor was detected. Dexamethasone but not dihydrotestosterone and progesterone decreased IL-6 and PTHrP secretion. These findings suggest that MPA decreases IL-6 and PTHrP secretion as a glucocorticoid mediated by GR in the KTC-2 cells. This KTC-2 cell line may be a suitable model for developing new strategies against paraneoplastic syndromes caused by anaplastic thyroid cancer.

Carcinoma, Papillary↗

PubMed2003

Pathological assessment of intraductal spread of carcinoma in relation to surgical margin state in breast-conserving surgery.

BACKGROUND: Spreading of carcinoma has been considered to be a prognostic factor for local failure after breast-conserving therapy. The extensive intraductal component (EIC) was defined as when the component of intraductal carcinoma constitutes more than 25% of the primary tumor with intraductal foci. However, the definition of EIC was based on the predominance of intraductal component surrounding the invasive lesions and not on the segmental anatomy. We designated carcinoma extension as the intraductal spread of carcinoma (ISC) along with the duct-lobular system by three-dimensional (3-D) reconstruction analysis. This study was initiated to simplify the method of two-dimensional (2-D) pathological examination based on 3-D mapping. METHODS: Thirty-four specimens from breast cancer patients were subjected to 3-D reconstruction. We investigated the correlation between actual extension of intraductal carcinoma and EIC defined by 2-D examination or ISC grading defined by 3-D reconstruction. Furthermore, using another 62 histological mappings, we investigated how correctly the simplified 2-D method using several paraffin blocks reflected the actual carcinoma spread and margin state. RESULTS: Carcinoma extension over 2 cm was observed in 64% specimens that were EIC positive and 26% specimens that were EIC negative. In contrast, according to the ISC grading defined by 3-D reconstruction, none of the specimens with a low grade of ISC demonstrated carcinoma extension over 2 cm. Carcinoma extension over 2 cm was observed in 71% of specimens with a high grade of ISC, thus demonstrating a correlation between carcinoma extension and ISC grading. In addition, the simplified 2-D method using only several blocks reflected both the 3-D ISC grading and surgical margin state. CONCLUSIONS: We conclude that ISC grading correlates with carcinoma extension and surgical margin state. From a clinical point of view, the simplified 2-D examination using paraffin blocks may contribute to routine surgical pathology in evaluating the degree of carcinoma extension in breast-conserving therapy.

Adult↗

PubMed2003

Loss of heterozygosity analyses of asynchronous lesions of ductal carcinoma in situ and invasive ductal carcinoma of the human breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of the pre-invasive stage of breast cancer and is the precursor to invasive ductal carcinoma (IDC). However, the natural history of the progression from DCIS to IDC remains unknown at the molecular level. METHODS: We investigated the loss of heterozygosities (LOHs) in tumors of seven patients with a history of breast biopsy. The seven specimens were diagnosed as DCIS on histopathological re-examination. These patients were diagnosed with ipsilateral breast cancer a few years after biopsy. We used thirteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOHs in breast cancer. DNA isolated from microdissected formalin-fixed, paraffin-embedded tissues was subjected to a PCR-LOH analysis for these chromosome loci, and the pattern of LOHs was compared between the two asynchronous lesions for the seven cases. RESULTS: In all patients except one, the LOHs were concordant at 91% as the informative chromosome loci in cases 1 to 6 were 56, and the concordance in LOH pattern between DCIS and IDC was detected at 50 loci. The LOHs had accumulated in accordance with the tumor progression from DCIS to IDC. The recurrent lesion occurred at or near the site of the primary biopsy and had similar or identical histopathologic features. CONCLUSIONS: These recurrences observed were probably residual disease rather than true recurrences. Our results suggest the following: (i) genetic alternations accumulate during cancer progression from DCIS to IDC, (ii) DCIS is a lesion that has a high risk of developing invasive transformation and (iii) after approximately 5 years without treatment, DCIS may develop into IDC.

Breast Neoplasms↗

PubMed2003

Estrogen receptors (alpha and beta) and 17beta-hydroxysteroid dehydrogenase type 1 and 2 in thyroid disorders: possible in situ estrogen synthesis and actions.

Both epidemiological and experimental findings suggest the possible roles of sex steroids in the pathogenesis and/or development of various human thyroid disorders. In this study, we evaluated the expression of estrogen receptors (ER) alpha and beta in normal thyroid glands (N = 25; female: n = 13, male: n = 10, unknown: n = 2) ranging in age from fetus to adult. Furthermore, using immunohistochemistry, we investigated the expression of ERalpha and beta in 206 cases of thyroid disorders, including 24 adenomatous goiters, 23 follicular adenomas, and 159 thyroid carcinomas. In addition, we also studied the mRNA expression of ERalpha and beta and 17beta-hydroxysteroid dehydrogenase Type 1 and 2, enzymes involved in the interconversion between estrone and estradiol, using reverse transcription polymerase chain reaction (RT-PCR), in 48 of these 206 cases (10 adenomatous goiters, 10 follicular adenomas, and 28 papillary thyroid carcinomas) in which fresh frozen tissues were available for examination to further elucidate the possible involvement of intracrine estrogen metabolism and/or actions in thyroid disorders. ERalpha labeling index, or percentage of cells immunopositive for ERalpha, was significantly higher in adenomatous goiter (14.2 +/- 6.4), follicular adenoma (13.4 +/- 5.1), and thyroid carcinoma (16.4 +/- 2.1) than in normal thyroid gland (0; P <.05). Few follicular cells were positive for ERalpha in normal thyroid glands. In papillary carcinoma, ERalpha labeling index was significantly higher in premenopausal women (28.1 +/- 4.5) than in postmenopausal women (14.2 +/- 2.9) and in men of various ages (7.6 +/- 2.7; P <.05). In other histological types of thyroid carcinoma, no significant correlations were detected. ERbeta immunoreactivity was detected in both follicular and C-cells of normal thyroid glands, including those in developing fetal thyroid glands. In addition, ERbeta immunoreactivity was detected in the nuclei of various thyroid lesions. But no significant correlations were detected between ERbeta labeling index and clinicopathological findings including age, menopausal status, gender, and/or histological type of thyroid lesions. 17beta-hydroxysteroid dehydrogenase Type 1 expression was detected in 31/48 (64.0%) of the cases examined, whereas Type 2 was detected only in 3/46 (6.3%) of all the cases examined. These results demonstrated that estrogens may influence the development, physiology, and pathology of human thyroid glands, and these effects, especially through ERalpha, may become more pronounced in neoplasms, particularly in papillary carcinoma arising in premenopausal women.

Adenocarcinoma↗

PubMed2003

Nuclear receptor DAX-1 in human common epithelial ovarian carcinoma: an independent prognostic factor of clinical outcome.

DAX-1 is a member of the nuclear receptor superfamily and is thought to be involved in the regulation of steroidogenesis. Its expression has been detected primarily in endocrine neoplasms such as adrenocortical as well as pituitary tumors in human, but its biological roles have not been examined well in sex steroid-dependent neoplasms. The aim of this study is to detect the expression of DAX-1 in common epithelial ovarian carcinomas in order to evaluate its possible biological significance. DAX-1 immunoreactivity was examined using immunohistochemistry. The correlation between the status of DAX-1 immunoreactivity and clinicopathological parameters and disease-free survival of the patients in a series of 60 cases of common epithelial ovarian carcinoma was examined. The status of DAX-1 immunoreactivity was evaluated using H score. DAX-1 immunoreactivity was widely detected in the nuclei of common epithelial ovarian carcinoma cells. There was a significant positive correlation between DAX-1 immunoreactivity and clinical staging (P = 0.0241), tumor grade (P = 0.0115), the residual size of the tumor (P = 0.0014) and Ki-67 labeling index (P = < 0.0001). In univariate survival analysis, a significant association was detected between DAX-1 immunoreactivity and shortened patient survival (P = 0.0157). Other significant prognostic parameters were clinical stage, residual size of tumor and Ki-67. In multivariate analysis, DAX-1 immunoreactivity, clinical stage, residual size of tumor and Ki-67 all turned out to be independent prognostic factors for shortened survival. In conclusion, DAX-1 immunoreactivity is considered to be a new independent marker of poor prognosis or adverse clinical outcome in patients with epithelial ovarian carcinoma, possibly through altering in situ steroids production.

Adenocarcinoma, Clear Cell↗

PubMed2003

Sex steroid hormone receptors in human thymoma.

In this study we examined the immunohistochemical localization of sex steroid receptors for estrogen alpha (ER alpha) and ER beta, progesterone-A (PR-A) and PR-B, and androgen (AR) in human thymoma (n = 132) and correlated these findings with various clinicopathological parameters. We used RT-PCR and real-time PCR to further study the expression of these receptors in 20 thymoma cases. Immunoreactivity for all sex steroid receptors was detected in the nuclei of thymoma epithelial cells. The percentage of immunopositive cases and the H-score values for each receptor (mean +/- SD) were: ER alpha, 66% and 85.8 +/- 80.2; ER beta, 7% and 7.2 +/- 8.7; PR-A, 4% and 2.7 +/- 4.9; PR-B, 49% and 55.8 +/- 68.3; and AR, 15% and 14.1 +/- 11.7, respectively. The results of real-time PCR were consistent with those of immunohistochemistry, especially results for ER alpha, PR-B, and AR. A significant positive correlation was detected between immunoreactivity for ER alpha and PR-B. ER alpha immunoreactivity was inversely correlated with tumor size, clinical stage, WHO classification, and Ki-67 labeling index. In addition, the status of ER alpha immunoreactivity was significantly associated with a better clinical outcome in thymoma patients. Results from our study suggest that estrogens may inhibit thymoma growth via ER alpha, and that ER alpha immunoreactivity may act as a prognostic factor in human thymoma.

Adult↗

PubMed2003

A missense mutation in the SH3BP2 gene on chromosome 4p16.3 found in a case of nonfamilial cherubism.

OBJECTIVE: Cherubism is a rare hereditary multilocular cystic disease of the jaws, characterized by its typical appearance. Although nonfamilial cases have been reported, it is difficult to distinguish nonfamilial cherubism from central giant cell granuloma. Recent studies have revealed the point mutations in the SH3BP2 gene on chromosome 4p16.3 in cherubism families. In this article, the SH3BP2 gene in nonfamilial cherubism was examined. PATIENT: A 21-year-old Japanese woman with nonfamilial cherubism. INTERVENTIONS: Genomic DNA was purified from a blood sample obtained from the patient and used for direct sequencing. In addition, a sample of the lesion, resected during surgery, was used for histologic and immunohistochemical purposes. RESULTS: Genomic DNA sequencing found a Pro418Arg mutation in the SH3BP2 gene of the patient. In a histochemical analysis, the multinucleated giant cells proved to be strongly positive for PGM-1, KP-1, and tartrate-resistant acid phosphatase and faintly positive for osteopontin. CONCLUSIONS: The missense mutation Pro418Arg was identified in the SH3BP2 gene from a nonfamilial case of cherubism. DNA diagnosis may play a significant role in the identification of cherubism.

Acid Phosphatase↗

PubMed2002

Expression of androgen receptor and 5alpha-reductases in the human normal endometrium and its disorders.

Androgen metabolism and actions are considered to play a very important role in the development and progression of the normal human endometrium and its disorders. Details regarding androgen actions in these tissues, however, have not been well studied. We first immunolocalized the androgen receptor (AR) and 5alpha-reductases, which catalyze the conversion of testosterone to the bioactive and potent androgen, 5alpha-dihydrotestesterone (DHT), in 18 normal cycling human endometria, 27 endometrial hyperplasia and 46 endometrioid endometrial adenocarcinomas. We also examined the mRNA expression of AR and 5alpha-reductases in 7 cases of endometrioid endometrial adenocarcinomas using reverse transcription polymerase chain reaction (RT-PCR). In the normal human endometrium, AR was immunolocalized predominantly in stromal cells of the proliferative phase of the menstrual cycle and in epithelial cells of the secretory phase, whereas 5alpha-reductase types 1 and 2 immunoreactivities were detected in the cytoplasm of epithelial cells but not in stromal cells throughout all phases of the menstrual cycle. In endometrial hyperplasia, the median labeling index (LI) for AR was 48.1%, whereas positive immunostaining for 5alpha-reductase Type 1 and Type 2 was detected in only 1 case. In endometrial carcinoma, AR immunoreactivity was detected in the nuclei of carcinoma cells and the number of positive cases was 39/44 (88.6%). Median LI for AR was 36.1%. Immunoreactivity for 5alpha-reductase Type 1 and Type 2 was detected in the cytoplasm of carcinoma cells and the number of positive cases was 37/44 cases (84.1%) and 34/44 (77.3%) for 5alpha-reductase Types 1 and 2, respectively. A significant positive correlation was detected between 5alpha-reductase Type 1 and Type 2 immunoreactivity (p < 0.001). AR LI was not correlated with the presence or absence of Type 1 and Type 2 5alpha-reductases. Results from our RT-PCR studies were consistent with those of immunohistochemistry. These results suggest that DHT may play more important roles than testosterone in the regulation of androgen action in endometrial cancer and normal human endometrium, especially in the secretory phase, in which both AR and 5alpha-reductase are increased. Androgenic actions may be also regulated predominantly by serum testosterone and not by DHT in endometrial hyperplasia because of the absence of 5alpha-reductases in the site of its actions.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2002

In situ production of estrogens in human breast carcinoma.

Recent studies have demonstrated that biologically active estrogens are locally produced from circulating inactive steroids in the estrogen-dependent breast carcinoma. The in situ production of estrogens in the breast carcinoma is considered to play an important role in the proliferation of breast cancer cells, especially in the postmenopausal women. Therefore, the total blockade of this pathway may inhibit estrogenic actions in breast cancer tissues and lead to an improvement in the prognosis in these patients. In this review, we describe the recent studies concerning the expression of enzymes related to intratumoral estrogen production, including aromatase, 17beta-hydroxysteroid dehydrogenase, steroid sulfatase, and estrogen sulfotransferase in human breast carcinoma tissues, and discuss the biological significance of local production of estrogens in human breast cancer.

17-Hydroxysteroid Dehydrogenases↗

PubMed2002

Analysis of intrapulmonary vessels and epithelial-endothelial interactions in the human developing lung.

The establishment of a sufficiently wide and functional blood-gas interface is of critical importance in lung development, but development of the intrapulmonary vascular system including alveolar capillary vessels still remains unclear. In this study, we first characterized the structural development of the vascular system in accordance with that of airways in human fetal lungs at the pseudoglandular phase (8, 13, and 16 weeks gestation) by examining the immunohistochemical distribution of CD34 and alpha-smooth muscle actin (SMA). Using double immunohistochemistry and 3-dimensional reconstruction techniques, endothelial cells in the developing lung could be classified into two different types according to the characteristics of their adjacent cells (presence or absence of SMA-positive cells) and their distribution (proximal or distal lung parenchyme). Endothelial cells without SMA-positive cells developed into a capillary network surrounding the budding components of distal airways during the mid-pseudoglandular phase before communicating with proximal vessels. We then examined the immunoreactivity of thrombomodulin and von Willebrand factor (vWF) in endothelial cells. Endothelial cells of the capillary network were mainly positive for vWF during the early gestational stages, but altered their phenotypes to those of mature lungs (vWF negative and thrombomodulin positive) during the terminal sac phase. We subsequently determined the immunohistochemical distribution of vascular endothelial growth factor (VEGF). Epithelial cells of the most distal airways were intensely positive for VEGF. These results suggest that VEGF present in airway epithelial cells is involved in the maturation as well as proliferation of capillary endothelial cells. Epithelial-endothelial interactions during lung development are considered very important in the establishment of the functional blood-gas interface.

Embryonic and Fetal Development↗

PubMed2002

Retinoid receptors in the developing human lung.

Nuclear receptors and their ligands are known to play very important roles in lung development. Among these receptors, retinoid receptors, members of the steroid/thyroid hormone receptor superfamily, are classified into retinoic acid receptor (RAR) isoforms alpha, beta, and gamma and retinoid X receptor (RXR) isoforms alpha, beta, and gamma. In addition, isoforms I and II of the orphan receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) have been shown to negatively regulate the activation of retinoid receptors. Both of these receptors have been shown to regulate lung development in the mouse. In the present study we utilized immunohistochemistry and real-time quantitative PCR to examine the expression of RAR-alpha, -beta and -gamma, RXR-alpha, -beta and -gamma and COUP-TFII in the human fetal lung at 13-16 gestational weeks, a very critical stage of human pulmonary development, in order to study possible roles in pulmonary morphogenesis by comparing these findings with those of the adult lung. RXR-gamma immunoreactivity was detected at both proximal (epithelia and mesenchyme of the trachea and bronchi associated with cartilage) and distal (epithelia and mesenchyme of smaller distal bronchi) sites in the fetal lung, but was markedly weaker in the adult lung. RAR-beta immunoreactivity was detected in distal mesenchymal cells of the fetal lung, but was not discernible in distal mesenchymal cells in the adult lung (bronchioles, alveolar ducts and alveolus). Relatively intense RAR-gamma immunoreactivity was detected in the chondrocytes of bronchial cells. COUP-TFII immunoreactivity was detected with a similar pattern to that of RAR-beta. Real-time quantitative PCR analyses revealed that mRNA levels of RXR-gamma at proximal and distal sites (ratio of fetal lung/adult lung: 3.4+/-0.05-fold and 3.1+/-0.03-fold respectively; P <0.01), RAR-beta at distal sites (2.4+/-0.01-fold; P <0.05) and RAR-gamma at proximal sites (2.2+/-0.11-fold; P <0.05) were significantly higher in the fetus than in the adult.

Adult↗

PubMed2002

Analysis of cell damage in Helicobacter pylori-associated gastritis.

Helicobacter pylori infection is currently considered to be a major cause of acute and chronic gastritis, and of gastric and duodenal ulcers. Superoxide dismutase (SOD) is well known for scavenging superoxide radicals such as reactive oxygen species (ROS), subsequently protecting cells from oxidative injury, and for maintaining tissue homeostasis. In this study, we therefore evaluated the level of SOD activity and protein expression, as well as various factors associated with oxidative injury, in H. pylori-positive (n = 46) and -negative (n = 28) gastric mucosa obtained from endoscopy, in order to elucidate the possible biological significance of SOD in these mucosa. Overall SOD activity was significantly higher in H. pylori-positive mucosa (15.5 +/- 7.0 U/mg protein) than in negative mucosa (9.2 +/- 10.6 U/mg protein), and decreased markedly following H. pylori eradication (8.2 +/- 4.2 U/mg protein). Enzyme-linked immunosorbent assay (ELISA) analysis of SOD revealed that the manganese SOD (Mn-SOD) level in H. pylori-positive mucosa (1166.7 +/- 435.2 ng/mg protein) was significantly higher than in control tissues (446.3 +/- 435.3 ng/mg protein) and in mucosa obtained following eradication therapy (431.9 +/- 189.9 ng/mg protein). The level of Mn-SOD protein showed a significant correlation with degree of inflammation in the gastric mucosa. Moreover, Mn-SOD immunolocalization patterns were well correlated with the activity and protein levels evaluated by ELISA. Factors presumably associated with oxidative injury in human gastric mucosa, including terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, Ki-67, 8-hydroxydeoxyguanosine and single-stranded DNA, were all significantly higher in H. pylori-positive gastric mucosa than in control tissue and in tissue following eradication. These results all suggest that Mn-SOD, but not cytoplasmic copper-zinc SOD, plays an important role as an anti-oxidant against ROS generated in H. pylori-infected gastric mucosa and, subsequently, in the maintenance of cell turnover in gastric mucosa.

DNA, Single-Stranded↗

PubMed2002

Genetics of synchronous uterine and ovarian endometrioid carcinoma: combined analyses of loss of heterozygosity, PTEN mutation, and microsatellite instability.

Synchronous development of carcinomas in the endometrium and ovaries is a fairly common phenomenon, but distinction of a single clonal tumor with metastasis from 2 independent primary tumors may present diagnostic problems. To determine clonality and the occurrence of progression, we microdissected multiple foci from 17 cases of synchronous endometrioid carcinomas and studied loss of heterozygosity (LOH), microsatellite instability (MI), and PTEN mutations. In 14 of the 17 cases, genetic alterations were either homogeneous or found in only some of the foci. LOH was detected for 10q (4 cases), 17p (2 cases), and 2p, 5q, 6q, 9p, 11q, 13q, and 16q (1 case each). Four cases had the MI phenotype with discordant MI patterns between both tumor sites, thus indicating a biclonal or triple clonal process. In 3 of 6 cases with PTEN mutations, identical mutations in both tumor sites indicated a single clonal neoplasm. Altogether, 14 synchronous tumors were genetically diagnosed as follows: single clonal tumor, characterized by concordant genetic alterations in both tumor sites, including identical LOH, identical PTEN mutations, and/or identical sporadic allelic instability patterns (4 cases); single clonal tumor with genetic progression, homogeneous LOH or identical PTEN mutations in both tumor sites and progressive LOH in ovarian metastatic foci (2 cases); and double (7 cases) or triple clonal tumors (1 case), determined by discordant PTEN mutations, heterogeneous LOH, and/or discordant MI patterns. Thus, 35% of synchronous tumors were monoclonal, 47% were polyclonal, and 18% were undetermined. The favorable prognosis of synchronous endometrioid carcinomas may be due to the occurrence of PTEN mutations in both independent and metastatic tumors, the MI-positive independent primary tumors, and the low frequency of LOH.

Adult↗