Biomedical subjects
Publications and source records attributed to H Kitamura.
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PURPOSE: We investigate the roles and possible interactions of the retinoblastoma, transforming growth factor-beta 1 and c-myc genes in bladder cancer. MATERIALS AND METHODS: The expression of these 3 genes was examined in 38 biopsy specimens of human bladder cancer by immunohistochemical analysis or Northern blotting. RESULTS: Loss of the retinoblastoma protein expression was most significantly correlated with high grade cancer. Over expression of c-myc or expression of transforming growth factor-beta 1 was less associated with tumor grade or stage, although c-myc over expression defined stage Ta against other stage tumors, since no stage Ta lesions had increased c-myc expression. Finally, loss of retinoblastoma gene function did not correlate with either c-myc or transforming growth factor-beta 1 expression. CONCLUSIONS: These results further support that retinoblastoma gene inactivation is an important factor in the progression of bladder cancer, and suggest that transforming growth factor-beta 1 and c-myc are not regulators or are not regulated by retinoblastoma gene expression.
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We report a rare case of renal oncocytoma containing occasional "chromophobe" cells. This case suggests an intimate relationship between oncocytoma and "chromophobe" renal cell carcinoma.
Rapid endothelialization of the inner surface was reported in an autologous tissue-seeded vascular prosthesis. We applied a three-dimensional in vitro culture system to elucidate the precise mechanism of rapid endothelial coverage of a tissue-seeded vascular prosthesis. Human venous, omental, adipose and striated muscle tissue fragments were harvested from surgical specimens. They were embedded in collagen gel, and 2.0 x 10(5) bovine aortic endothelial cells (BAECs) were seeded on the gel. The number of BAECs was counted on Days 2 and 7. Growth rate of BAECs was facilitated on the collagen gel with omental and striated muscle tissue fragments (p < 0.05). Factor VIII-negative spindle cells migrated around tissue fragments, especially around the omental and striated muscle tissue fragments. Rapid endothelialization of a tissue-seeded vascular prosthesis may result from facilitation of EC proliferation by viable tissue fragments and migrated cells. These results confirm tissue fragments regulate EC growth, and are useful as bioengineering tools.
The antiproteinuric effect of angiotensin I-converting enzyme (ACE) inhibitors in patients with renal diseases of various origins has been well recognized. However, individual responses regarding the degree of decrease in urinary protein excretion appear to vary considerably. The mechanism underlying this variable response to ACE inhibitors has not been clarified yet. A possible role of ACE gene insertion/deletion (I/D) polymorphism in the responsiveness to antiproteinuric effect of ACE inhibitors is examined. Thirty-six patients with proteinuria (23 men and 13 woman; mean age, 47 +/- 13 yr) were studied. These patients were classified into two groups on the basis of the percent decrease in their urinary protein excretion: the effective group, those with a decrease in proteinuria (18 patients, -64 +/- 19%) and the noneffective group (18 patients, +13 +/- 40%). A 287-base pair (bp) I/D polymorphism in the ACE gene was examined by polymerase chain reaction. The allelic frequencies of the ACE gene were I/D = 0.53/0.47 in the effective group and I/D = 0.81/0.19 in the noneffective group. The difference in the allelic frequencies between the two groups was significant (chi 2 = 6.25, P = 0.0114 < 0.05). Furthermore, the difference in the responsiveness of proteinuria to ACE inhibition between genotype II versus genotype ID + DD was statistically significant (chi 2 = 4.05, P = 0.0442 < 0.05). There was no significant difference between the two groups with regard to initial urinary protein level, blood pressure, renal function, and daily sodium intake. The genetic susceptibility to the antihypertensive effect of ACE inhibitors was also studied, but no significant relation was observed. This study suggests the association of ACE gene I/D polymorphism with the antiproteinuric efficacy of ACE inhibitors in patients with proteinuria.
Tumor metastasis to the hypophyseal system has rarely been reported with either clinical or radiographic evidence. A 52-year-old woman presented with polydipsia, polyuria, and loss of appetite. She was diagnosed as having diabetes insipidus caused by pituitary micrometatasis of lung adenocarcinoma. After she had been treated with radiation therapy to the pituitary gland, the gland size was reduced as confirmed by magnetic resonance imaging, and her urine volume decreased. However, meningitis carcinomatosa appeared later. This was a rare case of secondary diabetes insipidus due to pituitary metastasis of lung cancer.
To elucidate the effect of interleukin-6 (IL-6) on bone and bone marrow (BM), human IL-6 transgenic mice (hIL-6 tgm) were produced. Their bone and BM were examined histologically, radiologically, histomorphometrically, and hematologically on a temporal basis. hIL-6 tgm showed histologically evident neutrophilia in BM. Increase in precursors of granulocytes and monocytes in hIL-6 tgm was demonstrated by an assay for colony forming unit in culture (CFU-C) of BM cells. Decrease in osteoblasts and osteoid and suppression of primary spongiosa formation were predominantly observed in hIL-6 tgm at 14 weeks old, the terminal stage of life for hIL-6 tgm. An assay for colony forming unit in fibroblastic (CFU-F) of BM cells revealed a decrease in osteoblast precursor (with regard to alkaline phosphatase-positive colonies) in hIL-6 tgm at 15 weeks old. Histomorphometry demonstrated a decrease of both osteoclast number and bone resorption in hIL-6 tgm. These results suggested that enhanced granulocytic hematopoiesis, suppressed bone turnover, and alteration of cellular population in stromal cells in BM occurred in hIL-6 tgm. Thus we provide new findings that facilitate understanding of cellular interrelationships among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in BM.
A 54-year-old man developed renal failure, with renal biopsy findings of diffuse mesangiolysis with severe endocapillary proliferation. Immunohistochemical studies revealed that CD3-CD56-CD57+ large granular lymphocytes were present predominantly within glomerular tufts. Intercellular adhesion molecule-1 was more preferentially expressed in the glomerular endothelial cells with severe endocapillary proliferation as compared to those without endocapillary proliferation. These findings suggest that CD57+ large granular lymphocytes caused glomerular endothelial injury by a cell-mediated cytolytic mechanism, resulting in the development of mesangiolysis and microaneurysm formation.
PyNPase (pyrimidine nucleoside phosphorylase) activity and IL-1 alpha were measured in normal and tumor tissues of the specimens resected from gastric cancer patients who had been divided into two groups; one given preoperative 5'-DFUR (oral administration at a mean dose of 10.0 g) and one not given 5'-DFUR (control). PyNPase activities in both groups were higher in tumor than in normal tissues (p = 0.0001), but, less in tumor tissue of the preoperative administration group than the controls (p = 0.0376). IL-1 alpha levels in both groups were higher in tumor than in normal tissues (p < 0.01). Multiple regression analysis of the results showed that IL-1 alpha strongly influenced on PyNPase activity in tumor tissues (higher IL-1 alpha levels resulted in higher PyNPase activities in tumor tissues) (p = 0.0334).
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To elucidate the pathogenesis of bronchioloalveolar lung carcinoma (BAC), we evaluated the lesion size, growth fraction, and p53 overexpression of atypical adenomatous hyperplasia (AAH) and early stage BAC. AAH was classified as showing low grade or high grade atypia. AAH-like carcinoma, presumably very early stage BAC, was distinguished from AAH in that it exhibited remarkable atypia suggestive of malignant potential and from overt BAC in that it lacked unequivocal malignant features, including invasive/destructive growth. The growth fraction was determined immunohistochemically in terms of the Ki-67 labeling index. The overexpression of p53 was evaluated by assessing the nuclear accumulation of immunoreactive p53 protein. Both the lesion size and the growth fraction increased from low grade AAH, to high grade AAH, to AAH-like carcinoma, and to overt adenocarcinoma. The overexpression of p53 in AAH-like carcinoma was similar to that in overt adenocarcinoma and was more frequent than that in AAH. Our findings indicate that AAH, AAH-like carcinoma, and overt BAC represent different categories, although the cellular events occurring in these lesions presumably represent a continuous spectrum of the changes that are reflected in the cytomorphology and lesion size. The findings here suggest that AAH and AAH-like carcinomas constitute a population of heterogeneous lesions representing different steps toward overt BAC.
A system for combined in vitro and in vivo culture of epithelial cells from distal human airways was established. Lung tissues that appeared to be generally normal were obtained from lungs removed surgically from patients with lung cancer. Small pieces of peripheral lung tissue were placed on culture dishes and cultured in F-12 complete medium containing serum and various growth factors, to obtain outgrown cells. For in vivo culture, rat tracheal grafts were de-epithelialized by freezing and thawing and were then used as culture vessels. Outgrown cells were harvested after 4 weeks of in vitro culture, inoculated into the denuded tracheal grafts, and then implanted into nude mice. For comparative purposes, bronchial fragments were also cultured in vitro and in vivo, by the same method. In vitro efficiency of colony formation was about the same for cells derived from peripheral lung tissue and from bronchial tissue (14.8 +/- 8.9% and 16.0 +/- 4.7%, respectively). Four weeks after implantation, the grafts were retrieved and processed for morphologic evaluation. By that time, grafts in both groups had totally re-epithelialized. Therefore, the growth potential of the cells derived from peripheral lung tissue and from bronchi in vivo appeared to be almost the same. Newly formed epithelial cells in grafts showed the same well-developed pseudostratified columnar form in both groups at 4 weeks. The time course of epithelial cell differentiation was also studied, with outgrown cells from lungs. Two days after implantation, undifferentiated cells were attached to the inner surface of the grafts as a single cell layer, and at 4 days, small cell nests containing mitotic cells were observed. At 1 week, the grafts were totally covered with undifferentiated cells. Over 2 to 3 weeks, differentiated cells (ciliated, secretory, and basal cells) appeared, and the epithelia had become fully developed by 4 weeks. As reported previously, cells that outgrew from lung explants were considered to be derived from bronchioles. Therefore, this system may be useful for studies of growth and differentiation of human bronchiolar epithelial cells under various conditions.
A 31-year-old woman was admitted to our hospital because of cervical and axillar lymph node swelling. A chest X-ray film showed many nodular shadows and a cavity in the left upper lung field. The tuberculin test was positive. Transbronchial lung biopsy and cervical lymph node biopsy were done. Examination of the biopsy specimens revealed epithelial granulomas with caseous necrosis. Thus, pulmonary tuberculosis with systemic lymph node swelling was diagnosed. Examinations during the patient's hospital stay showed that she was not an immunocompromised host. Pulmonary tuberculosis with systemic lymph node swelling occurs only rarely in a non-immunocompromised host.
We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL) tumor suppressor gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positive cases in single strand conformational polymorphism analyses were further characterized by direct sequencing. Somatic mutations were detected in 22 (56%) of 39 clear cell renal carcinomas including 15 deletions, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Nineteen of these mutations predicted to produce truncation of the VHL protein. These mutations mainly occurred in the last one-third region of exons 1, 2, and 3. In addition, loss of heterozygosity of the VHL gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas. No somatic mutations were detected in 8 non-clear cell carcinomas. These results show that the VHL tumor suppressor gene is one of the major tumor suppressor genes in human renal cell carcinomas, especially in the clear cell subtype renal cell carcinoma. Clear cell carcinoma might be distinguished from other pathological types of renal cell carcinomas by molecular genetic techniques.
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Using a serum-free culture method, we investigated the effects of vitamin A on the proliferation of human distal airway epithelial cells. Outgrowth of epithelial cells from lung tissue explants was enhanced by treatment with all-trans retinol at concentrations of 10(-8) to 10(-7) M. The colony-forming activity of cells harvested from the primary culture and replated onto Swiss 3T3 fibroblastic feeders was, in contrast, significantly reduced by 10(-7) M to 10(-5) M retinol. When the primary cells were harvested and subcultured on Primaria plates, population expansion was also inhibited by retinol at 10(-10) to 10(-6) M. We further investigated the cells to determine whether there was any difference in sensitivity to the growth-inhibitory effects of vitamin A between cells from the primary culture incubated with and without retinol. The population increase in cells harvested from the primary culture was inhibited equally in retinol-treated and non-treated cells by subsequent treatment with retinol or retinoic acid, this inhibition being dose-dependent. DNA synthetic activity was also inhibited. Interestingly, both the growth rate and the colony-forming efficiency on feeders were greater in the subculture of cells from the retinol-treated primary culture than in those non-treated. When the cells in the secondary subculture were treated with retinoic acid and replated again, they showed a greater population increase rate than those non-treated. Our results showed that human distal airway epithelial cells isolated from lung tissue were sensitive to the growth-inhibitory effect of vitamin A, but the proliferative potential in some fraction of the epithelial cell population was possibly enhanced by vitamin A treatment.
Viscera slide is the normal, longitudinal movement of the intraabdominal viscera caused by respiratory excursions of the diaphragm. By detecting areas of restricted viscera slide, ultrasonic imaging was used to identify anterior abdominal wall adhesions prior to laparotomy or laparoscopy. Transcutaneous ultrasound examination was performed on 110 patients. A prediction of adhesions was made for each patient and then compared to the findings during subsequent laparotomy or laparoscopy. Only patients with previous abdominal surgery or history of peritonitis demonstrated adhesions. Sensitivity and specificity of viscera slide ultrasound in predicting adhesions were 90% and 92%. Nine out of 10 false results involved misinterpretation of ultrasound images of the lower one-third of the abdomen. Ultrasonic imaging of viscera slide is highly accurate in detecting abdominal wall adhesions. This technique is most useful in guiding the insertion of trocar in laparoscopic surgery, and as a noninvasive method in studying the formation of adhesions.