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To clarify the relationship between angiogenesis and the early development of colon cancer, expression of platelet-derived endothelial cell growth factor (PD-ECGF), a known angiogenic and endothelial cell chemotactic factor, was examined in 119 human colon premalignant adenomas and colon carcinomas. Localization of PD-ECGF was assessed by immunocytochemistry in 70 nonpolypoid growth (NPG) lesions that represented 29 carcinomas (NPG carcinomas) and 41 adenomas (NPG adenomas) and 49 polypoid growth (PC) lesions that included 15 carcinomas (PG carcinomas) and 34 adenomas (PC adenomas). Simultaneously, the expression of tranforming growth factor alpha (TGF alpha) and epidermal growth factor receptor (EGFR) were examined in serial sections from these lesions. Twenty (68.9%) of 29 NPC carcinomas and 20 (48.7%) of 41 NPC adenomas exhibited positive staining for PD-ECGF, whereas 15 (100%) of 15 PG carcinomas and 27 (79.4%) of 34 PG adenomas expressed PD-ECGF. There was a statistically significant difference in the frequency of PD-ECGF expression between NPG adenomas and PG adenomas (p<0.01). In addition, the incidence of PD-ECGF expression was higher in PG carcinomas than in NPG carcinomas (p<0.05). Positive staining for TGF alpha and EGFR was detected in 14 (48.2%) and 10 (34.5%) of 29 NPG carcinomas, respectively, whereas, 17 (41.5%) and 13 (31.7%) of 41 NPG adenomas expressed TGF alpha and EGFR, respectively. A significant trend for coexpression of PD-ECGF and TGF alpha was detected in either NPG adenomas (p<0.05) or PG adenomas (p<0.01). These data demonstrate that PD-ECGF may be involved in the early stages of colon cancer development during the adenoma-carcinoma transition and additionally that angiogenesis which may be induced by PD-ECGF and/or TGF alpha could play an important role of colon cancer development.

Histone deacetylase inhibitors such as sodium butyrate or (R)-trichostatin A {(R)-TSA; 7- [4-(dimethylamino) phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2, 4-heptadienamide} have been reported to modulate the proliferation and differentiation of certain cell types. In this study, we analyzed the effects of these agents on KM12 human colon carcinoma (HCC) cells in culture. We found that (R)-TSA induced cell flattening, inhibited anchorage-dependent and anchorage-independent growth, increased the level of the differentiation marker carcinoembryonic antigen, and increased the expression of gelsolin, a candidate tumor suppressor, in these HCC cells. Cells treated with (R)-TSA for 3 h exhibited a high degree of histone (primarily H4) acetylation. (R)-TSA exerted these effects at concentrations in the range between 0.1 to 1 mu M that are at least 1,000 times lower than those required to achieve similar effects by n-butyrate. Trichostatin C, which exhibits some histone deacetylase inhibitory activity but not the analogs (S)-TSA or (R)- or (S)-trichostatic acid, which lack histone deacetylase inhibitory activity, also showed some growth inhibitory activity. These results indicate that histone deacetylase inhibitors may lead to suppression of the transformed phenotype and enhanced differentiation in the KM12 HCC cells.

The efficiency of gene transfer into human cancer cells from digestive tract was evaluated using a replication-deficient recombinant adenovirus (Ad) vector harboring a lacZ gene of E. coli as a reporter gene (AxCALacZ). Average percent X-gal staining of esophageal cancer cell lines was 46%, that of gastric cancer cell lines 82% and that of colon cancer cell lines 70% at 3 days after Ad vector infection. X-gal staining in vitro continued 2 months after infection. By the direct injection of adenovirus vector to the tumors in nude mice, a certain percentage of tumor cells was stained by the X-gal. Colon26 cell line infected with AxCALacZ was implanted in BALB/c mice immunized with AxCALacZ, and tumor growth was suppressed. We presume this was due to anti-adenoviral immunity.

Harmonic competition is a learning strategy based upon winner-take-all or winner-take-quota with respect to a composite of heterogeneous subcosts. This learning is unsupervised and organizes itself. The subcosts may conflict with each other. Thus, the total learning system realizes a self-organizing multiple criteria optimization. The subcosts are combined additively and multiplicatively using adjusting parameters. For such a total cost, a general successive learning algorithm is derived first. Then, specific problems in the Euclidian space are addressed. Vector quantization with various constraints and traveling salesperson problems are selected as test problems. The former is a typical class of problems where the number of neurons is less than that of the data. The latter is an opposite case. Duality exists in these two classes. In both cases, the combination parameters of the subcosts show wide dynamic ranges in the course of learning. It is possible, however, to decide the parameter control from the structure of the total cost. This method finds a preferred solution from the Pareto optimal set of the multiple object optimization. Controlled mutations motivated by genetic algorithms are proved to be effective in finding near-optimal solutions.

With the aim of increasing complete response rates and improving survival in cisplatin (CDDP)-based combinations (CDDP + 5-fluorouracil (5FU) and/or CDDP+methotrexate (MTX)+bleomycin (BLM) of refractory advanced head and neck cancer, we scheduled 21 patients to receive PEM and Long CF, PEM regimens consisting of CDDP (P) Etoposide (Etop) (E) and mitomycin-C (MMC) (M) (CDDP 60 mg/m2/2 hr. infusion on day 1; Etop 40 mg/m2/1 hr. infusion on day 1, 2, 3; MMC 7 mg/m2 iv bolus on day 1). Of 12 patients evaluable for response, 2 CR, 3 PR were realized, with an overall response rate of 42%. Myelosuppression was the major side effect, and thrombocytopenia (8% greater than WHO grade III) was the dose-limiting toxicity. Long CF consisted of CDDP (C) and 5FU (F) (CDDP 8 mg/m2/2 hr. infusion on day 1-5, 8-12, 15-19, 22-26; 5FU 300 mg/m2/24 hr. infusion or tegaful.uracil (UFT-E) 400 mg/m2 P.O. on day 1-28. Of 8 patients evaluable for response, 3 PR were realized, with an overall response rate of 38%. N&V and leukopenia were the major side effects. These adverse reactions were all transient. We concluded that these two regimens produced beneficial effects in patients with advanced recurrent head and neck cancer which had already been treated with CDDP-based combinations.

The toxic effects of long-term administration of cadmium (Cd) on the kidneys, liver, and hind leg bones were studied histologically and roentgenologically in 29-day-old female ICR-strain mice separated into groups variously fed 1) a commercial (calcium [1.17%], vitamin D [220IU/100g], vitamin E [10mg/100g]) diet, 2) a low Ca (0.18% diet, 3) a low Ca and low D (50IU/100g) diet, and 4) a low Ca, low D and low E (5mg/100g) diet. Though the levels of vitamin D and vitamin E were designed to be low in each diet, their amounts fulfilled the nutritional requirements. Three subgroups in each category were fed Cd at dietary concentrations of 0, 20 or 40 ppm. After 12, 18 or 24 months on these diets the mice were sacrificed. 1) In the groups fed the commercial diet containing Cd, prominent swelling of the glomerulus and thickening of the basement membrane of glomerulus were observed. This did not occur in the groups fed the commercial diet without Cd. 2) In the groups fed the Cd-added low-Ca diet the following findings were more prominent compared with the low-Ca diet group. In the kidneys, swelling of the glomerulus, hyaline casts in tubular lumina and cellular infiltration of the interstitial tissue were present. In the liver, cellular infiltration on the interstitial tissue were present. In the liver, cellular infiltration of the interstitial tissue occurred. In the hind leg bones, thinning of trabeculae and ossification of the Achilles's tendon were seen. 3) In the Cd-added low-Ca, D diet groups, there was atrophy of glomerulus, thickening of basement membrane of glomerulus, and atrophy of tubular epithelial cells in the kidneys, while in the liver, binuclate cells, anisonucleosis and enlargement of Kupffer cells were seen. In the hind leg bones, thinning of the cortex and trabeculae were present. All of these findings were more prominent in this group than in the low-Ca, group. 4) In the Cd-added low-Ca, D, E, diet groups subjects the following findings were more prominent than in the low-Ca, D, E, diet group. In the kidneys, there was swelling of glomerulus and in the liver, there were binuclate cells, anisonucleosis, and cellular infiltration into interstitial tissue. In the hind leg bones, thinning of the cortex and trabeculae, a decrease of cartilage cells and a decrease of osteocytes were seen. These histological and roentgenological changes were seen to increase in a dose-dependent manner with the amount of dietary Cd.(ABSTRACT TRUNCATED AT 400 WORDS)

To reveal the signaling pathway leading to oncogenecity of human cancer cells, we examined the expression and tyrosine-phosphorylation of phosphatidylinositol (PI)-3 kinase in cancer cell lines. Of the 14 cell lines examined, two poorly differentiated human gastric cancer cell lines, NUGC-4 and MKN-45, which were previously found to have aberrant elevation of tyrosine phosphorylation showed elevated levels of PI-3 kinase 85-kDa subunit expression. In these cells, tyrosine-phosphorylation and overall activity of PI-3 kinase were apparently elevated, compared with normal human fibroblasts and another well differentiated gastric cancer cell line, MKN-28. Treatment of these cells with tyrosine kinase inhibitor, genistein, strongly suppressed the PI-3 kinase activity. Furthermore, wortmannin, a potent inhibitor of PI-3 kinase, strongly suppressed the growth of these gastric cancer cells. These results suggest that the growth signaling via tyrosine phosphorylation is required for the activation of PI-3 kinase in NUGC4 and MKN-45, and that this activation plays an important role in oncogenic growth of these cells. However, these two cell lines showed different responses of PI-3 kinase to acid-treatment and tyrosine kinase inhibitors. In MKN-45, activation of PI-3 kinase appeared to be constitutive, and could be relevant to the oncogenic nature of the cell line.

Positron emission tomography scans were performed on brains of homozygous and heterozygous English setters with neuronal ceroid-lipofuscinosis (NCL) from 13 months of age to 24-25 months of age for homozygous dogs and to 38 months for heterozygous dogs, respectively. After iv injection of 18F-fluorodeoxyglucose (FDG), 7 coronal brain scans as well as sequential arterial blood samplings were performed for 45 min under pentobarbital anesthesia. From these data, three different functional images (DAR (standardized uptake value), FDG uptake (fractional uptake) and glucose uptake) were reconstructed and quantitatively analysed. In the age range from 13 to 15 months, glucose images were comparable for both homozygous and heterozygous dogs, so that no differentiation was possible between healthy and diseased dogs on the basis of PET findings. Between 18 and 24 months of age, a drastic decline in glucose metabolism was observed in homozygous dogs, while the decline in glucose utilization was very mild in this period for heterozygous dogs. Furthermore, in PET scans, cerebral atrophy and ventricular enlargement were clearly shown in homozygous dogs. Consequently at the age from 20 to 24 months, a clear differential diagnosis between healthy (heterozygous) and diseased (homozygous) dogs became possible even if the clinical symptoms were still not clear in the latter. We conclude that the biochemical alterations in the brain in canine NCL occurs and progresses very rapidly in the last quarter of their lives.

There have been many studies on the effects of gravity on animals and humans. In particular, weightlessness and the time course of physiological shifts in space acclimation are the most significant problems in a space environment. In a laboratory setting, tail suspension in rats has been utilized for simulation of weightlessness. We therefore utilized this technique in order to study the influence of microgravity on blood constituents in rats. It was clarified that some blood biochemical parameters were effected for the duration of suspension exposure, and they are reported here.

The effects of retinoic acid (RA) analogues, Am80 and Ch55, on acute myeloblastic leukemia (AML) cells, acute promyelocytic leukemia (APL) cells, and normal bone marrow (BM) cells, were studied in vitro. These analogues have different binding affinity to RA receptors and cellular retinoic acid binding proteins (CRABP). All-trans RA (ATRA) showed various effects on the proliferation of AML cells and BM cells. These analogues showed similar effects. Regarding the differentiation of APL cells into neutrophils, Ch55 and Am80 were more potent than ATRA. Ch55, which does not bind to CRABP, may overcome the clinical problem of retinoid-resistance due to the induction of CRABP.

Deterioration of vital functions is observed in living organisms in microgravity. However, this deterioration can be arrested by adequate exercises. In this study, utilizing tail suspension in rats to simulate microgravity, we examined the influence of running exercise every other day on blood constituents, visceral parameters, and muscles.

Hyperplastic alveolar nodule (HAN) is a representative preneoplastic state in mammary glands of mice. We investigated the effect of Sho-saiko-to (SST; a Japanese modified traditional Chinese herbal medicine containing seven medicinal plants) on the formation and growth of HAN and mammary tumour growth in SHN virgin mice which showed a high incidence of spontaneous mammary tumours. Chronic oral administration of SST reduced the number and the area of HAN and mammary thymidylate synthetase (TS) activity with slight decrease of serum prolactin level. In the established mammary tumours of mice, 20-day administration of SST reduced the activity of TS and thymidine kinase (TK) with slight reduction of serum prolactin level, though the significant change of mammary-tumour growth was not observed. These results indicate that SST may prevent the mammary tumourigenesis by suppression of the de novo pathway for pyrimidine nucleotide synthesis and the mammary tumour growth by suppression of the salvage pathway as well as the de novo pathway in mice.

The purpose of present study is to know the effects of 20 days bed-rest on cardio-respiratory functions during sub-maximal exercise in different body positions which were in sitting, supine and 30 degrees head-down position respectively.

Chaos and fractal responses from an artificial neural cell stimulated by a periodic square wave are discussed. The dynamics are described by an autonomous equation, and the one-dimensional return map is derived explicitly. The relation between the exciting pulse-width tau(1), and the excited rate gamma(e) which is the number ratio of input pulses and output pulses investigated. Mathematical evidence for gamma(e) to be Cantor function for tau(1) is given. It corresponds to fractal responses. A condition for observable chaos generation in responses from the cell is proved. This condition is described only by parameters. Some of the theoretical results are verified by laboratory experiments.

Expression of src related proto-oncogenes in non-Hodgkin's lymphomas and non-malignant lymph nodes was analyzed by means of in situ hybridization assays with biotinylated DNA probes. In 36 cases of non-Hodgkin's lymphomas, both c-mos and c-abl were expressed in 27 cases, and c-erbB and c-src were expressed in 15 cases and 7 cases, respectively. No case expressed c-fps or c-yes. On the contrary, in 11 cases of non-malignant lymph nodes c-erbB and c-mos was expressed in only 3 cases. No other proto-oncogenes were expressed. Lymphomas in general express multiple proto-oncogenes simultaneously. A variety of combinations of expressed proto-oncogenes were observed suggesting diversity among non-Hodgkin's lymphomas in biological characteristics. However, a clear association with the expression of a single proto-oncogene or the number of expressed proto-oncogenes with T cell / B cell types, or the histopathological classification of NHL, or disease prognosis was not observed.

The Brown Norway Katholiek (B/N-Ka) strain rat is the only animal strain that demonstrates deficiency in plasma HMW- and LMW-kininogens with a low level of prekallikrein. We developed an RIA for rat HMW-kininogen, LMW-kininogen, and T-kininogen, and using them measured these proteins in B/N-Ka and normal strain (B/N-Ki) rats. Plasma level of immunoreactive as well as kinin-releasing HMW-kininogen and LMW-kininogen in B/N-Ka rats was either around 3% of their levels in the normal B/N-Ki rats. The cause of the plasma deficiency of kininogens in the B/N-Ka strain was examined by 35S-methionine uptake of primary cultures of hepatocytes from the B/N-Ki and B/N-Ka strains. The results indicated that the kininogens were synthesized in the B/N-Ka liver but not secreted into the medium. Northern blot analysis of poly A(+)RNA extracted from the livers of both strains demonstrated that the band corresponding to mRNA of HMW-kininogen was present in the mRNA from B/N-Ka liver as well as in that from the B/N-Ki one. The band was similar in size and intensity in both cases. This result confirmed the data that immunoreactive HMW-kininogen was found in the liver of B/N-Ka rats (12). Thus, the cause of plasma deficiency of HMW-kininogen in the mutant appears to be secretory defect in nature. The B/N-Ka rats showed less reactivity to the inflammatory stimulus, such as carrageenin or kaolin, but the strain expressed almost the same response as normal rats to phorbol ester (PMA) or zymosan for pleurisy induction. These results indicate that kinin may play an important role in exudation in carrageenin- and kaolin-induced edema but not in that induced by PMA or zymosan. The deficient rat strain could be useful for differentiation of the inflammatory model which shows involvement of the kinin system.

A typical image processing neuro chip consists of a regular array of very simple cell circuits. When it is implemented by a CMOS process, two stability issues naturally arise. First, parasitic capacitors of MOS transistors induce temporal dynamics. Since a processed image is given as the stable limit point of the temporal dynamics, a temporally unstable chip is unusable. Second, because of the array structure, the node voltage distribution induces spatial dynamics, and it could behave in a wild manner, e.g. oscillatory. The main contributions are: (i) a clarification of the spatial stability issue; (ii) explicit if and only if conditions for the temporal and the spatial stability in terms of circuit parameters; (iii) a rigorous explanation of the fact that even though the spatial stability is stronger than the temporal stability, the set of parameter values for which the two stability issues disagree is of (Lebesgue) measure zero; and (iv) theoretical estimates of the processing speed.

The Sertoli cell (blood-testis) barrier in the boar was visualized by the freeze-fracture, deep-etch, rotary-replication technique. Three kinds of cross-bridging structures were clearly recognized in the following three ectoplasmic specialization (ES) regions; (1) cross-bridges in the intercellular space between adjacent Sertoli cell membranes; (2) cross-bridges in the space between the Sertoli cell membrane and microfilament bundles; and (3) cross-bridges in the space between microfilament bundles and subsurface cisternae. Results from immunolocalization, vinculin and alpha-actinin were recognized in the Sertoli cell barrier. Our findings show that these structural elements of the Sertoli cell barrier are held together by these cross-bridging structures, and provide important morphological evidence that implicates the ES in the dynamic function of the microfilament bundles of the Sertoli cell barrier.

A new method is proposed to subtract the count of scattered photons from that acquired with a photopeak window at each pixel in each planar image of single-photon emission computed tomography (SPECT). The subtraction is carried out using two sets of data: one set is acquired with a main window centered at photopeak energy and the other is acquired with two subwindows on both sides of the main window. The scattered photons included in the main window are estimated from the counts acquired with the subwindows and then they are subtracted from the count acquired with the main windows. Since the subtraction is performed at each pixel in each planar image, the proposed method has the potential to be more precise than conventional methods. For three different activity distributions in cylinder phantoms, simulation tests gave good agreement between the activity distributions reconstructed from unscattered photons and those from the corrected data.

After fixating the center, human subjects were required to track two visual targets (T1, T2) presented in the horizontal plane in a dark room. When T2 was lit 200-600 msec after T1, T2 was given and also second saccadic eye movement unsolicited at various positions of eye and head during the course of gaze (eye position in the orbit plus head position) shift toward T1. Under all circumstances, the final gaze reached T2 without significant difference from the trials made by eye movement alone, suggesting head and eye positions are perfectly monitored to adjust the amplitude of gaze. As head velocity increased, gaze velocity increased and duration decreased with little change in eye velocity, contrary to the previous assumption that vestibulo-ocular reflex adjusts the time course of gaze shift to be constant.

It has been pointed out that the silicone oil tamponade can result in complications such as corneal damage, elevation of intraocular pressure and retinal toxicity against. The effect of silicone oil on the ocular tissues was investigated histopathologically by injecting silicone oil into the anterior chamber of the eyes of rabbits. In addition, in order to study its effect on the retina, silicone oil was injected into the vitreous cavity after vitrectomy. The eyes were extracted 3, 6, 9, 12 and 18 months after injection and various tissues were observed by light and electron microscopy. Silicone oil particles were first observed in the retro-corneal membrane 18 months after injection. In the trabecular meshwork silicone oil particles were seen for the first time 12 months after injection. Migrating cells engulfing silicone oil particles were attached to the internal limiting membrane of the retina three months after injection. Twelve and 18 months after injection, silicone oil particles passed through the internal limiting membrane and were engulfed by Mueller cells.

This report deals with the development of human conjunctival goblet cells. Fifty-six eyes of human embryos and fetus ranging from 5 to 41 weeks of gestational age were used in this study. Glycosaminoglycans in the goblet cells were investigated histochemically using 1% alcian blue staining (pH = 2.5) and PAS reagent staining and sialidase (neuraminidase) digestion. At 8 weeks, goblet cells appeared in the forniceal area, and they extended to the palpebral and bulbar conjunctiva. These cells were already similar to adult goblet cells. Alcian blue staining and the enzyme digestion method revealed the existence of sialic acid in the goblet cells from 9 weeks. These results suggest that at the early developmental stage the goblet cells develop from the forniceal area. It is also indicated that the goblet cells in the early developmental stage are already similar to cells in the adult stage because they contain mainly sialic acid as glycosaminoglycans.

The changes of viscosity, optical reflection and electrical resistivity of blood due to flow are dependent on the orientation and deformation of red cells. From electrical point of view, it can be assumed that blood is suspension of small insulating particles (red cells) in conductive fluid (plasma) when the frequency of supplied voltage is lower than several hundreds KHz. When blood flows, red cells deform and orient in flow direction. Therefore, flowing blood shows anisotropic electrical and optical properties. In steady flow, blood resistivity longitudinal to flow decrease with flow rate, and transverse one increases. Blood flow in living body is not steady but pulsatile. We measured both longitudinal and transverse resistivity changes, optical reflection change and viscosity change of sinusoidally flowing blood in a rectangular conduit. The results are 1) during one period of sinusoidal flow the longitudinal resistivity change is opposite to that of transverse one, 2) the waveform of reflection light change is similar to that of resistance change, and 3) minimum points of both longitudinal resistivity and viscosity changes do not appear at the moment when flow is zero but are delayed. When the amplitude of sinusoidal flow is small and oscillation frequency is high, the phase difference between the zero crossing period of flow and the period of minimum change in resistivity, increases up to 90 degrees. Viscosity of blood decreases with increase of amplitude and frequency of sinusoidal flow.