Preneoplastic and neoplastic growth of xenotransplanted lung-derived human cell lines using deepithelialized rat tracheas

The human lung tumor-derived cell lines A549, Calu-1, Calu-3, HuT292, and SW900 and the transformed human bronchial epithelial cell line TBE-1, that was transfected with the v-Harvey-ras oncogene, were inoculated into deepithelialized Fisher 344 rat tracheas (5 X 10(5) cells/trachea). After the ends of the tracheas were sealed, the tracheas were transplanted into s.c. tissues of nude mice. In a parallel experiment, 1 X 10(6) cells from each of these cell lines were injected s.c. Histological examination of the tracheal transplants 2, 4, 8, 12, and 16 weeks after cell inoculation proved to be of greater usefulness than either clinical or histological observation of the s.c. injection sites. A549, Calu-1, and TBE-1 produced intratracheal neoplastic nodules as early as 2 weeks after cell inoculation. Calu-3, HuT292, and SW900 grew relatively slowly in the tracheas, and simple or stratified epithelia with slight or moderate atypia (preneoplastic lesions) were seen at 2 weeks. After the 4th week, they produced tumor nodules in the tracheal transplants, whereas no tumor cells could be seen at the s.c. injection sites. The human derivation of the cells was confirmed by in situ hybridization using human-specific DNA probes. The intratracheal inoculation and xenotransplantation of human-derived cell lines offers a time-saving alternative to the s.c. inoculation assay for tumorigenicity and is at the same time a potentially valuable approach to studying preneoplastic and neoplastic progression with human cell subpopulations.     

Prognosis for patients with carcinoma in the middle third of the stomach

In 268 of the 1,115 patients (24.0%) with gastric cancer who underwent a curative resection in our clinics, the tumor was located in the middle third of the stomach. The clinicopathological features and prognosis of these patients were divided into two groups, according to site of the tumor: anterior wall (n = 58) vs. other sites (n = 210). Clinicopathological factors did not differ between the two groups. The survival time for patients with a tumor in the anterior group was shorter than that for patients with a tumor in other areas (P < 0.05). The five-year survival rate was 79.3% for patients with an anterior tumor and 91.9% for those with a tumor at a different site. A multivariate analysis indicated lymph node metastasis, serosal invasion, and anterior wall location to be independent prognostic factors indicative of a poor prognosis when the tumor was located in the middle third of the stomach. For such patients, close follow-up is needed to detect possible recurrences. © 1993 Wiley-Liss, Inc.     

Angiotensin-converting enzyme inhibition attenuates hypercholesterolemia and glomerular injury in hyperlipidemic Imai rats.

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. We investigated the effect of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneous hypercholesterolemia and the progressive renal injury in this rat strain. Male Imai rats (n = 7) were treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Body weight, blood pressure, urinary protein excretion and serum constituents were checked and compared with untreated controls (n = 5) up to 38 weeks of age. Enalapril treatment significantly reduced hypercholesterolemia (247 +/- 41 vs. 102 +/- 13 mg/dl, p < 0.01, at 38 weeks) and proteinuria (766 +/- 290 vs. 206 +/- 119 mg/kg/day, p < 0.01, at 38 weeks). The glomerulosclerosis index (SI) was significantly higher in untreated control rats than in the enalapril-treated group (227 +/- 57 vs. 27 +/- 9, p < 0.01). Although we could not clarify whether hypercholesterolemia is a primary event or secondary to the nephrotic syndrome, these results indicate that the ACE inhibitor has the property to protect remnant glomeruli from glomerulosclerosis in male Imai rats as well as in other animal models in which focal and segmental glomerulosclerosis is believed to represent a common pathologic pattern. This rat strain represents a unique model of a spontaneous proteinuria which can provide an important information on the pathogenesis of human focal and segmental glomerulosclerosis.     

Effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-aldosterone system following open heart surgery

The effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-aldosterone system and tissue metabolism, especially those which occur soon after surgery, were studied in 26 patients who required total cardiopulmonary bypass for longer than 60 minutes. These patients comprised 11 who underwent open heart surgery utilizing nonpulsatile cardiopulmonary bypass (Group I) and 15 who underwent open heart surgery utilizing pulsatile cardiopulmonary bypass (Group II). Plasma angiotensin II and serum aldosterene levels were significantly increased one and 5 hours postoperatively in Group I when compared with the preoperative values, whereas no significant elevations were observed in Group II. Plasma angiotensin II and serum aldosterone levels one hour postoperatively in Group II were significantly lower than those in Group I. Lactate levels in the arterial blood were significantly elevated, one and 5 hours postoperatively in both Groups I and II. Moreover, no significant difference was observed in the lactate levels between Groups I and II, one hour postoperatively. In the nonpulsatile group (Group I), plasma angiotensin II levels one hour postoperatively were correlated significantly with the duration of total cardiopulmonary bypass. In conclusion, pulsatile cardiopulmonary bypass offers significant advantages in terms of lower plasma angiotensin II and serum aldosterone levels, when compared with nonpulsatile cardiopulmonary bypass soon after open heart surgery requiring total cardiopulmonary bypass for longer than 60 minutes, however, it does not offer a definite advantage for tissue metabolism.     

Therapeutic effects of liposomal adriamycin in combination with tumor necrosis factor-alpha.

Liposomes as drug carriers in cancer chemotherapy have attracted considerable interest. To enhance the therapeutic effect of Adriamycin entrapped in liposomes (Lip-ADM) on human solid tumors, we investigated the therapeutic effects of Lip-ADM in combination with recombinant human tumor necrosis factor-alpha (rTNF-alpha), which is known to have specific effects on tumor vasculature. rTNF-alpha or saline solution was injected intravenously into nude mice bearing a human colon cancer strain, HC-1, at 1 hour before intravenous administration of Lip-ADM. The significant therapeutic effect of Lip-ADM in combination with rTNF-alpha was demonstrated by the evaluation with tumor growth curve and the actual tumor weights, in comparison with groups of mice treated with saline solution, rTNF-alpha alone, or with a Lip-ADM after saline. Levels of Adriamycin in tumor tissue in the Lip-ADM in combination with rTNF-alpha-treated group were higher than those in Lip-ADM with saline solution-treated group.     

Improved expression of gamma-aminobutyric acid receptor in mice with cerebral infarct and transplanted bone marrow stromal cells: an autoradiographic and histologic analysis.

Recent studies have indicated that bone marrow stromal cells (BMSC) have the potential to improve neurologic function when transplanted into animal models of central nervous system disorders. However, how the transplanted BMSC restore the lost neurologic function is not clear. In the present study, therefore, we aimed to elucidate whether BMSC express the neuron-specific gamma-aminobutyric acid (GABA) receptor when transplanted into brain that has been subjected to cerebral infarction. METHODS: The BMSC were harvested from green fluorescent protein-transgenic mice and were cultured. The mice were subjected to permanent middle cerebral artery occlusion. The BMSC or vehicle was transplanted into the ipsilateral striatum 7 d after the insult. Using autoradiography and fluorescence immunohistochemistry, we evaluated the binding of 125I-iomazenil and the expression of GABA receptor protein in and around the cerebral infarct 4 wk after transplantation. RESULTS: Binding of 125I-iomazenil was significantly higher in the periinfarct neocortex in the BMSC-transplanted animals than in the vehicle-transplanted animals. Likewise, the number of the GABAA receptor-positive cells was significantly higher in the periinfarct neocortex in the BMSC-transplanted animals than in the vehicle-transplanted animals. A certain subpopulation of the transplanted BMSC expressed a neuron-specific marker, microtubule-associated protein 2, and the marker protein specific for GABAA receptor in the periinfarct area. CONCLUSION: These findings suggest that BMSC may contribute to neural tissue regeneration through migrating toward the periinfarct area and acquiring the neuron-specific receptor function.