Adjuvant immunotherapy using fibroblasts genetically engineered to secrete interleukin 12 prevents recurrence after surgical resection of established tumors in a murine adenocarcinoma model

BACKGROUND: To explore effective therapeutic strategy against cancer of the gastrointestinal tract, tumor vaccination using fibroblasts secreting interleukin-12 (IL-12) was developed as an adjuvant therapy against murine tumor after surgical resection. METHODS: Initially, IL-12 was genetically engineered into fibroblasts (IL-12/3T3 cells), and then we evaluated in vivo and in vitro antitumor effects. In the vaccination model, irradiated C-26 tumor mass was reinoculated intradermally with IL-12/3T3 cells in mice as a tumor vaccine to examine how much it suppresses tumor recurrence. RESULTS: IL-12/3T3 cells producing 7.2 ng/10(6) cells/24 h murine IL-12 in vitro exerted dose-dependent potent tumor suppression when coinoculated with C-26 cells in vivo. Specific immunity was also acquired in 63% of mice in vivo. In the vaccination model, protective immunity was developed in 70% of mice that were inoculated with irradiated tumor mass and IL-12/3T3 cells. In addition, local recurrence was not observed in vaccinated mice, although 44% of control mice had recurrence. CONCLUSIONS: Coinoculation of genetically engineered fibroblasts secreting IL-12 with irradiated tumor mass was proved to be an effective tumor vaccine. This system of vaccination is easily applicable to clinical situations, particularly to human gastrointestinal tract cancers.     

Age-related differences in IgA nephropathy

To clarify age-related differences in the characteristics of IgA nephropathy, we investigated 117 patients of all ages. The number of patients in the second decade of age was larger than that in the other age decades. There was no difference in sex in all age brackets. About one half of the patients under ten years of age presented as acute nephritis, but their prognosis was favorable. Patients over 10 years, most of whom were detected by chance, tended to have a greater degree of proteinuria, a lesser degree of creatinine clearance, a higher frequency of hypertension, and a higher level of serum cholesterol with age. Although the intensity of mesangial cell proliferation was not changed, the grade of glomerulosclerosis, interstitial change, and arteriosclerosis increased and the prognosis became poor as age advanced. Treatment with corticosteroids and antiplatelet agents was less effective in adults, especially in the older age brackets than in children because the frequency of histologically chronic lesions increased. In these cases, lipid-lowering agents and angiotensin-converting enzyme inhibitors may be helpful in preventing the progression.     

Evaluation of child-rearing environmental factors that affect the occurrence of sudden infant death syndrome: interview conducted by public health nurses]

PURPOSE: We examined the child-rearing environmental factors that affect the occurrence of sudden infant death syndrome (SIDS) by using a nation-wide survey. METHOD: Infants who died due to SIDS between January 1996 and June 1997 in Japan were identified from death certificates. Controls of the same sex, birthplace, and birth months as the corresponding SIDS were chosen from birth certificates. Interviews of both cases and controls were undergone in January and February 1998 by public health nurses. RESULTS: The following Child-rearing factors exhibited a significant relationship with the occurrence of SIDS: 1. Concerning the sleeping position, the prone position was associated with increased risk compared to the supine position, with an odds ratio of 3.02 (95% c.i. 2.07-4.65). 2. Regarding the feeding method, artificial feeding only demonstrated a higher risk than breast feeding only, with an odds ratio of 4.92 (95% c.i. 2.78-9.63). 3. With regard to smoking, infants with both parents who smoked exhibited a higher risk than infants where neither parents smoked, with an odds ratio of 3.50 (95% c.i. 1.74-8.32).     

Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors.

To gain insights into the cellular responses evoked by nitric oxide (NO), we have studied the effects of NO donors with distinct chemistries on the expression of heme oxygenase-1 mRNA by northern blot analysis. The expression levels of heme oxygenase-1 mRNA were increased significantly in DLD-1 human colorectal adenocarcinoma cells by treatment with each of three NO donors: sodium nitroprusside (SNP), S-nitroso-L-glutathione (GSNO), and 3-morpholinosydnonimine (SIN-1). A combination of SIN-1 plus SNP or GSNO additively increased heme oxygenase-1 mRNA expression, whereas synergistic induction was seen with SNP plus GSNO. The SNP-mediated induction was not affected noticeably by extracellular superoxide dismutase, catalase, or mannitol, while the induction by SIN-1 was attenuated by superoxide dismutase. Thus, the SNP-mediated induction of heme oxygenase-1 mRNA expression may be independent of reactive oxygen species, and the induction by SIN-1 is mediated partly by peroxynitrite, which is generated by immediate reaction of NO and superoxide anion. Transient transfection assays suggested that treatment with SNP, but not with GSNO or SIN-1, increased the expression of a reporter gene through a cis-acting element, including the cadmium-responsive element, of the human heme oxygenase-1 gene. These results suggest that SNP induces heme oxygenase-1 mRNA expression through a mechanism different from that for GSNO or SIN-1. We therefore propose that induction of heme oxygenase-1 represents a common cellular response in sensing the signals evoked by distinct NO donors.     

Localization of B2 bradykinin receptor mRNA in the rat retina and sclerocornea

The expression of the B2 bradykinin receptor (BKR) mRNA in the adult rat eye was investigated by RNA blot and in situ hybridization analyses. Blot hybridization analysis of poly(A)+ RNA from the whole eye identified RNA species of 6000 and 4000 nucleotides, consistent with those observed in brain, lung, kidney and uterus. In situ hybridization analysis using digoxigenin-labeled riboprobes revealed intense labeling in the retinal ganglion cell layer and in a population of cells adjacent to the sclerocorneal junction. These data suggest that the B2 BKR is involved in biological processes in both retina and sclerocornea.     

Differences of milk-transmitted murine mammary tumor virus (MMTV) among mouse strains.

To clarify the oncological differences of milk-transmitted Murine Mammary Tumor Virus (MMTV) in various strains, BALB/c mice were foster-nursed on C3H/He, GR, DDD, DDD/1-Mtv-2/Mtv-2 and FM strains and observed for the development and morphology of mammary tumors, followed by testing tumors for pregnancy dependence (PD) after transplantation. MMTV were different in tumorigenicity and morphology and PD of induced tumors among the mouse strains. These differences of MMTV appeared not to be parallel with the difference in specificity of superantigens which are encoded by MMTV on the previous report. Interestingly, host factors influenced the properties of MMTV produced by the same endogenous Mtv gene.     

Immunolocalization of the components of the plasminogen activating system in breast carcinoma tissue

The plasminogen activating system plays an important role in the progression of carcinomas and the significance of this system in various carcinomas has been thoroughly investigated. To follow up these investigations, we examined the immunolocalization of the components of the plasminogen activating system, namely the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and two inhibitors (PAI-1 and PAI-2), in 72 cases of breast carcinomas. uPA, uPAR and PAI-1 were uniformly expressed in 75.0%, 84.7% and 80.6% of the cases respectively, although their expression was less uniform in T3 or larger carcinomas (p<0.05). Furthermore, the immunoreactivities of these three proteins were often very similar in the lesions. PAI-2 expression was, to the contrary, statistically less extensive (p<0.01)than PAI-1, and only 52.8% of the cases were uniformly positive. The incidence of PAI-2 expression was statistically lower in T3 or larger carcinomas (p<0.01), and in stage III (p<0.01) and grade III carcinomas (p<0.05). Moreover, PAI-1 immunoreactivity was more commonly found in lymph node positive (p<0.05), T3 or larger and stage III carcinomas than PAI-2 immunoreactivity. These findings suggest that uPA, uPAR and PAI-1, whose expression should be regulated by carcinomas once they have grown to a certain degree, work in association with one another, probably promoting carcinoma progression, while PAI-2 might act as the inhibitor in this system. Furthermore, breast carcinomas containing more PAI-I than PAI-2 are more active in respect to both local proliferation and metastasis.     

Iridoid glucosides of Melampyrum laxum

From the aerial part of MALAMPYRUM LAXUM, M IQ. three iridoid glucosides were isolated and identified as melampyroside, mussaenoside and aucubin.