Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases.

Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA "glucocorticoid response element (GRE)". To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type-1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA "GRE". Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy.

Immunohistochemical study on the expression of c-Fos and c-Jun in human skin wounds.

An immunohistochemical study on the temporal expression of c-Fos and c-Jun, both of which designate proto-oncogene products, was performed on 60 human skin wounds with different post-infliction intervals. In unwounded skin, c-Fos or c-Jun was immunolocalized at the nuclei of the epidermal cells in the basal layer, hair follicle cells and sweat gland cells. During the early inflammatory phase of wound healing, the nuclei of polymorphonuclear cells (probably neutrophils), mainly infiltrating at the wound site, were labeled with anti-c-Fos or -c-Jun antibody. As the wound age increased, the neutrophils had disappeared at the wound site, and both mononuclear cells (probably macrophages) and spindle-shaped fibroblastic cells, which expressed a c-Fos or c-Jun positive reaction in the nuclei, were mainly observed. Morphometrically, the distribution of the c-Fos-positive ratio was very similar to that of the c-Jun-positive ratio; the positive ratio was considerably increased in wound specimens with a post-infliction interval of > or = 1 day, thus indicating the late inflammatory or proliferative phase. This study showed that c-Fos and c-Jun were closely involved in the inflammatory phase as well as the proliferative phase of the wound healing process.

Frequent loss of copy number on the long arm of chromosome 21 in human esophageal squamous cell carcinoma.

To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative genomic hybridization (CGH) analysis using 10 esophageal squamous cell carcinomas. Frequent gains of 1q, 3q, 7p, 7q, 8q, 11q, and 20q and losses of 3p, 4p, 4q, 5q, 9p, 11p, 11q, 13q, 18q, 21q, and Y were observed. Among these regions, 21q has not yet been investigated in detail. We performed an allelotype study using 55 squamous cell carcinomas of the esophagus and 20 microsatellite markers on 21q and found LOH in 36 cases (65%): 22 (61%) of 36 cases with LOH indicated allelic loss in all informative loci, suggesting loss of the whole chromosome arm 21q, and five smallest regions of overlap were found. Our present results suggest the existence of a tumor suppressor gene(s) that plays a role in the genesis of squamous cell carcinoma of the esophagus.

The whorl-specific action of a petunia class B floral homeotic gene.

BACKGROUND: GREEN PETAL (GP) is thought to be a petunia class B floral homeotic gene, because the gp mutant flower displays a severe homeotic conversion of petals into sepals in the second whorl. However, since the third whorl stamens remain unaffected in the gp null mutant, gp is different from class B mutants in Arabidopsis and Antirrhinum, which also show a conversion of the third whorl stamens into the carpelloid tissue. BLIND (BL) is thought to be a petunia class A floral homeotic gene, because the bl mutant flower displays homeotic conversions of sepals into the stigmatoid tissue in the first whorl and of the corolla limb into antheroid structures in the second whorl. RESULTS: A double mutant line homozygous for both bl and gp mutations was constructed. The bl gp double mutant flower displays homeotic conversions of sepals into the stigmatoid tissue in the first whorl and of the corolla limb into antheroid structures with stigmatoid tips in the second whorl. In the third and fourth whorls of the mutant flower, organs remained unchanged. In the gp flower, a petunia B-type gene FBP1 is expressed strongly in the third whorl organs, but much more weakly in the second whorl organs. In the bl gp flower, FBP1 was found to be expressed strongly in the second whorl organs as well as in the third whorl organs. CONCLUSIONS: Petunia has a class B gene other than GP that determines organ identities, both in the second and third whorls of the double mutant flower, and the action of the postulated class B gene (here called PhBX) is prevented by the BL gene in the second whorl of the gp flower. PhBX appears to be a gene that specifically interacts with the FBP1 gene, and is involved in the up-regulation of FBP1.

[Frequent loss of heterozygosity on the long arm of chromosome 21 in human esophageal, squamous cell carcinoma].

We investigated human esophageal squamous cell carcinoma using microsatellite markers on the long arm of chromosome 21 (21q) and found frequent loss of heterozygosity (LOH). The frequency of LOH was more than 50% in most of the microsatellite markers examined. Whole chromosome deletion suspected cases were observed in 25% of all cases. No case with microsatellite instability was found. Three common regions of allelic loss were identified. The frequent LOH was observed from early stage in pTNM classification. An unknown tumor suppressor gene in the genesis of esophageal squamous cell carcinoma may exist in 21q.

Analysis of the p53 gene mutations in patients with multiple primary cancers of the oesophagus.

We investigated genetic alterations of the p53 gene in two patients with multiple primary oesophageal squamous cell carcinomas (ESCs). We found that each primary tumour could be distinguished by mutation of p53. Moreover, mutations detected in the p53 gene in metastatic lymph nodes were the same as those detected in at least one of the primary tumours. Our results presented the possibility of: (1) discrimination of primary and metastatic legions in patients with multiple primary ESCs; (2) determination of metastatic pathway to regional lymph nodes; and (3) application for the development of a better clinical management of patients with multiple primary ESCs.

Postmarketing surveillance on side-effects of cefminox sodium (Meicelin).

A postmarketing surveillance of cefminox sodium (Meicelin, CMNX) for intravenous injection was conducted for about 4 years from August 1987 through June 1991, and 13,431 patients were followed up to evaluate the safety of the drug. The incidence of side-effects was 1.76%. By organ, the most frequently observed were hepatic and of the bile duct system (0.87%) followed by those on leukocytes and reticuloendothelial system (0.24%), skin and adnexa (0.24%) and digestive tract (0.16%) indicating a tendency similar to that of other injectable cephalosporins. The incidence of the side-effects among elderly patients (65 years old or older) was 2.12%, whereas among patients 64 years old or younger it was 1.58% with no significant differences between the two groups. No side-effects specific to the elderly were observed. Among children 15 years old or younger the incidence was 0.59%, which was lower than that for patients 16 years old or older (1.90%). Potential side-effects on pregnant women (n = 101) and their babies were also checked. No side-effects occurred among the 52 pregnant women evaluated and no abnormalities were detected in their babies who were followed up for up to 4 years. Cefminox is thus considered to be a highly safe cephalosporin antibiotic.

Analysis of oral fosfomycin calcium (Fosmicin) side-effects after marketing.

For about 6 years after the marketing of oral formulations of fosfomycin calcium (FOM-Ca) in December, 1980, we collected the data on 35,481 cases and analyzed it regarding safety. Primary side-effects consisted mainly in gastrointestinal disturbances, damage to skin and adnexa, liver and bile duct disorders. Specifically, diarrhea, nausea, abdominal pain, anorexia, eruption and increased serum transaminase were frequent. Serious and newly detected side-effects after marketing were pseudomembranous colitis and melena, one case each. As for the oral administration of FOM-Ca to 83 patients hypertensive to beta-lactams, gastrointestinal side-effects were seen but none of them developed hypersensitivity, an allergic reaction.

A survey of the side effects of midecamycin acetate (Miocamycin) dry syrup after marketing.

Three-year post-marketing surveillance (PMS) on midecamycin acetate dry syrup from July, 1985 through April, 1988 resulted in collection of reports on 12,169 patients. Among these, a total of 66 patients (0.54%) with side effects were reported. The main side effects caused by this drug were gastrointestinal and skin appendages disorders. They included diarrhea, abdominal pain, eruption and others. Side effects, which had not been observed up to the approval were itchiness and multiple erythema. None of these side effects were serious. When the drug was administered to 26 patients hypersensitive to beta-lactam agents, no allergy symptoms developed. Based on these results, midecamycin acetate dry syrup can be evaluated to be a highly safe macrolide in clinical use.