Target of skin tumorigenesis: cyclin D1-cdk4.
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Biomedical subjects
Publications and source records attributed to Y Kitano.
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BACKGROUND: Overexpression of cyclin D1 and p53 protein has been reported in many types of malignant tumors. OBJECTIVES: We investigated whether cyclin D1 was detected immunohistochemically in various types of malignant tumors of the skin, comparable with p53 protein. METHODS: Immunohistochemical staining of cyclin D1 and p53 protein was applied to squamous cell carcinoma, malignant melanoma and malignant fibrous histiocytoma and various kinds of benign skin tumors. RESULTS: Cyclin D1 was positive only in malignant tumors at the same incidence as p53 protein. CONCLUSION: Cyclin D1 immunohistochemical staining may be a malignant marker for various skin tumors.
Pathogenesis of Aino virus (AIV), a suspected causative agent of congenital abnormalities of calves, has not yet been established by experimental infection of dams. To investigate the pathogenesis, 10(3) median tissue culture infective doses per 0.2 ml of AIV strain JaNAr 28 was inoculated into the yolk sac of 8-day-old chick embryos. At 4, 7, 10, and 13 days post-inoculation (PI) 20 eggs were opened and macro- and microscopic studies combined with virus recovery and immunohistochemical detection of the virus antigen were performed. At 7 to 13 days PI chick embryos manifested marked hydranencephaly, cerebellar hypoplasia, arthrogryposis, and scoliosis, with the highest incidences of 86.7%, 73.3%, 80.0%, and 20.0%, respectively. At 4 days PI the viral antigen was found in nerve cells, gitter cells in mild necrotic foci of the central nervous system (CNS), degenerative myotubules, and macrophages in the interstitium, which was associated with the early phase of AIV-induced encephalitis and polymyositis, with occasional accompanying hemorrhage and clumping of myotubular fragments. From 7 to 10 days PI, AIV antigen increased markedly in the liquefactive necrosis and in both degenerative and normal-looking myotubules in conjunction with developing hydranencephaly and arthrogryposis. The encephalitis and myositis had a tendency to mitigate by 10 days PI, coincident with a slight decrease in amount of AIV antigen. At 13 days PI there was almost no detectable AIV antigen in CNS and skeletal muscles, probably due to depletion of cells having affinity to AIV.
Wild-type p53 accumulation induced by DNA damaging agents such as ultraviolet (UV) radiation, gamma-irradiation and drugs, may arrest the cell cycle until DNA damage is repaired. p21Waf1/Cip1 is a cyclin-dependent kinase (CDK) inhibitor induced by wild-type p53. CDK is activated by cyclin and progresses the cell cycle. On the other hand, CDK inhibitors inhibit CDK activity to arrest the cell cycle. Thus, p21Waf1/Cip1 is thought to mediate the signal of p53 induced by DNA damaging agents to arrest the cell cycle. p21Waf1/Cip1 is induced by wild-type, but not mutant p53. To investigate p21Waf1/Cip1 regulation by p53 in epidermis in vivo, immunohistochemical staining of p21Waf1/Cip1 and p53 were conducted in chronically sun-exposed normal epidermis and in neoplastic epidermis, p21Waf1/Cip1 expression was found to be coincident with the p53-positive regions or not coincident with the p53-positive regions in chronically sun-exposed normal epidermis, whereas there was only low or undetectable p21Waf1/Cip1 expression in any regions including the p53-positive regions of solar keratosis and squamous cell carcinoma of the skin. This suggests that wild-type p53 and p21Waf1/Cip1 may play a part in chronically sun-exposed normal epidermis response to UV exposure, whereas p21Waf1/Cip1 cannot be induced by mutated p53 in solar keratosis and squamous cell carcinoma of the skin.
Low-density-lipoprotein (LDL) apheresis has the theoretical advantage over anion-exchange resins and hydroxymethylglutaryl coenzyme A inhibitors of decreasing lipoprotein(a) as well as LDL. To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg daily. Quantitative coronary angiography was repeated after a mean of 2.1 years in 20 patients undergoing apheresis and in 19 on combination drug therapy. Changes in serum lipoproteins were similar in both groups apart from greater lowering by apheresis of LDL cholesterol (3.2 vs 3.4 mmol/L in drug group, p = 0.03) and lipoprotein(a) (geometric means 14 vs 21 mg/dL, p = 0.03). There were no significant differences in primary angiographic endpoints per patient but lesion-based and segment-based secondary endpoints were biased in favour of the drug group (change in minimum lumen diameter of lesions 0.07 vs -0.004 mm, p = 0.046; change in mean lumen diameter of segments 0.02 vs -0.06 mm, p = 0.01). None of the angiographic changes correlated with lipoprotein(a) concentrations. Per patient changes in % diameter stenosis and minimum lumen diameter in the two groups were as or more favourable than those observed in five published trials that assessed lipid-lowering drug therapy by quantitative coronary angiography. Although LDL apheresis combined with simvastatin was more effective than colestipol plus simvastatin in reducing LDL cholesterol and lipoprotein(a), it was less beneficial in influencing coronary atherosclerosis and should be reserved for patients unresponsive to drugs. Decreasing lipoprotein(a) seems to be unnecessary if LDL cholesterol is reduced to 3.4 mmol/L or less.
Epstein-Barr virus antigen-specific killer T cell (EBV-KT) activity and Epstein-Barr virus (EBV) shedding at uterine cervix and oropharynx were examined in patients with cervical carcinoma. EBV-KT activity was determined by a modified EBV-induced B cell focus regression assay. EBV shedding was examined by infectivity assay. EBV-KT activity in the patients was decreased significantly compared with that of controls (P < 0.001) and became increasingly lower as the clinical stage of the disease advanced. EBV-KT activity was changed by treatment, and decreased EBV-KT activity after treatment was clearly related to patient survival. EBV shedding at oropharynx and uterine cervix were also higher in the patients than in the controls (P < 0.01 and < 0.05). These results suggest that EBV-KT activity is closely associated with the prognosis in patients with cervical carcinoma and that it may be a useful parameter in monitoring the cell-mediated immunity of patients with cervical carcinoma.
Two cases of esophageal duplication cyst associated with pulmonary cystic malformations (cystic bronchiectasis with pneumonia in one, intrapulmonary bronchogenic cysts with bronchial atresia in the other) are reported. The coexistence of these complex anomalies supports the recognition that esophageal duplication cyst also is an entity of a broad spectrum of developmental abnormalities caused by abnormal budding of the primitive foregut. Nine cases of similar complex anomalies in the lung and esophagus have been reported. Although rare, this malformation complex should be borne in mind in the treatment of pediatric mediastinal and pulmonary malformations.
Based on a review of operative notes of recurrent inguinal hernia cases from the authors' primary series, a surgical technique modified from the Marcy repair is described. With this technique, emphasis is placed on preservation of the intact internal spermatic fascia and reduction in the size of the internal inguinal ring. Through the inguinal approach, the sleeve-like extension of the internal spermatic fascia is incised longitudinally along the cord and up to the internal ring. The cord structures are dissected off the sac, and as much of the fascial tissue as possible is preserved intact. Both edges of the fascial defect are approximated with an unabsorbable suture; great care is taken to not penetrate the wall of the sac. The same suture is then used for high ligation, via a stay suture placed on the transversalis fascia on the other side of the neck, to reduce the size of the internal ring. The technique can be used in premature babies who have a flimsy, easily torn sac, and in some cases of giant hernia with a widely dilated internal inguinal ring, if the direct wall integrity remains adequate.
Serum levels of major basic protein (MBP) were measured in patients with atopic dermatitis (AD). The severity of the disease in the AD patients was examined using our clinical scoring system. AD patients showed significantly elevated serum levels of MBP compared with normal controls. There were significant correlations between serum MBP and clinical score. These data indicate that serum MBP could be a possible marker for the disease activity.
Atopic dermatitis (AD) is characterized by alterations in cellular and humoral immunity. The objective of this study is to determine whether soluble E-selectin (sE-selectin) plays a role in AD. We examined the serum sE-selectin levels in patients with atopic dermatitis (n = 23), patients with urticaria (n = 9), and normal healthy individuals (n = 15). The severity of the disease in the AD patients was graded using an established clinical scoring system. We found that sE-selectin levels were significantly higher in atopic dermatitis than in urticaria (P < 0.001) or normal controls (P < 0.0001). In addition, there was a significant correlation between serum sE-selectin and the clinical score (R = 0.73, P < 0.0001). Clinical improvement was associated with a decrease in both the clinical score (P < 0.01) and serum sE-selectin (P < 0.01). E-selectin was recognized on the vascular endothelial cells of the erythematous lesions of AD patients. These results indicate that sE-selectin may play a role in AD.
We report a patient with graft versus host disease (GVHD) with mixed chimerism (MC). The patient had chronic myelogenous leukemia and received bone marrow transplantation (BMT) from his elder sister. Eighty days after BMT, erythematous lesions appeared on his chest. Histological examination from the skin lesion revealed lymphocytic infiltration into the upper dermis. Eosinophilic necrotic keratinocytes were scattered through the epidermis. Liquefaction degeneration was also recognized. Sicca syndrome appeared from 110 days after BMT. Detection of host origin Y-chromosome-specific DNA by polymerase chain reaction (PCR) method in bone marrow and peripheral blood showed that all bone marrow samples obtained 6 months from BMT were positive for Y-specific DNA, while peripheral blood became positive in the 60th month after BMT. The host origin normal karyotype (46,XY) in the bone marrow samples was identified for the first time in the 60th month after BMT. These results indicate that host-origin hematopoietic cells survived after BMT.
In clinical use, irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin), a novel antitumor agent, causes a relatively high incidence of severe forms of diarrhea. We investigated whether baicalin, an inhibitor of beta-glucuronidase, which deconjugates the glucuronide of the active metabolite of CPT-11, SN-38 (7-ethyl-10-hydorxycamptothecin), and Japanese herbal medicines (Kampo medicines) which contain baicalin can ameliorate CPT-11-induced intestinal toxicity in rats. CPT-11 (60 mg/kg i.v. once daily for 4 consecutive days) induced intestinal toxicity characterized by diarrhea, loss of body weight, anorexia and disruption of intestinal epithelium. Treatment with baicalin (25 mg/kg p.o. twice daily) or Kampo medicines (TJ-14 and TJ-114; 1 g/kg p.o. twice daily) from the day before to 4 or 10 days after the start of CPT-11 administration resulted in significantly decreased weight loss, improved anorexia and delayed onset of diarrheal symptoms. Histological examination revealed that Kampo medicine-treated animals had less damage to the intestinal epithelium and that damage was repaired more rapidly than in control rats. These results suggest that the prophylactic use of Kampo medicines (TJ-14 and TJ-114) may be of value against CPT-11-induced intestinal toxicity.
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It has recently become clear that cyclin-dependent kinase (cdk) complex regulates the cell cycle by phosphorylating Rb protein, a tumor suppressor protein. It is likely that this complex is a target of various growth factors and anti-growth factors (UV, TGF-beta etc.) in keratinocyte (KC). It has also been suggested that abnormalities in the cell cycle regulating mechanism such as increased activity of cyclin-cdk due to mutation of p53, a tumor suppressor gene, and overexpression of cyclin D may be concerned with carcinogenesis of KC. Thus, recent studies indicate that the cyclin-cdk complex is a common target of proliferation and carcinogenesis in KC.
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