Relationship between expression of the sodium/iodide symporter and 131I uptake in recurrent lesions of differentiated thyroid carcinoma

The sodium/iodide symporter (NIS) is known to be responsible for the active accumulation of iodide within the thyroid gland. We evaluated the relationship between the expression of NIS in primary or lymph node lesions and iodine-131 uptake in recurrent lesions of differentiated thyroid cancer. In 67 patients with differentiated thyroid cancer (5 follicular and 62 papillary carcinomas), the expression of NIS was analysed by immunohistochemical staining using polyclonal antibodies against human NIS. We used paraffin block tissues of primary tumours or metastatic lesions, and also assessed 131I uptake in recurrent lesions of thyroid cancer on post-operative 131I whole-body scan. Immunohistochemical staining was positive in 22 patients (32.8%), including 2 of 5 follicular and 20 of 62 papillary carcinomas. Recurrence was confirmed in 40 patients pathologically or clinically by serum thyroglobulin, 131I scan, fluorine-18 fluorodeoxyglucose positron emission tomography and/or computed tomography. Among these 40 patients, 28 showed positive uptake on 131I scan. Fourteen tumour specimens out of 28 (50%) were positive by NIS immunohistochemical staining. The remaining 12 patients with recurrent cancer showed negative 131I scans, and all specimens were negative by NIS immunohistochemical staining. Thus, NIS immunohistochemical staining predicted 131I uptake in recurrent cancer with a 100% positive predictive value and a 46.2% negative predictive value. There was no difference in the positivity of NIS according to the site of recurrence on 131I scan. Outcome of 131I therapy could be assessed in 22 of the 28 patients who showed 131I uptake in recurrent lesions. Patients with positive NIS immunostaining responded to 131I therapy better than did patients with negative immunostaining (P<0.05). In conclusion, NIS immunohistochemical staining showed a high positive predictive value in predicting iodine uptake. Positive immunohistochemical staining of human NIS in primary or lymph node lesions may predict 131I accumulation and effectiveness of 131I therapy in recurrent lesions.     

Human in-vivo 31P MR Spectroscopy of Benign and Malignant Breast Tumors

Objective

To assess the potential clinical utility of in-vivo 31P magnetic resonance spectroscopy (MRS) in patients with various malignant and benign breast lesions.

Materials and Methods

Seventeen patients with untreated primary malignant breast lesions (group I), eight patients with untreated benign breast lesions (group II) and seven normal breasts (group III) were included in this study. In-vivo 31P MRS was performed using a 1.5 Tesla MR scanner. Because of the characteristics of the coil, the volume of the tumor had to exceed 12 cc (3×2×2 cm), with a superoinferior diameter at least 3 cm. Mean and standard deviations of each metabolite were calculated and metabolite ratios, such as PME/PCr, PDE/PCr, T-ATP/PCr and PCr/T-ATP were calculated and statistically analyzed.

Results

Significant differences in PME were noted between groups I and III (p=0.0213), and between groups II and III (p=0.0213). The metabolite ratios which showed significant differences were PME/PCr (between groups II and III) (p=0.0201), PDE/PCr (between groups I and III, and between groups II and III) (p=0.0172), T-ATP/PCr (between groups II and III) (p=0.0287), and PCr/T-ATP (between groups II and III) (p=0.0287). There were no significant parameters between groups I and II.

Conclusion

In-vivo 31P MRS is not helpful for establishing a differential diagnosis between benign and malignant breast lesions, at least with relatively large lesions greater than 3 cm in one or more dimensions.     

Kaempferol induced the apoptosis via cell cycle arrest in human breast cancer MDA-MB-453 cells

The aim of present study was to investigate the effects of kaempferol on cellular proliferation and cell cycle arrest and explore the mechanism for these effects in human breast carcinoma MDA-MB-453 cells. Cells were treated with kaempferol at various concentrations (ranging from 1 to 200 µM) for 24 and 48 hrs. Kaempferol significantly inhibited cancer cell growth in cells exposed to 50 and 10 µM of kaempferol and incubated for 24 and 48 hrs, respectively. Exposure to kaempferol resulted in cell cycle arrest at the G2/M phase. Of the G2/M-phase related proteins, kaempferol down-regulated CDK1 and cyclin A and B in cells exposed to kaempferol. In addition, small DNA fragments at the sub-G0 phase were increased by up to 23.12 and 31.90% at 10 and 50 µM incubated for 24 and 48 hrs, respectively. The kaempferol-induced apoptosis was associated with the up-regulation of p53. In addition, the phosphorylation of p53 at the Ser-15 residue was observed with kaempferol. Kaempferol inhibits cell proliferation by disrupting the cell cycle, which is strongly associated with the induction of arrest at G2/M phase and may induce apoptosis via p53 phosphorylation in human breast carcinoma MDA-MB-453 cells.     

Vascular decompression surgery for severe tinnitus: Selection criteria and results

Seventy-four patients were operated on within a period of 10 years to treat incapacitating tinnitus; 72 underwent microvascular decompression (MVD) of the intracranial portion of the auditory nerve, and 2 underwent section of the eighth nerve close to the brain stem. Of those who underwent MVD, 2 had no change in symptoms and later also underwent section of the eighth nerve near the brain stem. Two patients did not return for follow-up. Of the 72 remaining patients, 13 (18.1%) experienced total relief from tinnitus, 16 (22.2%) showed marked improvement, 8 (11.1%) showed slight improvement, 33 (45.8%) had no improvement, and 2 (2.8%) became worse. The patients who experienced total relief and those who showed marked improvement had experienced their tinnitus for an average of 2.9 years and 2.7 years, respectively; those who showed slight improvement and those who had no improvement had experienced their tinnitus for a longer time before the operation (mean, 5.2 and 7.9 years, respectively). Of the 72 patients who were operated on and followed, 32 were women. Of these, 54.8% experienced total relief from tinnitus or marked improvement, while only 29.3% of the men showed such relief or improvement. Selection of the patients for operation was mainly based on patient history and, to some extent, on auditory test results (brainstem auditory evoked potentials [BAEP], acoustic middle ear reflexes, and audiometric data).     

Effect of Vitex rotundifolia on immediate-type allergic reaction

We investigated the effect of aqueous extract of Vitex rotundifolia (L.) (Verbenaceae) fruits (VRFE) on the immediate-type allergic reactions in vivo and in vitro. VRFE (10(-4)-1.0 g/kg) dose-dependently inhibited systemic allergic reaction induced by compound 48/80. When VRFE was employed in a systemic allergic reaction test, the plasma histamine levels were reduced in a dose-dependent manner. VRFE (5x10(-1) and 1.0 g/kg) inhibited passive cutaneous anaphylaxis activated by anti-dinitrophenyl (DNP) IgE. VRFE (10(-3)-1.0 mg/ml) also dose-dependently inhibited the histamine release from the rat peritoneal mast cells (RPMC) by compound 48/80 or anti-DNP IgE. Moreover, VRFE (10(-3) mg/ml) had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-alpha production from RPMC. These results suggest that VRFE may be beneficial in the regulation of immediate-type allergic reaction.     

Germline mutations of the dpc4 gene in Korean juvenile polyposis patients

Juvenile polyposis is an uncommon condition characterized by the development of multiple (usually more than 5) juvenile polyps in the gastrointestinal tract, especially in the colon. This disease usually occurs during childhood, and is inherited in an autosomal dominant fashion. It has been suggested that the dpc4 (deleted in pancreatic carcinoma, locus 4) gene, which is located on chromosome 18q21.1, might cause juvenile polyposis. The dpc4 (smad4) gene is a candidate tumor-suppressor gene and may play a role in the TGF-beta-signaling pathway. To confirm the idea that alterations of the dpc4 gene may result in juvenile polyposis, we screened 5 Korean juvenile-polyposis patients by PCR-SSCP (single-strand conformation polymorphism) analysis and bi-directional sequencing. There were germline mutations of the dpc4 gene in 3 out of the 5 patients: 2 had a genetic alteration in exon 9 and the third had a mutation in exon 8. These germline mutations occurred in the C-terminus of the dpc4 gene, similar to most published mutations. One patient exhibited a non-sense mutation (codon 388), which changed a glutamine codon (CAG) to a stop codon (TAG). The second patient harbored a mis-sense mutation (codon 390), causing a non-conservative amino-acid change . The third patient had a mis-sense mutation in exon 8 (codon 361), which altered an arginine codon (CGC) into a histidine codon (CAC).     

Immunotoxicity of ethyl carbamate in female BALB/c mice: role of esterase and cytochrome P450

Ethyl carbamate, a potent carcinogen, has been characterized to be metabolized by cytochrome P450 (P450) and esterase. It has recently been demonstrated that P450 may activate ethyl carbamate to immunotoxic metabolites. To investigate the role of esterase in ethyl carbamate-induced immunosuppression, mice were pretreated intraperitoneally with an esterase inhibitor, diazinon, at 20 mg/kg 30 min prior to the administration of ethyl carbamate intraperitoneally at 100 and 400 mg/kg for 7 consecutive days. Pretreatment with diazinon completely blocked the serum esterase activity. Histopathologically splenic and thymic atrophy was observed when mice were treated with ethyl carbamate, which was potentiated by the pretreatment with diazinon. In spleen, lymphocytes in the periarteriolar lymphoid sheath and the marginal zone appeared to be depleted in the white pulps. In thymus, ethyl carbamate caused a marked depletion of cells in cortex. The antibody response to sheep red blood cells (SRBCs) was more suppressed by ethyl carbamate in diazinon-pretreated groups than in corn oil-pretreated groups. These results suggest that the metabolism of ethyl carbamate by esterase may be an inactivation pathway in ethyl carbamate-induced immunosuppression. In addition, ethyl N-hydroxycarbamate, a P450 metabolite, suppressed the lymphoproliferative response induced by lipopolysaccharide and concanavalin A in splenocyte cultures. These results indicate that the metabolism of ethyl carbamate by P450 may be an activation pathway in immunosuppression by ethyl carbamate.     

Author Index to Volume 17 (2000)

Authors Index

Author Index to Volume 17 (2000)     

Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells

Cellular stress can initiate prostaglandin (PG) biosynthesis which, through changes in gene expression, can modulate cellular functions, including cell growth. PGA(2), a metabolite of PGE(2), induces the expression of stress response genes, including gadd153 and hsp70, in HeLa cells and human diploid fibroblasts. PGs, gadd153, and hsp70 expression are also influenced by the cellular redox status. Polyphenolic glutathione conjugates retain the ability to redox cycle, with the concomitant generation of reactive oxygen species. One such conjugate, 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), is a potent nephrotoxic and nephrocarcinogenic metabolite of the nephrocarcinogen, hydroquinone. We therefore investigated the effects of TGHQ on PGE(2) synthesis and gene expression in a renal proximal tubular epithelial cell line (LLC-PK(1)). TGHQ (200 microM, 2 h) increases PGE(2) synthesis (2-3-fold) in LLC-PK(1) cells with only minor (5%) reductions in cell viability. This response is toxicant-specific, since another proximal tubular toxicant, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), stimulates PGE(2) synthesis only after massive (68%) reductions in cell viability. Consistent with the ability of TGHQ to generate an oxidative stress, both deferoxamine mesylate and catalase protect LLC-PK(1) cells from TGHQ-mediated cytotoxicity. Only catalase, however, completely blocks TGHQ-mediated PGE(2) synthesis, implying a major role for hydrogen peroxide in this response. TGHQ induces the early (60 min) expression of gadd153 and hsp70. However, while inhibition of cyclooxygenase with aspirin prevents TGHQ-induced PGE(2) synthesis, it does not affect TGHQ-mediated induction of gadd153 or hsp70 expression. In contrast, a stable PGE(2) analogue, 11-deoxy-16, 16-dimethyl-PGE(2) (DDM-PGE(2)), which protects LLC-PK(1) cells against TGHQ-mediated cytotoxicity, modestly elevates the levels of gadd153 and hsp70 expression. In addition, catalase and, to a lesser extent, deferoxamine mesylate block TGHQ-induced gene expression. Therefore, although TGHQ-induced generation of reactive oxygen species is required for PGE(2) synthesis and stress gene expression, acute TGHQ-mediated increases in gadd153 and hsp70 mRNA levels are independent of PGE(2) synthesis.