Intravesical bacillus calmette-guerin( BCG) therapy for superficial bladder carcinoma is believed to exert its antitumor effects through immune mechanisms which have yet to be more clearly defined. Recently, BCG infection is known to induce nitric oxide(NO) production by macrophages through a T cell mediated process. NO is known to be microbicidal and tumoricidal. Therefore, we studied the effects of intravesical BCG instillation on the induction of inducible NO synthase(iNOS) which is responsible for the production of NO in the vesical tissue of rat Forty Sprauge-Dawley female rats were equally divided into 5 groups. In group 1, normal saline( 0.85 ml/kg) was intravesically instilled one time. In group 2 and group 3, BCG of Pasteur strain(2 mg/kg, normal saline 0.85 ml/kg) was instilled one time and 3 times weekly respectively. In group 4, 10-fold dose of the strain( 20 mg/kg, 0.86 ml/kg) and in group 5, 1/10-fold dose of the strain (0.2 mg/kg, 0.85 ml/kg) were instilled one time respectively. We sacrificed two rats to excise the bladders in each group 1, 3, 7, and 14 days after the instillation( after the last instillation in group 3). iNOS mRNA was not detected in the vesical tissues from the rats of group 1, whereas it was strongly detected in all the vesical tissues from the rats in group 2, 3. or 4. More iNOS mRNA was detected 14 days after the instillation in group 3 than group 2 or 4. In group 5, iNOS mRNA was weakly detected 1, 3, and 7 days and not detected 14 days after the instillation. Our results indicate that intravesical BCG instillation of rat induces the expression of iNOS mRNA in the vesical tissue and suggest that the duration and degree of iNOS mRNA expression is dependent on the dose of BCG and the frequency of the instillations. On the basis of these observations, we conclude that adequate dose and frequency are required for effective treatment of superficial bladder carcinoma in the intravesical BCG therapy.
Animals ; Bacillus ; Female ; Humans ; Macrophages ; Mycobacterium bovis* ; Nitric Oxide Synthase Type II* ; Rats* ; RNA, Messenger ; Urinary Bladder

Recently, BCG infection is known to induce nitric oxide(NO) production by macrophages through T cell mediated process and NO is known to be microbicidal and tumoricidal. There are several strains of BCG which are commercially available and vary in the number, pathogenicity, viability, and immunogenicity of organisms. Therefore, we wanted to know if there are any differences between three different strains of BCG(Pasteur, Connaught or Tice strain) on the induction of inducible NO synthase(iNOS) and the histological changes in vesical tissue after intravesical instillation of BCG in rats. Thirty two Sprauge-Dowley female rats were equally divided into 4 groups. In group 1, normal saline(0.85 ml/kg) was intravesically instilled one time. In group 2, 3, and 4, BCG of Pasteur strain(2mg/kg, normal saline 0.85ml/kg), Connaught strain(1.35mg/kg, normal saline 0.85ml/kg), Tice strain(0.21mg/kg, normal saline 0.85ml/kg) was instilled one time, respectively. The bladders were excised from each group on day 1, 3, 7, and 14 after BCG instillation. iNOS mRNA was not detected in the vesical tissues of control group, whereas it was strongly detected in group 2, 3, or 4. Also, iNOS mRNA was more strongly detected on day 1, 3, and 7 after intravesical BCG instillation than day 14 in the vesical tissues of group 2, 3, and 4. Histologic findings were well related with expression of iNOS mRNA. Our results indicate that intravesical BCG instillation of rat induces expression of iNOS mRNA in the vesical tissue accompanying the infiltration of inflammatory cells and suggest that all of the 3 strains of BCG including Pasteur, Connaught, and Tice are good at inducing expression of iNOS mRNA without significant differences between the strains.
Administration, Intravesical* ; Animals ; Female ; Gene Expression* ; Humans ; Macrophages ; Mycobacterium bovis* ; Nitric Oxide Synthase Type II* ; Rats* ; RNA, Messenger ; Urinary Bladder ; Virulence

PURPOSE: The prognosis of patients with advanced non-small-cell lung cancer (NSCLC) is extremely poor. Many prospective randomized trials on patients with advanced NSCLC suggested systemic chemotherapy improves both the survival and quality of life. A phase II trial was conducted to evaluate the efficacy and safety profile of the combination chemotherapy of gemcitabine and cisplatin in advanced NSCLC. MATERIALS AND METHODS: Forty-four patients with locally advanced or metastatic NSCLC were enrolled. The patients received a cisplatin, 75 mg/m(2), infusion over 30 minutes on days 1, followed by a gemcitabine, 1, 250 mg/m(2), infusion over 30 minutes on days 1 and 8 every 3 weeks. RESULTS: The median age of the patients was 64 years (range: 27~75). Forty-one patients were assessable for response and toxicity analyses. The overall response rate was 53.6%, but with no complete remissions. The median time to progression was 5.6 months (range: 1~15.4). The median survival was 14.2 months (95% confidence interval (CI), 13.8~22.5). A total of 179 cycles were administered, with a median of 4 cycles of chemotherapy, ranging from 2 to 9 cycles. The most common hematological toxicities were NCI grades 3/4 neutropenia (24%) and thrombocytopenia (7.8%). The most common non-hematological toxicity was fatigue (42.4%). There were no life-threatening toxicity or treatment related mortalities. The median duration of follow up was 9.4 months, ranging from 1.6 to 30.3 months. CONCLUSION: In this trial, the combination of gemcitabine and cisplatin showed significant activity, with acceptable and manageable toxicities as a first-line regimen for patients with advanced NSCLC.
Cisplatin* ; Drug Therapy ; Drug Therapy, Combination ; Fatigue ; Follow-Up Studies ; Humans ; Lung Neoplasms* ; Lung* ; Mortality ; Neutropenia ; Prognosis ; Prospective Studies ; Quality of Life ; Thrombocytopenia

IL-28RA is one of the important candidate genes for complex trait of genetic diseases, but there is no published information of the genetic variation in this gene. We scanned the seven exons and their boundary introns sequence of IL-28RA including the promoter regions to analyze genetic variation sites, and identified eighteen single nucleotide polymorphisms (SNPs) and two variation sites. We chose seven SNPs (g.-1193 A>C, g.-30 C>T, g.17654 C>T, g.27798 A>G, g.31265 C>T, g.31911 C>T and g.32349 G>A) of them for large sample size genotyping, and assessed the association of genotype and allele frequencies of these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. We also compared the genotype frequencies between Korean controls and Han Chinese control or Korean Chinese control. We investigated the frequencies of haplotype constructed by these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. Our results suggested that the g.32349 G>A polymorphism of IL-28RA might be associated with susceptibility to allergic rhinitis (P=0.032), but seems to have no relationship with serum total IgE levels. The haplotype frequencies by these SNPs also show significant association between controls and allergic rhinitis patients.
Variation (Genetics) ; Rhinitis, Allergic, Seasonal/blood/*genetics ; Rhinitis, Allergic, Perennial/blood/*genetics ; Receptors, Cytokine/*genetics ; Promoter Regions (Genetics)/genetics ; Polymorphism, Single Nucleotide/*genetics ; Male ; Immunoglobulin E/blood ; Humans ; Haplotypes ; Genotype ; Genetic Predisposition to Disease/genetics ; Gene Frequency ; Female ; Exons/genetics ; Case-Control Studies ; Alleles ; Adult

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumor suppressor protein (pRb) and poly (ADP- ribose) polymerase (PARP) cleavages. Moreover, down-regulation of MDM2 level was not coupled with its mRNA down-regulation. However, the level of MDM2 was partially restored by proteasome inhibitors such as LLnL and lactacystin, even in the presence of etoposide. Our results suggest that, in the p53 null status, MDM2 protein level is decreased by proteasome-mediated proteolysis prior to caspase-3-dependent PARP and pRb cleavages.
Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects/physiology ; Caspases/*metabolism ; Cysteine Endopeptidases/*metabolism ; Down-Regulation (Physiology)/physiology ; Etoposide/pharmacology ; HL-60 Cells ; Human ; Multienzyme Complexes/*metabolism ; NAD+ ADP-Ribosyltransferase/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Retinoblastoma Protein/*metabolism

Skeletal muscle is one of the most unusual metastatic sites for any malignancy. Duodenal cancer is extremely rare, and no cases of skeletal muscle metastasis from duodenal cancer have been reported. We report here in a case of metastasis to the skeletal muscle of the left thigh from duodenal cancer. Our patient was a 47-year-old man, exhibiting a painful mass in the posterior aspect of his left thigh over a 4 month period. An imaging study, and a biopsy, revealed a duodenal adenocarcinoma metastasize to the skeletal muscle. The patient refused chemotherapy and has followed up for 4 months.
Adenocarcinoma* ; Biopsy ; Drug Therapy ; Duodenal Neoplasms ; Duodenum* ; Humans ; Middle Aged ; Muscle, Skeletal* ; Neoplasm Metastasis* ; Thigh*

Mesenchymal stem cells (MSCs) have recently been identified and characterized in humans. Moreover, MSC secrete cytokines that can support hematopoietic progenitor growth. In the present study, we evaluated whether the efficacy of hematopoietic stem cell transplantation is improved by their co-transplantation with MSC, and whether this is positively correlated with the dose of infused MSCs. Accordingly, irradiated NOD/SCID mice were transplanted with 1x10(5) human CD34+ cells in the presence or absence of culture expanded MSCs (1x10(6) or 5x10(6)). We evaluated human hematopoietic cell engraftment by flow cytometry and assessed MSC tissue distributions by fluorescence in situ hybridization. We found that CD45+ and CD34+ cell levels were significantly elevated in a dose-dependent manner in cotransplanted mice 4 weeks after transplantation. The engraftments of CD33+ and CD19+ cells also increased dose-dependently. However, the engraftment of CD3+ cells did not increase after co-transplantation with MSCs. Human Y chromosome+ cells were observed in multiple tissues and were more frequently observed in mice co-transplanted with 5x10(6) rather than 1x10(6) MSCs. These results suggest that MSCs are capable of enhancing hematopoietic cell engraftment and distribution in multiple organs in a dose-dependent fashion.
Animals ; Antigens, CD34/*biosynthesis ; Cell Differentiation ; Cells, Cultured ; Dose-Response Relationship, Drug ; Female ; Fetal Blood/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mesenchymal Stem Cells/*cytology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Microscopy, Fluorescence/methods ; Stem Cell Transplantation/*methods

PURPOSE: We prospectively conducted a non-randomized phase II trial to evaluate the efficacy and safety of combination irinotecan, leucovorin (LV) and 5-fluorouracil (FU) as a first-line regimen for treating patients with previously untreated advanced colorectal cancer (CRC). MATERIALS AND METHODS: Twenty-six previously untreated patients with advanced, recurrent or metastatic CRC were enrolled in this study. The patients received either irinotecan 180 mg/m2 on day 1 with LV bolus of 200 mg/m2 and FU bolus of 400 mg/m2, and this was followed by FU continuous infusion of 600 mg/m2 on day 1 and day 2 (the FOLFIRI regimen), or they were treated with LV bolus of 400 mg/m2 and FU bolus of 400 mg/m2 followed by FU continuous infusion of 2,400 mg/m2 for 46 hours (the simplified FOLFIRI regimen), and these treatments were repeated every 2 weeks until disease progression. RESULTS: The objective response rate was 23.1% (6/26) respectively, for both treatments. The median time to progression was 5.3 months (range: 0.4~19.9), and the overall survival was 11.2 months (range: 0.5~52.3). The prognostic factor for longer survival was the Eastern Cooperative Oncology Group (ECOG) performance status (PS). The non-hematological toxicities were similar for both treatment groups, with more frequent grade > or =3 neutropenia being noted for the simplified FOLFIRI regimen. CONCLUSION: The biweekly irinotecan based regimen was demonstrated to have a moderate antitumor activity with acceptable toxicity profiles, and the ECOG PS was the independent prognostic factor.
Colorectal Neoplasms* ; Disease Progression ; Fluorouracil* ; Humans ; Leucovorin* ; Neutropenia ; Prospective Studies

Prostaglandin E2(PGE2), a major product of cyclooxygenase, has been implicated in modulating angiogenesis, vascular function, and inflammatory processes, but the underlying mechanism is not clearly elucidated. We here investigated the molecular mechanism by which PGE 2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE 2 increased angiogenesis. PGE 2 increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), eNOS activity, and nitric oxide (NO) production by the activation of cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K). Dibutyryl cAMP (DB-cAMP) mimicked the role of PGE 2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE 2. Furthermore, PGE 2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE 2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE 2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.
1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Animals ; Aorta ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cyclic AMP/metabolism/pharmacology ; Cyclic GMP/biosynthesis/*metabolism ; Dinoprostone/*pharmacology ; Endothelial Cells/*drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Mice, Knockout ; Neovascularization, Physiologic/*drug effects ; Nitric Oxide/biosynthesis/*metabolism ; Nitric Oxide Synthase Type III/deficiency/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Signal Transduction/*drug effects ; Umbilical Veins/cytology/*drug effects/metabolism

Development of pseudomembranes in the gastrointestinal tract during acute inflammatory or vascular disease has been confined to the small and/or large bowel, with rare occurrences in the esophagus. Primary gut involvement by Aspergillus is a rare and often fatal complication of intensive antileukemic therapy. To our knowledge, there has been only two case reports of pseudomembranous gastritis. We experienced a case of isolated pseudomembranous gastritis due to Aspergillus after chemotherapy for relapsed acute myelogenous leukemia. The diagnosis was made by gastrofiberscopic findings and histologically.
Aspergillosis ; Aspergillus* ; Diagnosis ; Drug Therapy ; Esophagus ; Gastritis* ; Gastrointestinal Tract ; Humans ; Leukemia, Myeloid, Acute* ; Vascular Diseases