A relationship between the mevalonate pathway and isoprenoid production in actinomycetes

Most Streptomyces strains are equipped with only the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the formation of isopentenyl diphosphate. In addition to this pathway, some Strepromyces strains have the mevalonate pathway to produce terpenoid antibiotics. We have previously shown that a gene cluster for biosynthesis of terpentecin, a diterpene antibiotic, was located in adjacent the mevalonate pathway gene cluster. In this study, a mevalonate pathway gene cluster was cloned from Actinoplanes sp. strain A40644, an isoprenoid antibiotic BE-40644 producer, to examine whether the mevalonate pathway genes and isoprenoid biosynthetic genes are clustered in genomic DNA. By sequencing flanking regions a probable BE-40644 biosynthetic gene cluster was found in the downstream region of the mevalonate pathway gene cluster. Heterologous expression of a 9-kb fragment confirmed that a set of the BE-40644 biosynthetic genes was involved in the fragment. This result suggested that the presence of the mevalonate pathway might be a good landmark to detect the production of isoprenoid compounds by actinomycetes.     

A case of breast cancer metastasizing to cervix after resection of pancreatic metastasis

A case of breast cancer that metastasized to the cervix 10 years and 8 months after mastectomy is reported. The patient had undergone pancreaticoduodenectomy due to solitary metastasis to the head of the pancreas 4 years previously. The cervical metastasis was associated with abnormal genital bleeding. After pancreaticoduodenectomy the serum levels of CEA, CA15-3 and NCC-ST-439, which are markers of breast cancer, were within normal limits, but the serum level of CA15-3 had increased month by month. The patient had abnormal genital bleeding and presented to the department of gynecology at our hospital. The tumor was in the cervix, bled easily and 2.5x2.0 cm in size on ultrasonography. It was thought to be carcinoma of the cervix, but biopsy revealed the tumor to be an adenocarcinoma pathologically and CA15-3 was immunohistochemically demonstrated in the resected specimen, similar to lobular carcinoma of the breast. Abdominal CT scan revealed involvement of the ovaries and uterus, prompting hysterectomy with bilateral oophorectomy. After discharge, she received chemoendocrine therapy. However, she subsequently died due to peritoneal carcinomatosis.     

Chemosensitivity of human pancreatic carcinoma cells is enhanced by IkappaBalpha super-repressor

Pancreatic cancer has an unfavorable prognosis; surgery and chemotherapy at present have only limited value. To improve the prognosis of pancreatic cancer, effective non-surgical therapy is necessary. NF- k B is reported to be related to resistance to apopto-sis, but its role in Chemosensitivity remains controversial. We examined the effects on Chemosensitivity of inhibition by induction of the super-repressor I k Bα in pancreatic cancer cell lines, BxPC-3, Capan-1 and Panc-1. I k Bα protein was transduced by infection of adenovirus vector AxCAhlkBδN. Sensitivity to VP-16 and doxorubicin was increased significantly by I k Bα induction in all three pancreatic cell lines. To investigate molecular events during I k Bα induction, we examined the changes in expression of drug-resistance-related genes by real-time RT-PCR and those in apoptosis-related genes by cDNA microarray. There was no common change of gene expression before and after I k Bα induction among the three pancreatic cancer cell lines, except for mdm2. Further examination of other genes is necessary for a better understanding of the molecular mechanisms of enhancement of Chemosensitivity through I k Bα induction. However, we have confirmed that I k Bα induction leads to an increase of Chemosensitivity of pancreatic cancer. Many problems remain before clinical application of this adenoviral system will be feasible, but our results may ultimately lead to an improved therapy of pancreatic cancer. (Cancer Sci 2003; 94: 467–472)     

Attenuation of microcirculatory disturbance after liver ischemia by newly synthesized inflammatory cytokine suppressor,FR167653

BACKGROUND/AIMS: Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia. METHODOLOGY: Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed. RESULTS: The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells. CONCLUSIONS: These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.     

Submucous electrocautery following submucous resection of turbinate bone--a rationale of surgical treatment for allergic rhinitis

OBJECTIVE: Since the majority of the key elements such as trigeminal nerves, parasympathetic nerves, nasal glands, and blood vessels targeted by histamine and leukotrienes are found in the lamina propria of the nasal mucosa, its selective electrocautery has a rationale to improve the symptoms of allergic rhinitis with preservation of epithelial layer. To achieve the above goal, we performed the submucous electrocautery of the lamina propria (SECLP) following the submucous resection of the inferior turbinate bone (submucous turbinectomy: SMT). This paper discusses the efficacy of this procedure for the patients with persistent perennial allergic rhinitis. METHODS: An intranasal initial incision was made along the piriform aperture. The mucoperiosteum was elevated from the inferior turbinate bone followed by its complete resection. The SECLP was performed by applying a high-frequency coagulation current with a ball tip electrode, which was inserted into the mucoperiosteal sack after the completion of the SMT and was drawn forward on the medial surface of the mucoperiosteum with drawing a wavy line. We performed this surgery in 43 patients with perennial allergic rhinitis who were refractory to pharmacotherapy or were reluctant to take medicine. Symptoms, macroscopic intranasal findings, the results of allergic tests, nasal resistance, mucociliary function with saccharin, and the number of mast cells were compared pre- and postoperatively. RESULTS: The patients exhibited satisfactory improvement in symptoms only with a few crust formations. The macroscopic intranasal findings and allergic tests improved after surgery. Saccharin transport time remained normal. The number of anti-tryptase positive mast cells significantly decreased in the epithelial layer and in the superficial layer of the lamina propria of the postoperative inferior turbinate mucosa. CONCLUSION: The SECLP following the SMT is evaluated to be a useful surgical modality for allergic rhinitis with preservation of the nasal mucosal function.     

Laparoscopic enucleation of insulinoma in the pancreas: case report and review of the literature

We report a case of islet cell tumor of the pancreas managed by laparoscopic surgery. A 27-year-old woman was admitted to the hospital after fainting from hypoglycemia. Diagnostic imaging showed a small tumor 1 cm in diameter in the body of the pancreas. Laparoscopic enucleation of the tumor was performed with laparoscopic coagulating shears. The operation time was 210 minutes, and there were no perioperative complications such as pancreatic leakage. The postoperative course was uneventful, and the patient was discharged from the hospital on the seventh postoperative day. The histopathologic diagnosis was insulin-producing islet cell tumor. This method is technically feasible and safe for the management of small islet cell tumors located on the surface of the pancreas.     

Structures of ADP-ribosylated rifampicin and its metabolite: intermediates of rifampicin-ribosylation by Mycobacterium smegmatis DSM43756

23-(O-ADP-Ribosyl)rifampicin [RIP-TAs (3, Na+ form), RIP-TAf (4, H+ form)] was obtained as an intermediate in the conversion process of rifampicin (1) to RIP-Mb (2) that is mediated by cell homogenates of Mycobacterium smegmatis DSM43756 or of Escherichia coli carrying a mycobacterial mono(ADP-ribosyl) transferase gene, in the presence of NADH. 23-[O-(5'-Phosphoribosyl)]rifampicin (5, RIP-TAp) was also obtained by the reaction of rifampicin with NADH in the presence of a homogenate of M. smegmatis. The structures of 3, 4, and 5 were determined by means of MS and NMR analyses.     

Co-overexpression of p53 protein and epidermal growth factor receptor in human papillary thyroid carcinomas correlated with lymph node metastasis, tumor size and clinicopathologic stage.

Expressions of p53 protein and epidermal growth factor receptor (EGFR) were immunohistochemically investigated in 111 patients with papillary thyroid carcinomas (PTC) in order to evaluate their co-expression in relation to lymph node metastases (LNM), tumor size and clinicopathologic stage. In PTC, positive staining for p53 in dewaxed sections was present in nuclei or cytoplasm, or in both, whereas surface linear or cytoplasmic staining for EGFR was observed with varying degrees of extent and intensity. Positive reaction (more than 10% of tumor cells positive) was observed in 65 cases (58. 5%) for p53, and in 87 cases (78.4%) for EGFR. A significant correlation was found between p53 protein and EGFR overexpressions (p<0.01). Notably, p53-positive cases always exhibited positive staining for EGFR. Forty-four patients (39.6%) exhibited concomitant LNM, most of whom had both p53 and EGFR expression in primary foci. Statistical analysis revealed that co-expression of p53 protein and EGFR was significantly correlated with LNM, tumor size and clinicopathologic stage, but no correlation was found between their co-expression and age or sex. Our findings suggest that overexpression of p53 protein or EGFR in PTC tends to be associated with a high frequency of LNM, increased tumor size and advanced clinicopathologic stage, and that co-expression of both p53 protein and EGFR may predispose to growth and progression of PTC. Our findings also suggest that p53 protein and EGFR expressions may be clinicopathologic and prognostic indicators of PTC.