Stereoselective synthesis of (±)-epibatidine analog: (±)-2β-(2-chloro-5-pyridinyl)-8-azabicyclo[3.2.1]octane

Stereoselective synthesis of (+/-)-epibatidine analog 2, which contains the 8-azabicyclo[3.2.1]octane ring system, was achieved by using palladium-catalyzed Heck-type coupling reaction from 3.     

Biological evaluation of Korean medicinal plants(III)

The extracts of sixty Korean plants were evaluated for their biological activities such as antitumor activities against Sarcoma 180, Leukemia SN-36 and Ehrlich ascites carcinoma, antimicrobial activities and behavioral observation in mice. The results are tabulated.     

Marrow regeneration after mechanical depletion

The origin of marrow regeneration after mechanical depletion was reinvestigated in mouse chimeras. The results were compatible with the local origin of stem cells from remnants of incompletely removed marrow, but not with their origin from a common precursor of both bone and hemopoietic cell lines. In transplanted femurs depleted by a modified technique of in vivo evacuation of marrow, hemopoietic regeneration failed to occur. The presence of hemopoietic stem cells in the Haversian canals was thus excluded. The demonstration of ample hemopoiesis with minimal bone formation in nondepleted controls in which bone marrow initially became necrotic provided new evidence that osteogenesis was not a prerequisite of hemopoietic regeneration.     

Effect of melatonin on the regulation of proenkephalin and prodynorphin mRNA levels induced by kainic acid in the rat hippocampus

The in vivo short-term effect of melatonin on kainic acid (KA)-induced proenkephalin (proENK) or prodynorphin (proDYN) mRNA, and on AP-1 protein levels in the rat hippocampus, were studied. Melatonin (5 mg/kg) or saline was administered intraperitoneally (i.p.) to rats 30 min prior to and immediately after i.p. injection of KA (10 mg/kg). Rats were sacrificed 1 and 3 h after KA injection. The proENK and proDYN mRNA levels were significantly increased 3 h after KA administration. The elevations of both proENK and proDYN mRNA levels induced by KA were significantly inhibited by the preadministration with melatonin. The increases of proENK and proDYN mRNA levels induced by KA were well-correlated with the increases of c-Fos, Fra-2, FosB, c-Jun, and JunB protein levels, which were significantly increased 3 h after KA administration and effectively inhibited by administration with melatonin. In an electrophoretic mobility shift assay, both AP-1 and ENKCRE-2 DNA binding activities were increased by KA, which were also attenuated by the administration of melatonin. In addition, cross-competition studies revealed that AP-1 or ENKCRE-2 DNA binding activity was effectively reduced by the 50x unlabeled cross-competitor. Therefore, these data suggest that melatonin has an inhibitory role in KA-induced gene expression, such as proENK and proDYN mRNA expression, and this may be due to a reduction of KA-induced AP-1 or ENKCRE-2 DNA binding activity.     

Interfractional variation in position of the uterus during radical radiotherapy for cervical cancer.

BACKGROUND AND PURPOSE: This study was conducted to investigate the positional change of the uterus during radiotherapy which can degrade the accuracy of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT). PATIENTS AND METHODS: Sixty-six patients received radical radiotherapy for cervical cancer in Samsung Medical Center. For each patient, two MRI scans were taken; one was before beginning radiotherapy and the other was in the third or fourth week of radiotherapy. In T2-weighted MRI images, the positional change of the uterus was quantified by measuring six parameters; the distance from the external uterine opening to the isthmus of the uterus (Dcx), the distance from the isthmus of the uterus to the uterine fundus (Dco), the perpendicular distance of the uterine body to the uterine corpus (Dco-per), the angle between the vertical line and the cervical canal in sagittal images (Acx), the uterine corpus angle from the vertical line in sagittal plan (Aco), the angle between the uterine corpus from an arbitrary bony landmark and a vertical mid line in axial images (Aco-axi) RESULTS: Mean value of change in Dcx+Dco of tumor size during treatment was 8.0 mm in small tumors and 17.9 mm in large tumors. Among 44 anteflexed uterus patients, 5 changed into a retroflexed position. 12 patients (18%) had a greater than 30 degrees variation in any angle. For patients under 60 years, the difference in Acx was statistically significant. CONCLUSIONS: Positional changes of the uterus during radiotherapy should be considered in the treatment planning of 3DCRT or IMRT, particularly in patients under 60 years or those with tumor size greater than 4 cm in diameter.     

Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors.

PURPOSE: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial. EXPERIMENTAL DESIGN: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced. RESULTS: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts < 5 mitoses/50 high power field, spindle-cell histology, tumor size < 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count > or = 5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (> or = 5 cm; OR = 4.2). CONCLUSIONS: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.     

Peroxiredoxins in breast carcinoma.

PURPOSE: Peroxiredoxins (Prxs) are a novel group of peroxidases containing high antioxidant efficiency and some of them having also effects on cell differentiation and apoptosis. The mammalian Prx family has six distinct members located in various subcellular locations, including peroxisomes and mitochondria, places where oxidative stress is most evident. EXPERIMENTAL DESIGN: We examined immunohistochemically a large set of samples from patients with breast carcinoma and investigated associations with parameters such as tumor-node-metastasis classification, hormone receptor status, and patient survival. Three biopsies of healthy breast tissue were used as controls. RESULTS: Expression of peroxiredoxins I, III, IV, and V was found in >or=80% of cases, whereas the expression of Prx II and VI was less frequent. Increased expression of Prx III was found to associate with the presence of progesterone (P = 0.02) and estrogen (P = 0.03) receptors, and Prxs IV (P = 0.009) and VI (P = 0.04) were overexpressed in progesterone receptor positive cases. Prx V was the only isoform that associated with items of tumor-node-metastasis classification, it was connected to a larger tumor size (P = 0.05) and positive lymph node status (P = 0.04). Prx V positivity was also connected with shorter survival (P = 0.04), whereas Prxs III (P = 0.002) and IV (P = 0.02) were related to better prognosis, probably resulting from their connection with a positive hormone receptor status. CONCLUSIONS: In conclusion, we found that expression of peroxiredoxins, especially III, IV and V, is increased in breast malignancy, suggesting the induction of Prxs as response to increased production of reactive oxygen species in carcinomatous tissue.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.     

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system

Depletion of glutathione in the substantia nigra is one of the earliest changes observed in Parkinson's disease (PD), and could initiate dopaminergic neuronal degeneration. Nevertheless, we have previously demonstrated that mesencephalic dopaminergic neurons in primary monolayer cultures are more resistant to the toxicity of glutathione depletion than nondopaminergic neurons. To extend this finding to a system that more closely resembles the in vivo situation, we characterized the effects of glutathione depletion on reaggregate cultures derived from ventral mesencephalic and their striatal target neurons, as well as supporting elements including glia. Dopaminergic neurons were found to be more resistant to the toxicity of buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis, than other nigrostriatal neurons, while striatal target cells exhibited an intermediate susceptibility when examined after 48 h. Glutathione depletion, however, decreased the intracellular content of catecholamines after 48 h and eventually led to the loss of dopaminergic neurons after 7 days. Our data indicate that the intrinsic resistance of dopaminergic neurons to the toxicity of glutathione depletion occurs in a variety of experimental paradigms, and suggest that global glutathione depletion alone is unlikely to account for the selective loss of dopaminergic neurons in PD. Rather, it is more likely that either the selective loss of glutathione from dopaminergic neurons, or the combination of glutathione loss with other insults contributes to the preferential death of dopaminergic neurons in PD.