三尖杉属植物中生物碱的研究——Ⅸ.三尖杉酯碱类似物的半合成及其抗白血病活性

报道三尖杉碱的十七个新的酯类化合物的半合成及其抗肿瘤作用。药理实验结果表明1,2,2+3,6和8有显著的抗癌活性,4,5,15和16有中等的抗肿瘤作用。通过化学结构和抗肿瘤活性的比较,初步探讨了此类生物碱的构效关系。     

Abstracts of the First FEPS Congress 9–12 September 1995, Maastricht, The Netherlands

Abstracts of the First FEPS Congress 9–12 September 1995, Maastricht, The Netherlands     

CYFRA 21-1 serum levels in women with adnexal masses and inflammatory diseases.

The aim of the present study was to evaluate the clinical usefulness of the cytokeratin marker CYFRA 21-1 as a screening marker for ovarian cancer, as a predictive marker in patients with adnexal masses and as a prognostic marker in women suffering from ovarian cancer. In order to determine the specificity of the CYFRA 21-1 test, we have investigated CYFRA 21-1 serum levels in several benign conditions. This retrospective study comprises 37 patients suffering from ovarian cancer FIGO stages Ia-III. Sera from patients with benign ovarian cysts, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and liver cirrhosis were evaluated in 90, 10, 38, 10 and 20 cases respectively. With a sensitivity of 41% and a specificity of 95%, CYFRA 21-1 was not suitable as a screening marker for ovarian cancer. Although CYFRA 21-1 was able to discriminate between ovarian cancer and benign adnexal tumours (univariate regression model, P = 0.0001), CYFRA 21-1 did not reveal additional information to CA 125 in a multivariate regression analysis (P = 0.06). CYFRA 21-1 serum levels were elevated in benign conditions such as liver cirrhosis, but not in endometriosis and inflammatory diseases. In ovarian cancer patients, elevated CYFRA 21-1 serum levels before therapy were associated with a poor overall and disease-free survival (log-rank test, P = 0.02 and log-rank test, P = 0.005 respectively). CYFRA 21-1, while obviously not suitable for screening or differential diagnosis of adnexal masses, could be useful as an additional prognostic factor in ovarian cancer patients.     

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Cytomegalovirus (CMV) has been associated with immunosuppression. Previously CMV was reported to interfere with signal transduction pathways in T cells. In this report the mechanisms underlying CMV-mediated immunosuppression were examined. Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO) cultures inhibited mitogenic T cell proliferative responses by > 95%. The inhibitory activity was observed 24 h through day 7 postinfection. The infection of MO was associated with a sustained elevation of intracellular levels of cAMP and the release of arachidonic acid (AA) and its metabolite PGE2 (activator of adenylate cyclase) in culture supernatants. The AA release was incidentally associated with TNF-alpha production. Monoclonal antibodies to TNF-alpha and pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE2 release. The release of AA required protein synthesis and occurred under conditions consistent with the expression of CMV immediate early genes. Treatment of MO cultures at time of infection with 100 microM indomethacin or 1 microg of TNF-alpha mAb abolished the CMV-induced T cell inhibitory activity of the supernatants by 100%. These data suggest that TNF dependent release of AA and PGE2 contributes to CMV-induced immunosuppression.     

Analysis of longitudinal data from twins

Longitudinal data from twin pairs may be used to determine how the genetic effects influencing a quantitative trait change with age. Here a model for mixed longitudinal data of Huggins and Loesch [1998] on unrelated individuals is extended to twin studies. The model is fitted using robust statistical methods and a bootstrap procedure is proposed to estimate the percentiles. The method is applied to longitudinal twin data on body mass index in male and female twin pairs aged 5-18 years.     

A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy

We performed a phase I trial of recombinant human interleukin-11 (rhIL- 11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels of rhIL-11 (10, 25, 50, 75, and 100 micrograms/kg/d). rhIL-11 alone was administered by a daily subcutaneous injection for 14 days during a 28-day prechemotherapy "cycle 0." Patients (pts) subsequently received up to four 28-day cycles of cyclophosphamide (1,500 mg/m2) and doxorubicin (60 mg/m2) chemotherapy followed by rhIL-11 at their assigned dose (days 3 through 14). Sixteen pts (13 stage IV, 3 stage IIIB) were accrued to this study. Median age was 53 years and median Eastern Cooperative Oncology Group Performance Status was 0. A grade 3 neurologic event was seen in 1 pt at 100 micrograms/kg. Because of the degree of grade 2 constitutional symptoms (myalgias/arthralgias and fatigue) at 75 micrograms/kg, dose escalation was stopped and 75 micrograms/kg was the maximally tolerated dose. No other grade 3 or 4 adverse events related to rhIL-11 were seen. The administration of rhIL-11 was not associated with fever. Reversible grade 2 fatigue and myalgias/arthralgias were seen in all pts at 75 micrograms/kg. Weight gain of 3% to 5% associated with edema was seen at doses > 10 micrograms/kg but a capillary leak syndrome was not seen. rhIL-11 alone was associated with a mean 76%, 93%, 108%, and 185% increase in platelet counts at doses of 10, 25, 50, and 75 micrograms/kg, respectively. No significant changes in leukocytes were seen. A mean 19% decrease in hematocrit was observed. Acute-phase proteins increased with treatment at all doses. Compared with patients at the 10 micrograms/kg dose, patients receiving doses > or = 25 micrograms/kg experienced less thrombocytopenia in the first two cycles of chemotherapy. We conclude that rhIL-11 has thrombopoietic activity at all doses studied, is well tolerated at doses of 10, 25, and 50 micrograms/kg, and at doses > or = 25 micrograms/kg has the potential to reduce chemotherapy-induced thrombocytopenia in this model.     

Ultrastructural evidence for alterations of pituicytes in reanimated rats in connection with experimentally induced clinical death

This work was undertaken to elucidate some ischaemic and postischaemic changes appearing in the neurohypophysial pituicytes of rats which underwent the incident of clinical death. The incident was experimentally induced by compression of the vascular bundle of the heart for 2.5 min. The ultrastructural organization of pituicytes was investigated directly after reanimation and 3 days after surviving the clinical death. These studies provided evidence for numerous alterations in pituicytes indicating a high sensitivity of the cells to the ischaemic conditions. Thus, four varieties of pituicytes were revealed based on their ultrastructural characteristic, namely: "swollen", "dark", "vacuolated" and "intermediate". Except for the "intermediate" pituicytes (abounding in liposomes), embedding of neurosecretory axons in pituicytes was commonly observed, and thus, several phases of axon degeneration due to pituicytes were noted, including disintegrated axolemma and appearance of a peculiar arrangement of microtubules. These findings strongly support the hypothesis of neuronal-glial interaction in the neurohypophysis under physiological and/or pathophysiological conditions. Thus, the results of the present study are discussed in terms of pituicytes involvement in the mechanisms of control (restriction) of neurohypophysial hormones release in reanimated rats.     

Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS)

Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.     

Surgical trauma and vein graft failure: further evidence for a role of ET-1 in graft occlusion

The saphenous vein (SV) is the most commonly used conduit for coronary artery bypass surgery. However, using traditional techniques, the occlusion rate for the SV is high, with over 50% of grafts failing within 10 years. In conventional coronary artery bypass surgery the SV is exposed to considerable damage during preparation for grafting. Recently, an increased graft patency has been described using a 'no-touch' technique, whereby the vein is prepared with minimal vascular trauma. There is evidence that the success of this form of coronary artery bypass surgery is a result, at least in part, of the retention of tissue-derived nitric oxide. We have examined the effects of conventional SV harvesting on vessel morphology, cell proliferation, endothelin-1 and its receptors. Considerable damage was observed in veins prepared using conventional surgery compared to 'no-touch' veins. The vessel wall exhibited evidence of surgical trauma, with regions of denudation of the luminal endothelium caused by distension. Endothelin-1 and endothelin-A receptors were present at subintimal regions of conventional SV segments where proliferating cells were identified. Endothelial endothelin-B receptors were also revealed that were absent at areas of distension-induced damage to the endothelium. These results suggest that endothelin-1 plays a role in vein graft failure, predominantly via the endothelin-A receptor.