Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

银杏叶提取物对兔心肌缺血再灌注损伤时中性粒细胞活化的影响

目的 观察兔心肌缺血再灌注前后ＰＭＮ（中性粒细胞）的活性变化过程。了解银杏叶提取物保护心肌是否与影响中性粒细胞活化作用有关。方法 取３０只日本大耳白兔随机均分为３组,假手术对照组、缺血再灌注组和实验用药组。用药方法：用自制的银杏叶提取物注射剂（总黄酮含量５ｍｇ／ｍｌ）５ｍｌ静滴给药。分别于冠脉结扎前和结扎缺血１ｈ后采血用布式显微镜观察白细胞活化状态的变化。检测白细胞表面粘附分子ＣＤ１１／ＣＤ１８表     

Ginkgo biloba extract EGb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors

Pretreatment of rats with the extract of Ginkgo biloba termed EGb761 reduced the behavioral sensitization induced by successive -amphetamine administrations (0.5 mg/kg) as estimated by increasing values of locomotor activity. EGb761 pretreatment also prevented the reduced density of [³H]dexamethasone binding sites in the dentate gyrus and the CA1 hippocampal regions of -amphetamine treated animals. These observations suggest that EGb761, by reducing glucocorticoid levels, could modulate the activity of the neuronal systems involved in the expression of the behavioral sensitization.     

Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography

The augmentation effect of (–)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-¹¹C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT_1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT_1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT_1A receptor occupancy was within the range 7–21% in the three subjects. The study confirms that the 5-HT_1A-receptor may be a clinically significant target for pindolol. Received: 8 March 1999 / Final version: 15 March 1999     

A high-yield and simplified procedure for the synthesis of α-[C]Methyl-l-tryptophan

Alpha-[¹¹C]methyl-l-tryptophan (AMT) has been synthesized by stereoselective methylation with [¹¹C]methyl iodide of the lithium-enolate generated by treating dimethyl 2(S),3a(R),8a(S)-(+)-hexahydro-8(phenylsulfonyl) pyrrolo[2,3-b]indole-1,2-dicarboxylate (2) with lithium diisopropyl amide (LDA) at −55 °C, followed by ring opening using trifluoroacetic acid and alkaline hydrolysis of the protecting groups. The crude product was purified by a simple reverse-phase C-18 Sep-Pak procedure. The purified product was isolated with an average radiochemical yield of 53 ± 12% (decay corrected) in 30–35 min from [¹¹C]methyl iodide. At end of synthesis (EOS), 138 ± 35 mCi (n = 24) of product was collected with a specific activity of ca. 1–1.3 Ci/μmol (EOS) (4–5 Ci/μmol @ EOB) starting from 1.5 Ci (EOB) of [¹¹C]CO₂.     

Immunocytochemical localization of 11 Beta-hydroxysteroid dehydrogenase in hippocampus and other brain regions of the rat

The dehydrogenase form of 11 β-hydroxysteroid dehydrogenase (11-DH) which catalyzes the oxidation of the biologically active steroid, corticosterone, to its inactive metabolite, 11-dehydrocorticosterone, is found in rat brain. The distribution and localization of 11-DH-like labeling in the rat brain was examined by immunocytochemistry. 11-DH-like immunostaining was found in all subfields of the hippocampus and in many other parts of the brain, including the preoptic area (POA), central nucleus of the amygdala, bed nucleus of the stria terminalis (NIST) and the cerebral cortex. Percentages of 11-DH-positive cells ranged from 10% in the POA and NIST to 50% to 60% in the hippocampus. When combined with neuronal or glial markers, 11-DH-like immunostaining was found to be predominantly localized within neurons, ranging from 10% or less glial labeling in hippocampus, amgydala and cortex to 22% glial labeling in the POA and NIST. Immunostaining was present in both the cytoplasmic and nuclear components of some cells in addition to their projections. In the kidney, 11-DH has been postulated to be a key component in a mechanism by which aldosterone gains access to renal Type I receptors despite the presence of much higher concentrations of glucocorticoids. The present data is consistent with a similar mechanism occurring in at least some parts of the brain, although the hippocampus appears to be an important exception because it does not appear to be differentially responsive to aldosterone in spite of its high 11-DH activity and immunoreactivity. However, the hippocampus is not implicated in neural control of salt appetite and fluid balance, whereas some of the other brain regions like the POA, NIST and amygdala are believed to be involved. Other aspects of 11-DH localization must therefore be examined in future studies, including the co-presence of mineraiocorticoid receptors and 11-DH in the same or adjacent cells and the possible significance of the relatively high glial localization of 11-DH immunoreactivity in the POA and NIST.     

红霉素环11,12-碳酸酯的体外抗菌活性研究

目的评 价红霉素环11，12-碳酸酯的体外抗菌活性。方法 采用琼脂平皿二倍稀释法测定国产和进口红霉素环11，12-碳酸酯对临床分离致病菌的体外抗菌作用，并与红霉素、罗红霉素、克拉霉素、地红霉素、阿奇霉素和乙酰螺旋霉素进行了比较。结果 国产和进口红霉素环11，12-碳酸酯对579株临床分离菌的抗菌活性相近，对革兰氏阳性菌和厌氧菌的抗菌活性比红霉素强2～8倍，优于罗红霉素、克拉霉素、地红霉索、阿奇霉素、乙酰螺旋霉素，但对革兰氏阴性菌的抗菌活性稍弱于阿奇霉素。红霉索环11，12-碳酸酯对金葡菌显示抑菌作用，对化脓链球菌在2～4倍MIC浓度时显示杀菌作用；红霉素环11，12-碳酸酯抗金葡菌和化脓链球菌的活性随着pH的增加而增强，接种量和血清浓度对国产红霉素环11，12-碳酸酯抗金葡菌和化脓链球菌的活性无明显影响。结论 红霉素环11，12-碳酸酯具有较强的体外抗菌活性，国产红霉素环11，12-碳酸酯抗菌活性与进口相近，优于红霉素、罗红霉素、克拉霉素、地红霉素、阿奇霉素和乙酰螺旋霉素。     

Isoform-specific effects of a novel BmK 11(2) peptide toxin on Na channels.

BmK 11(2) is a 7216Da polypeptide toxin purified from the venom of the scorpion Buthus martensii Karsch. Nanomolar concentrations of the toxin prolong amphibian nerve action potentials without attenuation of the amplitude. The pharmacological action of the toxin and its sequence similarity to other alpha-scorpion toxins suggest that BmK 11(2) selectively alters voltage-gated Na channels. In order to test whether BmK 11(2) preferentially modulates the gating or kinetics of certain channel isoforms, we applied BmK 11(2) to muscle, heart and neuronal Na channels. 100nM BmK 11(2) increased the peak current amplitude of skeletal muscle (micro1) and neuronal (N1E-115) Na currents by 40 and 20%, respectively, and reduced the cardiac Na (hH1) current by 15%. The toxin slowed current decay of all isoforms, most prominently in N1E-115 (tau(BmK)/tau(Control)=12), micro1 (11), and less so for hH1 (1.3). BmK 11(2) shifted the voltage dependence of activation of micro1 and N1E-115 currents. BmK 11(2) had no effect on steady-state inactivation, use-dependent availability, and the kinetics of entry into slowly recovering inactivated states.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.     

Efficient synthesis of [11C]befloxatone,a selective radioligand for the in vivo imaging of MAO‐A density using PET

Carbon‐11 labelled befloxatone ((5R)‐5‐(methoxymethyl)‐3‐[4‐[(3R)‐4,4,4‐trifluoro‐3‐hydroxybutoxy]phenyl]‐2‐oxazolidinone) is a reversible and selective monoamine oxidase‐A (MAO‐A) inhibitor and appears to be a new potent PET tracer for the in vivo imaging of MAO‐A density. In this paper, the radiosynthesis of befloxatone was investigated and orientated towards the preparation of multi milliCuries of radiotracer. Typically, using no‐carrier‐added [¹¹C]phosgene, 150–300 mCi (5.55–11.10 GBq) of [¹¹C]befloxatone was obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 500 to 2000 mCi/µmol (18.5–74.0 GBq/µmol). The high efficiency of these radiosyntheses allows for multi‐injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2003 John Wiley & Sons, Ltd.