Aurora A激酶研究进展

Aurora A激酶是进化上保守的有丝分裂丝/苏氨酸激酶Aurora激酶家族成员之一,在细胞内随细胞周期的变化呈动态分布,它广泛的参与了细胞周期不同阶段的各种事件,并在人类多种恶性肿瘤的发生发展过程中起到了至关重要的作用,因而很有可能成为一个极具前途的恶性肿瘤的分子治疗靶点。     

A phase I trial of CGS 16949A. A new aromatase inhibitor

CGS 16949A is a new, nonsteroidal competitive inhibitor of the aromatase enzyme. In this Phase I trial, 16 heavily pretreated postmenopausal patients with metastatic breast cancer were treated with escalating doses of CGS 16949A from 0.6 to 16 mg total daily oral dose. No hematologic, biochemical, or significant clinical toxicity was encountered. Endocrinologic and pharmacologic data were available from 12 of these patients. Maximum inhibition of estrogen biosynthesis was observed at a dose of 2 mg CGS 16949A daily. At this dose, the inhibition of estrogen biosynthesis was equivalent to 1000 mg aminoglutethimide (AG). The fall in plasma and urinary estrogens without a concomitant drop in androgens confirmed the specific blockade of aromatase activity. At doses of 4 to 16 mg daily, CGS 16949A appeared to inhibit the C21-hydroxylase enzyme as well. The t1/2 of CGS 16949A in the circulation was 10.5 hours. Of 16 evaluable patients there were two partial responses and seven patients with stable disease.     

A gist of gastrointestinal stromal tumors: A review

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mes-enchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularlytargeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors.     

Expression of blood group A antigen during erythroid differentiation in A1 and A2 subjects

The expression of blood group A antigen on marrow and blood cells from A1 and A2 subjects was investigated by the binding of Helix pomatia and Dolichos biflorus lectins using immunofluorescence. These two lectins stained BFU-E-derived colonies from A subjects in the early days of culture before the expression of glycophorin. The erythroid origin of these cells was ascertained by the coexpression of two other very early erythroid markers. In bone marrow, the ultrastructural immunogold method revealed that the entire erythroid lineage including proerythroblasts was labeled by HPA, whereas no staining was observed on granulomonocytic cells including myeloblasts. Platelets from A subjects were HPA-labeled and so were platelets from an O subject preincubated in A plasma. Megakaryocytes obtained in CFU-MK-derived colonies were weakly and heterogeneously labeled by the HPA lectin. Cultures from A1 and A2 subjects were the reflection of the genetic differences only when investigations were performed on mature erythroblasts. In contrast, the great majority of immature erythroblasts both from A2 and A1 subjects were equally labeled by both lectins; during further erythroid maturation, binding of both lectins markedly diminished only on A2 erythroblasts. When marrow erythroblasts were investigated at electron microscopic level, heterogeneity of labeling among all stages of maturation was clearly observed in A2 subjects, with staining stronger on immature than on mature erythroblasts. Therefore, the genetic differences between A1 and A2 subjects are revealed during terminal erythroid differentiation.     

A novel CYP1A1 gene polymorphism in African-Americans

A new Mspl RFLP in the CYP1A1 gene has been found in genomicDNA from African-Americans. The polymorphism results from asingle A-T to G-C transition in the 3' noncoding region {smalltilde}300 bp upstream from the polyadenylation site. This mutationleads to cleavage of the normal 2.3 kb Mspl restriction fragmentinto 1.3 and 1.0 kb fragments. The heterozygous mutation hasbeen seen in 8 of 47 African-Americans, but was not detectedin 191 Caucasians or 30 Asians. No linkage was observed witheither of the two previously described polymorphisms in thisgene.     

A human monoclonal antibody that binds serotype A botulinum neurotoxin

Monoclonal antibodies have demonstrated significant potential as therapeutics for botulinum neurotoxin exposures. We previously described a hybridoma method for cloning native human antibodies that uses a murine myeloma cell line that ectopically expresses the human telomerase catalytic subunit gene (hTERT) and the murine interleukin-6 gene (mIL-6). Here we describe a heterohybridoma cell line that ectopically expresses mIL-6 and hTERT and has improved stability of hTERT expression. We fused this cell line to human peripheral blood B cells from a subject who had received the botulinum toxoid vaccine, cloning a high-affinity antibody (13A) specific for serotype A botulinum neurotoxin (BoNT/A). The 13A antibody is an affinity-matured, post-germinal center IgG(1) lambda antibody that has partial neutralization activity in vivo. 13A binds an epitope on BoNT/A that overlaps the binding epitope of an IgG antibody previously shown to fully neutralize a lethal dose of BoNT/A in vivo. The 13A antibody may be useful for diagnostic testing or for incorporation into an oligoclonal therapeutic to counteract BoNT/A exposure.     

Comparison of intracytoplasmic A particles and intracisternal A particles.

Intracytoplasmic A particles and intracisternal A particles are associated with mouse tumors of various types, and both can coexist in the cytoplasm of the same cell. The designation of both as A particles is based on the recognition that they share morphological similarities. A comparison of purified isolates of these two particles reveals that the structural protein profiles are different, but that there is some antigenic cross-reaction as demonstrated by immunodiffusion and complement fixation. This result does not appear to involve the major structural protein of intracisternal A particles, but may reflect the presence of common antigenic determinants located on minor proteins.     

细节决定成败：神经外科的信条之一

成功的手术应该是由于正确的理由对正确的患者和疾病在正确的时间进行的正确的一系列围手术期处理和外科操作过程，每一个细节决定了手术的成败，患者的安全取决于许多方面：患者疾病的性质，医生的素质和技术，以及生活和工作的环境。因此其是一个系统工程。所以，完整的神经外科治疗过程是应包括术手术适应证和手术时机选择、术前计划、手术实施、围手术期的处理和后期康复等一整套的侦查、判断、决策的过程。