基本药物今昔25年

二十世纪初 ,广为普及的现代药物只有一个 :乙酰水杨酸 (阿司匹林 )。二十世纪四十年代 ,人类发现第一种抗菌素、第一种批量生产的抗疟药和第一种抗痨药。五、六十年代 ,很快研制出口服避孕药 ,治疗糖尿病的药 ,及治疗精神疾病、各种感染疾病、心血管疾病和癌症的药物。到七十年代 ,几乎每大类疾病都能找到有效药物 ,尽管这些药物的效果不很理想。但全球约有一半的人口似乎依然生活在十九世纪。他们由于贫穷 ,得不到、买不起现代药物 ;因用法不当而不能正确发挥药物疗效。1 975年 ,世界卫生大会提出“基本药物”和“国家药品政策”的概念 ,…     

Native aortic valve tissue systemic embolization complicating bacterial endocarditis

Systemic embolic events are known complications of bacterial endocarditis. Embolization of prosthetic valves has previously been reported in the literature. We report a case of embolization of native aortic valve tissue to the popliteal artery as the presenting event in a patient with subacute bacterial endocarditis. To our knowledge, this rare complication has not been previously reported.     

Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: switching between enzymatic and genetic function?

The iron-responsive element-binding protein (IRE-BP) is an RNA-binding protein that regulates the expression of several mRNAs in response to availability of cellular iron. The iron-dependent control of IRE-BP activity has been reconstituted in vitro. Incubation of purified IRE-BP with iron salts in the presence of the reducing agent cysteine decreases IRE-BP binding to the cognate RNA element. The specificity of this effect is established by several parameters: (i) the interaction of the spliceosomal protein U1A with its U1 small nuclear RNA target sequence as an internal control is unaffected by iron perturbations, (ii) non-iron metals fail to mimic the iron effect, and (iii) iron chelator activates the IRE-binding activity of IRE-BP and titrates the effect of iron salts. Modulation of IRE-BP activity by chelatable iron is reversible and thus does not involve permanent alterations of the integrity of the protein. These findings accurately mirror the physiological basis for iron regulation of transferrin receptor mRNA stability as well as ferritin and erythroid 5-aminolevulinate synthase mRNA translation in vivo. We discuss these data vis-a-vis the structural homology of IRE-BP with the iron-sulfur protein aconitase and propose a mechanism by which the same cytoplasmic protein serves a dual function as an RNA-binding factor and an enzyme.     

Diagnostic dilemmas and potential pitfalls in the evaluation of endometrial adenocarcinoma

Endometrial adenocarcinoma is the most common malignancy of the gynaecologic tract, and therefore one of the most commonly encountered surgical pathology specimens. Accurate diagnosis, grading and staging are necessary to direct therapy for this common disease. Evaluation of these cases is usually straightforward. Some cases, however, may be complicated by a variety of issues such as difficulty assessing depth of invasion; difficulty assessing cervical involvement; possibility of synchronous ovarian primaries; evaluation of lymphovascular space invasion; difficulties with FIGO grade (especially in the company of altered differentiation); and subtle patterns of myoinvasion. The purpose of this review is to emphasize these problematic areas and offer straightforward guidelines to apply when these situations are encountered. Proper recognition of these diagnostic challenges will hopefully improve grading and staging accuracy, and subsequently therapy, for the multitudes of women affected by this disease.     

Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses

PURPOSE: Saccharomyces cerevisiae, a nonpathogenic yeast, has been used previously as a vehicle to elicit immune responses to foreign antigens, and tumor-associated antigens, and has been shown to reduce tumor burden in mice. Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic (CEA-Tg) mice (where CEA is a self-antigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specific T-cell responses and antitumor activity. EXPERIMENTAL DESIGN: CEA-Tg mice were vaccinated with yeast-CEA, and CD4(+) and CD8(+) T-cell responses were assessed after one and multiple administrations or vaccinations at multiple sites per administration. Antitumor activity was determined by tumor growth and overall survival in both pulmonary metastasis and s.c. pancreatic tumor models. RESULTS: These studies demonstrate that recombinant yeast can break tolerance and that (a) yeast-CEA constructs elicit both CEA-specific CD4(+) and CD8(+) T-cell responses; (b) repeated yeast-CEA administration causes increased antigen-specific T-cell responses after each vaccination; (c) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; and (d) tumor-bearing mice vaccinated with yeast-CEA show a reduction in tumor burden and increased overall survival compared to mock-treated or control yeast-vaccinated mice in both pulmonary metastasis and s.c. pancreatic tumor models. CONCLUSIONS: Vaccination with a heat-killed recombinant yeast expressing the tumor-associated antigen CEA induces CEA-specific immune responses, reduces tumor burden, and extends overall survival in CEA-Tg mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.