An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

The conserved oligomannose epitope, Man₉GlcNAc₂, recognized by the broadly neutralizing human mAb 2G12 is an attractive prophylactic vaccine candidate for the prevention of HIV-1 infection. We recently reported total chemical synthesis of a series of glycopeptides incorporating one to three copies of Man₉GlcNAc₂ coupled to a cyclic peptide scaffold. Surface plasmon resonance studies showed that divalent and trivalent, but not monovalent, compounds were capable of binding 2G12. To test the efficacy of the divalent glycopeptide as an immunogen capable of inducing a 2G12-like neutralizing antibody response, we covalently coupled the molecule to a powerful immune-stimulating protein carrier and evaluated immunogenicity of the conjugate in two animal species. We used a differential immunoassay to demonstrate induction of high levels of carbohydrate-specific antibodies; however, these antibodies showed poor recognition of recombinant gp160 and failed to neutralize a panel of viral isolates in entry-based neutralization assays. To ascertain whether antibodies produced during natural infection could recognize the mimetics, we screened a panel of HIV-1-positive and -negative sera for binding to gp120 and the synthetic antigens. We present evidence from both direct and competitive binding assays that no significant recognition of the glycopeptides was observed, although certain sera did contain antibodies that could compete with 2G12 for binding to recombinant gp120.     

Differential expression of drug-resistance-related genes between sensitive and resistant blasts in acute myeloid leukemia

Drug resistance constitutes a considerable problem in the therapy of acute myeloid leukemia (AML). In order to identify genes which might be related to drug resistance, we retrospectively studied gene expression patterns in blast populations of 14 patients with de novo AML, focusing on known or potential resistance mechanisms against cytosine arabinoside and anthracyclines. Following induction and postremission chemotherapy, 7 patients achieved a complete remission (CR) for more than 1 year, while 7 patients showed blast persistence (BP) after induction and salvage chemotherapy. Gene expression analysis was performed using RNA extracted from archived guanidine extracts and Affymetrix HGU133A gene chips. We utilized the Gene Ontology category Biological Process to select genes implicated in DNA metabolism, nucleoside and nucleotide metabolism and transport, reactive oxygen species metabolism, apoptosis and response to drugs and identified 32 differentially expressed genes. From this functional perspective, we found differences between the CR and BP groups with regard to nucleotide metabolism (PBEF1, G6PD; p = 0.048), apoptosis (TNFAIP3, TNFAIP8, MPO, BCL2A1, BAX, SON, BNIP3L; p = 0.039) and reactive oxygen species metabolism (SOD2, KIAA0179; p = 0.048). However, the attempt to construct a predictive model of chemoresistance failed. BP samples had a 2-fold higher expression of CD34 than CR samples. Thus, our findings are in line with reports describing differences in apoptosis resistance between CD34+ and CD34- blast populations. Taken together, our results suggest that drug resistance in AML is a heterogenous phenomenon that might be better defined by means of disturbed biological processes than by focusing on the alteration of the expression of distinct genes.     

商陆多糖Ⅱ体外对小鼠脾细胞增殖及产生集落刺激因子的影响

用[³H]TdR参入法检测小鼠脾细胞增殖能力及产生集落刺激因子(colony stimulating factor. CSF)含量.证明商陆多糖Ⅱ(PAP-Ⅱ)在31～500 μg·m^-1范围内显著促进小鼠稗细胞增殖。PAP-Ⅱ,31～125 μg·ml^-1可剂量依赖性地促进Con A(1,2.8μg·ml^-1),LPS(3,10,30 μg·ml^-1)诱导的淋巴细胞细咆增殖,随着PAP-Ⅱ剂量加大,对丝裂原诱导的淋巴细胞增殖反呈抑制作用。PAP-Ⅱ。10～500μg·ml^-1呈剂量及时间依赖性地促进脾细胞产生CSF,其最适剂量为100 μg·ml^-1。最佳时间为5 d,提示PAP-Ⅱ能增强免疫及促进造血功能。     

Interferon alfa as primary treatment of chronic myeloid leukemia: long-term follow-up of 71 patients observed in a single center.

The purpose of this study was to evaluate the long-term outcome of interferon (IFN) alfa treatment in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). Between 1984 and 1990, a total of 71 patients with newly diagnosed CML had been enrolled into two consecutive IFN trials at our institution. Follow-up extended to December 1998, resulting in a median observation period for surviving patients of 11.4 years. The median survival time from diagnosis was 5.9 years. A plateau in the actuarial survival curve was found from 8.2 to 12.3 years following diagnosis with a projected 10-year survival rate of 32%. 'Landmark' studies showed a significant survival advantage for patients with karyotype responses. Of 68 patients accessible to calculation of the Hasford score, three were in the high risk group, 24 belonged to the medium risk group, and 41 had low risk features. The majority of cytogenetic responders including all eight assessable patients in complete cytogenetic remission were in the low risk group. Achieving a cytogenetic remission was found to provide a survival advantage also for patients with low risk disease. Of the seven patients surviving more than 11 years, six were in continuous complete cytogenetic remission. Their favorable outcome appears to translate into an out-flattening of the survival curve for the 71 single center patients presented. It will be of interest to see whether prolonged follow-ups of the large multicentric randomized trials will similarly show a subset of long-term surviving patients with ongoing IFN-induced remission.