Anticoagulant activity of sulfated polysaccharides

The paper reviews published data on the chemical structure of sulfated polysaccharides of animal, plant, and microbial origin as well as synthetic or semi-synthetic derivatives, and on the anticoagulant activity of these compounds in vitro and in vivo. The influence of sulfated polysaccharides on the plasma and cell hemostasis links is considered. Relationships between the structure and activity and the mechanisms of action are discussed.     

Structural and mutational analysis of a conserved gene (DGSI) from the minimal DiGeorge syndrome critical region

The majority of patients with DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAFS) and some individuals with familial or sporadic conotruncal cardiac defects have hemizygous deletions of chromosome 22. Most patients with these disorders share a common large deletion, spanning > 1.5 Mb within 22q11.21-q11.23. Recently, the smallest region of deletion overlap has been narrowed to a 250 kb area, the minimal DGS critical region (MDGCR), which includes the locus D22S75 (N25). We have isolated and characterized a novel, highly conserved gene, DGSI, within the MDGCR. DGSI has 10 exons and nine introns encompassing 1702 bp of cDNA sequence and 11 kb of genomic DNA. The encoded protein has 476 amino acids with a predicted mol. wt of 52.6 kDa. The intron-exon boundaries have been analyzed and conform to the consensus GT/AG motif. The corresponding murine Dgsi has been isolated and localized to proximal mouse chromosome 16. The mouse gene contains the same number of exons and introns, and the predicted protein has 479 amino acids with 93.2% identity to that of the human DGSI gene. By database searching, both genes have significant homology to a Caenorhabditis elegans hypothetical protein, F42H10.7. Further, mutation analysis has been performed in 16 patients, who have no detectable 22q11.2 deletion and some of the characteristic clinical features of DGS/VCFS. We have detected eight sequence variants in DGSI. These occurred in the 5'- untranslated region, the coding region and the intronic regions adjacent to the intron-exon boundaries of the gene. Seven of the eight variants were also present in normal controls or unaffected family members, suggesting they may not be of etiologic significance.      

Functional correction of short-chain acyl-CoA dehydrogenase deficiency in transgenic mice: implications for gene therapy of human mitochondrial enzyme deficiencies

We report the therapeutic effects of liver-specific expression of a short-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD- deficient mouse model. Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background. In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values. All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background. These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial enzyme deficiencies, as well as insights into the mechanisms of the disease.      

Genetics of multiple sclerosis [published erratum appears in Hum Mol Genet 1997 Nov;6(12):2189]

Multiple Sclerosis (MS) is a common chronic central nervous system disease in young adults. Relative familial risk appears to be determined largely by genes while population risk is strongly influenced by environmental factors. This is supported by genetic epidemiological studies which also suggest an oligogenic inheritance of susceptibility. The HLA DRB1*1501, DQA1*0102, DQB1 0602 haplotype is associated with the disease but HLA contributes only modestly to overall susceptibility. The results of three genomic searches are concordant with the genetic epidemiology and imply a number of genes with interacting effects will be found. Importantly, no single region has been identified with a major influence on familial risk.      

丙氧鸟苷对转TK基因的人外周血单个核细胞的毒性作用

目的 探讨减少异体干细胞移植中移植抗宿主病（GVHD）,同时最大限度提高移植抗白血病（GVL）效应的有效方法。方法 采用逆转录病毒介导的基因转移方法将I型单纯疱疹病毒胸苷激酶（HSV－TK）基因、绿色荧光蛋白（GFP）基因及抗新霉素（NeoR）基因插入人外周血单个核细胞（PBMC）,MTT法测定丙氧鸟苷（GCV）对转化细胞抑制率。结果 转化细胞表达GFP,且主要为T淋巴细胞,占11．4％,而且被转化的T淋巴细胞中,CD4阳性细胞转化率较高,占7．6％,CD8,CD19,CD33阳性细胞转化率分别为2．9％,2．1％和4．7％,PCR鉴定表明,转染的人外周血单个核细胞DNA中整合中有NeoR基因,MTT法测定丙氧鸟苷（GCV）对转化细胞与未转化细胞抑制率,显示转化细胞生长明显受抑。结论 异体干细胞移植后,如产生严重GVHD应用GCV选择性清除HSV－TK基因转导的T淋巴细胞,使控制GVHD已成可能。     

Effect of Transforming Growth Factor-β_2 on Phagocytosis in Cultured Bovine Trabecular Meshwork Cells

A gradual loss of cells occurs within the humantrabecular meshwork (TM) during normal aging andappears to be increased in patients with primary openangle glaucoma (POAG) [1] .The exactmechanism bywhich cells are lost in either condition is not known,however phagocytosis has been suggested[2 ] .It hasbeen found that,when compared with the non- POAGpatients,the level of transforming growth factor- β2(TGF- β2 ) which may be involved in the pathogenesisof POAG increased in the aqueous humo…     

Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66–84; placebo, 77 mo, IQR 69–85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80–1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m² compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC.Patient summaryIn the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC.This trial is registered at Clinicaltrials.gov as NCT01235962.