4-O-卤代酰基-4′-去甲基表鬼臼毒素类似物的合成与抗肿瘤活性

为考察4′-去甲表鬼臼毒素C₄位上联结含卤素原子的酯化侧链时对化合物抗肿瘤活性的影响,设计并采用选择性酯化方法合成了9个新的4′-去甲基表鬼臼毒素酯化产物。其中标题化合物在L₁₂₁₀白血病肿瘤细胞与KB细胞的体外生长抑制试验中普遍表现出显著的抑制活性,大部分化合物活性超过依托泊甙。而普通脂酸酯的活性较弱。     

Simulation and its role in medical education

Medical education is increasingly laying emphasis on a curriculum based on cognitive, psychomotor, and affective domains of learning which were originally proposed nearly 50 years ago. These reforms are framed around best standards of care, error management and patient safety, patient autonomy, and resource allocation. There is a worldwide shift in the method of medical education towards experiential (‘hands-on’) medical learning; however, applying this concept to real patients is less acceptable to society and is subject to legal and ethical issues.     

Characterization of a factor IX variant with a glycine207 to glutamic acid mutation

Factor IXTaipei9 is a factor IX variant from a hemophilia B patient with reduced levels of circulating protein molecules (cross-reacting material reduced, CRM). This variant contained a glycine (Gly) to glutamic acid (Glu) substitution at the 207th codon of mature factor IX. The functional consequences of the Gly-->Glu mutation in factor IXTaipei9 (IXG207E) were characterized in this study. Plasma-derived IXG207E exhibited a mobility similar to that of normal factor IX on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its specific activity was estimated to be 3.5% that of the purified normal factor IX in a one-stage partial thromboplastin time assay (aPTT). Cleavage of factor IXG207E by factor XIa or factor VIIa-tissue factor complex appeared to be normal. When the calcium-dependent conformational change was examined by monitoring quenching of intrinsic fluorescence, both normal factor IX and IXG207E exhibited equivalent intrinsic fluorescence quenching. Activated factor IXG207E (IXaG207E) also binds antithrombin III equally as well as normal factor IXa. However, aberrant binding of the active site probe p-aminobenzamidine was observed for factor XIa-activated factor IXG207E, indicating that the active site pocket of the heavy chain of factor IXaG207E was abnormal. Moreover, the rate of activation of factor X by factor IXaG207E, as measured in a purified system using chromogenic substrates, was estimated to be 1/40 of that of normal factor IXa. A computer-modeled heavy-chain structure of factor IXa predicts a hydrophobic environment surrounding Gly-207 and this Gly forms a hydrogen bound to the active site serine-365. The molecular mechanism of the Gly-->Glu mutation in factor IXTaipei9 might result in the alteration of the microenvironment of the active site pocket which renders the active site serine-365 inaccessible to its substrate.     

The treatment of malignant histiocytosis

Twenty-four consecutive cases of malignant histiocytosis (MH) treated at Stanford Medical Center between 1973 and 1983 have been reviewed. Most patients presented with systemic symptoms (91%) and advanced disease (stage IV, 80%). Multiple organ involvement was common. In six cases, pathologic tissue was further characterized by frozen section immune histochemistry, using a panel of monoclonal antibodies known to react with monocytes and macrophages, as well as a variety of hematopoietic cells. One case expressed a mature monocyte/macrophage phenotype; three cases were considered null cell or primitive lesions; and two cases were identified as probable T cell lymphomas. Seven patients underwent splenectomy. Two patients died prior to any treatment. Twenty-two patients were treated with CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) +/- bleomycin (B), +/- midcycle high-dose methotrexate (HD-MTX) with leucovorin rescue. Seven patients received prophylactic intrathecal MTX. Of 22 evaluable patients, there was a 68% complete response rate (CR), a 23% partial response rate (PR), and a 9% no response rate (NR). Median duration of CR was 30+ months; median duration of PR was 2.4 months. Median survival for patients attaining a CR has not been reached v 3 months for the PR and NR groups. For all 24 patients, median survival was 2 years, with a 5-year actuarial survival of 40%. Multivariate analysis revealed that a platelet count less than 150,000 (P Cox = .005) and the dose of drug delivered (P Cox = .057) were the most important prognostic factors. Prophylactic intrathecal MTX therapy and splenectomy did not influence survival. Although MH is an aggressive disease with a poor prognosis, it is potentially curable. Systematic and aggressive treatment should further improve the outcome.     

Multiple unconfirmed-reactive screening tests for viral antibodies among blood donors

BACKGROUND: In December 1991, the United States Food and Drug Administration received reports of blood donations with unconfirmed reactivity on screening tests for antibodies to human immunodeficiency virus, human T-lymphotropic virus type I, and hepatitis C virus (HCV). Of 91 donors with these test results, 57 (63%) reported a recent influenza vaccination. STUDY DESIGN AND METHODS: To determine the extent of unconfirmed reactivity, the time at which it began, and its association or nonassociation with specific manufacturers' tests, a nationwide survey of blood centers was conducted. A case-donation was defined as a blood donation that was repeatedly reactive, but not confirmed positive, on at least two of the three tests from May 1990 through December 1991. RESULTS: Among 14 million donations screened by 110 centers, 582 case-donations were identified. An increase in case- donations was evident in the fall of 1990 (2.8/100,000 donations). In 1991, rates increased from 0.9 per 100,000 donations in the first quarter to 1.3, 3.2, and 19.7 in subsequent quarters. A significantly higher rate of case-donations was observed among donations tested with one of the two available anti-HCV screening tests (8.0 vs. 1.2/100,000 donations; risk ratio = 6.8; 95% CI = 5.4-8.5). CONCLUSION: Although unconfirmed reactivity on multiple screening tests appeared to be seasonal, its documentation prior to the availability of influenza vaccine in 1991 and higher rates among donations tested with one manufacturer's anti-HCV test indicated that test-specific factors were also involved.     

Prevalence of Human T Cell Leukaemia Virus amongst Blood Donors

Background

Human T cell leukaemia virus (HTLV) I/II are retroviruses implicated in transfusion transmitted infection. Present study was undertaken to assess seroprevalence of HTLV in voluntary blood donors along with pattern of blood utilisation. Methods: A total of 258 healthy blood donors who were free from infectious markers in transfusion as per current transfusion guidelines were enrolled. They were screened for HTLV-I/II antibodies by commercially available enzyme immuno assay (EIA) and their blood utilisation data was analysed.

Result

Five (1.9%) donors were found seropositive for HTLV-I/II of which 1.2 % were first time and 0.9% were repeat donors. Blood utilisation data revealed 20.9% and 38.8% units were utilised within 5 and 6–14 days of collection respectively. 45.9% recipients were transfused with single blood unit. 42.9% recipients were immunosuppressed due to underlying disease. Conclusion: The high prevalence of HTLV in blood donors, coupled with single unit transfusion, use of fresh blood, non availability of acellular blood products and immunosuppression in recipients can lead to significant transfusion transmitted HTLV infection. We suggest judicious use of blood products and screening of blood donors in prevention of transfusion transmitted HTLV-I/II.Key Words: HTLV-I/II, Blood donors; Transfusion transmitted infection; Retrovirus     

Interactions between human mesenchymal stem cells and natural killer cells

Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for regenerative medicine. They possess unique immunomodulatory properties, being capable of suppressing T-cell responses and modifying dendritic cell differentiation, maturation, and function, whereas they are not inherently immunogenic, failing to induce alloreactivity to T cells and freshly isolated natural killer (NK) cells. To clarify the generation of host immune responses to implanted MSCs in tissue engineering and their potential use as immunosuppressive elements, the effect of MSCs on NK cells was investigated. We demonstrate that at low NK-to-MSC ratios, MSCs alter the phenotype of NK cells and suppress proliferation, cytokine secretion, and cyto-toxicity against HLA-class I- expressing targets. Some of these effects require cell-to-cell contact, whereas others are mediated by soluble factors, including transforming growth factor-beta1 and prostaglandin E2, suggesting the existence of diverse mechanisms for MSC-mediated NK-cell suppression. On the other hand, MSCs are susceptible to lysis by activated NK cells. Overall, these data improve our knowledge of interactions between MSCs and NK cells and consequently of their effect on innate immune responses and their contribution to the regulation of adaptive immunity, graft rejection, and cancer immunotherapy.