人端粒酶逆转录酶启动子介导的靶向性肿瘤基因治疗的研究进展

端粒酶与肿瘤发生发展的关系是近年来肿瘤研究领域的热点之一．端粒的磨耗限制大多数体细胞的复制,肿瘤细胞主要通过转录上调端粒酶限制成分催化亚基端粒酶逆转录酶（hTERT）维持端粒长度．由于hTERT启动子区域已被克隆,其特点也已被鉴定,hTERT启动子介导的靶向性肿瘤基因治疗成为研究的热点．我们综述了hTERT启动子介导的靶向性肿瘤基因治疗最新研究进展．     

Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment.

Oropharyngeal candidiasis is the most common opportunistic infection seen in patients infected with the human immunodeficiency virus (HIV). As HIV disease progresses and immunosuppression worsens, the incidence and severity of oropharyngeal candidiasis increase. The predominant pathogen in initial and recurrent episodes is Candida albicans, which responds to a variety of topical (nystatin and clotrimazole) and systemic azole antifungal agents (ketoconazole, itraconazole, and fluconazole). Since the introduction of the oral azoles, increasing evidence indicates that C. albicans strains are developing resistance to azoles, particularly fluconazole, and other Candida strains are emerging that are intrinsically less susceptible to azole therapy. The advent of effective antiretroviral therapies for the treatment of HIV disease has led to a scenario in which antifungal strategies are likely to be highly effective. To minimize the risk of resistance, topical therapies should be considered first-line candidates for treatment of initial or recurrent cases of uncomplicated oropharyngeal candidiasis. Systemic azole therapy should be reserved for cases unresponsive to topical therapies or for more severe oropharyngeal candidiasis with esophageal involvement.     

Fibrinopeptide A and the phosphate content of fibrinogen in venous thromboembolism and disseminated intravascular coagulation

Concentrations of plasma fibrinopeptide A (FPA) were measured by radioimmunoassay in 50 patients with venous thromboembolism or disseminated intravascular coagulation or both. A consistent discrepancy was observed in values obtained with two anti-FPA antisera. Analysis of extracts from plasma of these patients by high-performance liquid chromatography (HPLC) revealed the presence of a phosphorylated and an unphosphorylated form of the A peptide. Differences in concentrations of FPA measured with the two antisera could be accounted for by their different reactivity with phosphorylated FPA (FPA-P). The differences were abolished by treatment with alkaline phosphatase. A good correlation was observed between the FPA-P content of free A- peptide material and of fibrinogen in plasma as determined by HPLC (r = .88, P less than .001, n = 11). In patients with elevated FPA levels, the mean FPA-P content of fibrinogen was significantly higher (P less than .002, n = 13) than in patients with normal FPA levels (n = 8) and in healthy controls (n = 14). Phosphorus in fibrinogen did not correlate with fibrinogen degradation products or fibrinogen levels and became normal on adequate anticoagulation. Therefore, blood-clotting activation may lead to a high phosphate content of fibrinogen and of free FPA in plasma.     

Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study

Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.     

The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling

Highly active antiretroviral therapy (HAART), which includes HIV protease inhibitors (PIs), has been associated with bone demineralization. To determine if this complication reflects accelerated resorptive activity, we studied the impact of two common HIV PIs, ritonavir and indinavir, on osteoclast formation and function. Surprisingly, we find that ritonavir, but not indinavir, inhibits osteoclast differentiation in a reversible manner and also abrogates bone resorption by disrupting the osteoclast cytoskeleton, without affecting cell number. Ritonavir given in vivo completely blunts parathyroid hormone-induced osteoclastogenesis in mice, which confirms that the drug is bone sparing. In keeping with its antiresorptive properties, ritonavir impairs receptor activator of nuclear factor kappaB ligand-induced (RANKL-induced) activation of NF-kappaB and Akt signaling pathways, both critical to osteoclast formation and function. In particular, ritonavir is found to inhibit RANKL-induced Akt signaling by disrupting the recruitment of TNF receptor-associated factor 6/c-Src complex to lipid rafts. Thus, ritonavir may represent a bone-sparing PI capable of preventing development of osteopenia in patients currently on HAART.     

Studies investigating platelet aggregation and release initiated by sera from patients with thrombotic thrombocytopenic purpura

Many patients with thrombotic thrombocytopenic purpura (TTP) have a platelet aggregating factor in their serum that may be pathologically linked with the disease process. To help characterize the type of platelet aggregation and platelet release induced by the sera from seven TTP patients, we measured the ability of a variety of inhibitors of platelet function as well as the ability of monoclonal antibodies (MoAbs) against platelet glycoproteins to inhibit TTP sera-induced platelet aggregation and release. These results were compared with the ability of the same inhibitors to block platelet aggregation induced by ristocetin, collagen, ADP, thrombin, and IgG-immune complexes. Monoclonal antibody directed against platelet glycoprotein Ib totally inhibited ristocetin-induced aggregation and release but had no effect on aggregation and release induced by the TTP sera or by any of the other platelet agonists. However, the MoAb against glycoproteins IIb/IIIa inhibited aggregation and release caused by TTP sera as well as by collagen, thrombin, and ADP but had no effect on aggregation and release induced by ristocetin. The aggregating activity could be abolished by heparin but not by the serine protease inhibitor PMSF (1 mmol/L). And although monomeric human IgG and purified Fc fragments of IgG inhibited IgG-immune complex-induced aggregation and release, they had no effect on TTP sera-induced aggregation and release nor on aggregation and release induced by any of the other agonists. Consistent with these in vitro studies showing no effect of IgG were the in vivo observations that intravenous (IV) IgG was without effect when administered to three patients with TTP. This study indicates that although a von Willebrand factor (vWF)-rich preparation of cryoprecipitate enhances the in vitro platelet aggregation and release caused by sera from the seven TTP patients we studied, the pathway of aggregation and release is not via platelet glycoprotein Ib. Also the aggregating factor of TTP sera is not neutralized in vitro or in vivo by IgG.