叶酸受体及其在介导药物靶向肿瘤细胞治疗中的应用

肿瘤细胞表面过度表达一系列受体,能与特异性的配体结合并诱导细胞内化.以这些受体为作用靶点,使药物与特异性配体结合即可将药物主动靶向肿瘤细胞.叶酸受体在多种肿瘤细胞特别是髓细胞白血病细胞中都有过度表达,它可通过介导细胞内化将叶酸摄取入细胞胞浆,利用叶酸受体进行肿瘤,特别是白血病的靶向性治疗颇有应用前景.本文就叶酸受体生物学性质、染色体定位及与配体的相互作用,叶酸受体在正常组织、肿瘤组织,特别是白血病细胞中的分布特点,以及叶酸受体介导主动靶向肿瘤细胞,特别是白血病细胞的研究进展进行了概述.     

Identification of a Folate Receptor-Targeted Near-Infrared Molecular Contrast Agent to Localize Pulmonary Adenocarcinomas

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Effect of Observer Experience in the Differentiation Between Benign and Malignant Liver Tumors After Ultrasound Contrast Agent Injection

Objective. The purpose of this study was to assess the impact of the observer level of experience on the diagnostic performance of contrast‐enhanced ultrasound imaging (CEUS) for differentiation between benign and malignant liver tumors. Methods. From a computerized search, we retrospectively identified 286 biopsy‐proven liver tumors (105 hepatocellular carcinomas, 48 metastases, 7 intra‐hepatic cholangiocarcinomas, 33 liver hemangiomas, and 93 nonhemangiomatous benign lesions) in 235 patients (140 male and 95 female; mean age ± SD, 56 ± 11 years) who underwent CEUS after sulfur hexafluoride‐filled microbubble injection. The digital cine clips recorded during the arterial (10–35 seconds from injection), portal (50–120 seconds), and late (130–300 seconds) phases were analyzed by 6 independent observers without experience (group 1, observers 1–3) or with 2 to 10 years of experience in CEUS (group 2, observers 4–6). Specific training in the diagnostic and interpretative criteria was provided to the inexperienced observers. Each observer used a 5‐point scale to grade diagnostic confidence: 1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; or 5, definitely malignant on the basis of the enhancement pattern during the arterial phase and enhancement degree during the portal and late phases compared with the liver (hypoenhancement indicating malignant and isoenhancement to hyperenhancement indicating benign). Results. The analysis of observer diagnostic confidence revealed higher intragroup (κ = 0.63–0.83) than intergroup (κ = 0.47–0.63) observer agreement. The experienced observers showed higher diagnostic performance in malignancy diagnosis than did inexperienced observers (overall accuracy: group 1, 63.3%–72.8%; group 2, 75.9%–93.1%; P < .05, χ² test). Conclusions. The diagnostic performance of CEUS in liver tumor characterization was dependant on the observer's level of experience.     

子宫内膜癌T分期经阴道超声与病理诊断对照研究

目的通过与病理对照研究,探讨经阴道超声子宫内膜癌的表现与分期的相关性。方法41例子宫内膜癌经阴道超声检查,先观察子宫内膜及肌层的二维图像,记录二维图像特征,然后观察彩色血流情况,测得动脉血流阻力指数并记录。最后将超声结果与手术病理分期结果对照,进行统计学处理。结果经阴道腔内超声测得内膜厚度范围5.6~52mm,Ⅰa期患者平均子宫内膜厚度为7.2mm,Ⅰb期为23.2mm,Ⅰc期为29.7mm,各期之间有显著差异(P<0.01);Ⅰa期为66.6%(2/3例),Ⅰb期为85.7%(18/21例),Ⅰc期血流显示率为88.2%(15/17例),肿瘤内血流分级越高,肿瘤浸润深度越深;Ⅰa期患者阻力指数平均为0.52,Ⅰb期为0.42,Ⅰc期为0.50,肿瘤内血管的阻力指数在各期肿瘤中无显著差异。结论经阴道超声检查可提供子宫内膜厚度和血流情况的准确信息,二者与子宫内膜癌的浸润深度相关,可作为子宫内膜癌手术前分期的检查方法。     

超声超影联合ROMA指数列线图模型在卵巢上皮性癌中的诊断价值

目的：探究超声造影联合卵巢癌风险模型(ROMA)指数列线图模型在卵巢上皮性癌(EOC)中的诊断价值。方法：以2019年4月至2022年4月在甘肃省妇幼保健院妇科就诊,初步诊断为卵巢肿物且接受手术治疗的214例患者为目标人群进行回顾性研究。将2019年4月至2020年12月收治的130例患者作为建模集,2021年1月至2022年4月收治的84例患者作为验证集。根据病理诊断结果,将建模集分为良性肿瘤组(n=85)和EOC组(n=45)。比较两组患者ROMA指数及超声造影定量参数,通过logistic回归筛选差异因子建立列线图诊断模型,通过建模集及验证集的校准曲线及ROC曲线验证列线图模型对EOC的诊断价值。结果：与良性肿瘤组患者比较,EOC组患者CA125阳性比例、HE4阳性比例、ROMA阳性比例,PI、V1、TIC-AUC显著升高(P<0.05),IT、TTP显著降低(P<0.05)。多因素logistic回归结果示,ROMA、IT、TTP、PI、TIC-AUC是EOC患者和良性肿瘤组患者的差异因子(P<0.05)。建模集和验证集ROC曲线下面积分别为0.919(95%CI：0.873-0.965,P<0.001)、0.835(95%CI：0.737-0.933,P<0.001)。当诊断概率取最佳截断值0.244时,列线图诊断模型的灵敏度、特异度、准确度分别为86.67%、80.00%、82.31%。结论：超声造影定量参数联合ROMA指数构建的列线图模型区分度和校准度较好,对EOC患者具有较高的诊断价值。     

亚微米级超声微泡造影剂的制备及体外基因转染效率的实验研究

目的 探索制备亚微米级超声微泡造影剂的方法 ,以GFP作为目的 基因验证其作为一种新型基因载体的可行性.方法 以高剪切分散法制备超声微泡造影剂,透射电镜及激光粒度分析仪检测其形态及粒径;将超声微泡造影剂与不同剂量的绿色荧光蛋白质粒PShuttle-IRES-hrGFP-1结合后转染HepG2细胞,利用荧光显微镜观察并检测其基因转染效率.结果 自制超声微泡造影剂为均匀分散的圆泡,粒径分布在282.2～415.7 nm之间,平均值为(335±5)nm,达到亚微米级;该微泡能将GFP基因成功转运到HepG2细胞内并高效表达,转染效率达32.61%±3.42%.结论 自制亚微米级超声微泡造影剂粒径小、分散均匀,并能成功转运外源DNA进入细胞内,可作为一种新型基因载体.     

3-D Quantitative Dynamic Contrast Ultrasound for Prostate Cancer Localization

To investigate quantitative 3-D dynamic contrast-enhanced ultrasound (DCE-US) and, in particular 3-D contrast-ultrasound dispersion imaging (CUDI), for prostate cancer detection and localization, 43 patients referred for 10–12-core systematic biopsy underwent 3-D DCE-US. For each 3-D DCE-US recording, parametric maps of CUDI-based and perfusion-based parameters were computed. The parametric maps were divided in regions, each corresponding to a biopsy core. The obtained parameters were validated per biopsy location and after combining two or more adjacent regions. For CUDI by correlation (r) and for the wash-in time (WIT), a significant difference in parameter values between benign and malignant biopsy cores was found (p?<?0.001). In a per-prostate analysis, sensitivity and specificity were 94% and 50% for r, and 53% and 81% for WIT. Based on these results, it can be concluded that quantitative 3-D DCE-US could aid in localizing prostate cancer. Therefore, we recommend follow-up studies to investigate its value for targeting biopsies.     

Influence of Repetitive Contrast Agent Injections on Functional and Molecular Ultrasound Measurements

Quantitative contrast-enhanced ultrasound plays an important role in tumor characterization and treatment assessment. Besides established functional ultrasound techniques, ultrasound molecular imaging using microbubbles targeted to disease-associated markers is increasingly being applied in pre-clinical studies. Often, repeated injections of non-targeted or targeted microbubbles during the same imaging session are administered. However, the influence of repeated injections on the accuracy of the quantitative data is unclear. Therefore, in tumor-bearing mice, we investigated the influence of multiple injections of non-targeted microbubbles (SonoVue) on time to peak and peak enhancement in liver and tumor tissue and of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agents (MicroMarker) on specific tumor accumulation. We found significantly decreasing values for time to peak and a tendency for increased values for peak enhancement after multiple injections. Repeated injections of VEGFR2-targeted microbubbles led to significantly increased tumor accumulation, which may result from the exposure of additional binding sites at endothelial surfaces caused by mechanical forces from destroyed microbubbles.     

USA Update on Paclitaxel in Ovarian Cancer

In the United States, the role of paclitaxel in the treatment of advanced ovarian cancer has expanded markedly in the last 2 years. The drug was initially approved by the Food and Drug Administration for refractory ovarian cancer. However, on the basis of a large prospective randomized trial by the Gynaecologic Oncology Group, paclitaxel together with a platinum compound has now become accepted as a standard form of chemotherapy for previously untreated patients with ovarian cancer. There still remain many unanswered questions as how to best utilize paclitaxel together with platinum compounds. Clinical trials are currently in progress evaluating the dose intensity of paclitaxel, the effect of schedule of administration, and the relative efficacy and toxicity of paclitaxel plus carboplatin vs. paclitaxel plus cisplatin.     

Estimating the Delivery Efficiency of Drug-Loaded Microbubbles in Cancer Cells with Ultrasound and Bioluminescence Imaging

The application of drug-loaded microbubbles (MBs) in combination with ultrasound (US), which results in an increase in capillary permeability at the site of US-sonication-induced MB destruction, may be an efficient method of localized drug delivery. This study investigated the mechanism underlying the US-mediated release of luciferin-loaded MBs through the blood vessels to targeted cells using an in vivo bioluminescence imaging (BLI) system. The luciferin-loaded MBs comprised an albumin shell with a diameter of 1234 ± 394 nm (mean ± SD) and contained 2.48 × 10⁹ bubbles/mL; within each MB, the concentration of encapsulated luciferin was 1.48 × 10⁻¹⁰ mg/bubble. The loading efficiency of luciferin in MBs was only about 19.8%, while maintaining both the bioluminescence and acoustic properties. In vitro and in vivo BLI experiments were performed to evaluate the US-mediated release of luciferin-loaded MBs. For in vitro results, the increase in light emission of luciferin-loaded albumin-shelled MBs after destruction via US sonication (6.24 ± 0.72 × 10⁷ photons/s) was significantly higher than that in the luciferin-loaded albumin-shelled MBs (3.11 ± 0.33 × 10⁷ photons/s) (p < 0.05). The efficiency of the US-mediated release of luciferin-loaded MBs in 4T1-luc2 tumor-bearing mice was also estimated. The signal intensity of the tumor with US destruction at 3 W/cm² for 30 s was significantly higher than without US destruction at 3 (p = 0.025), 5 (p = 0.013), 7 (p = 0.012) and 10 (p = 0.032) min after injecting luciferin-loaded albumin-shelled MBs. The delivery efficiency was, thus, improved with US-mediated release, allowing reduction of the total injection dose of luciferin.     

Optimal Chemotherapy of Ovarian Cancer with an Old Regimen

When the optimal chemotherapy regimen for advanced ovarian cancer is discussed the following should be considered: the type and number of drugs, the dose of individual drugs and the number of cycles. Optimal chemotherapy should include a platinum compound, because platinum-based chemotherapy yields a superior response rate, progression-free survival and probably also superior long-term survival. However, the choice of platinum compound could be discussed. Several studies have shown similar effect of cisplatinum and carboplatin regimens, but if there is any difference in respect to effect, it is in favour of cisplatinum. Whether or not single drug platinum chemotherapy has an effect similar to that of combination chemotherapy is still under discussion, but most analyses favour combination chemotherapy. The combination should include at least an alkylating agent. Antracyclines are effective in advanced ovarian cancer and a meta-analysis including almost 1200 patients has shown superiority of regimens including antracyclines. However, the difference is not significant in individual randomized trials. Several randomized studies have examined the effect of the dose of chemotherapy, both cumulative dose and dose intensity. There is no convincing data to show that a higher dose will give better results. The number of cycles of chemotherapy is also discussed. Most studies employ five to ten cycles, but there are no well designed studies elucidating this question. It is generally agreed that at least six cycles should be given and that no concrete evidence is present about the benefit of additional treatment. In conclusion, a standard regimen for advanced ovarian cancer should include a platinum compound, cisplatinum or carboplatin and an alkylating agent. The dose should be cisplatinum 50–75 mg/m², cyclophosphamide 500–1000 mg/m² in six courses.     

Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery

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超声造影剂增强HIFU消融作用的病理学研究

目的探讨超声造影剂增强高强度聚焦超声（HIFU）消融生物组织作用的病理学改变。 方法24只新西兰大白兔按体质量配对分为两组，A组肝脏接受单纯HIFU辐照，B组动物接受辐照前经静脉注射超声造影剂SonoVue。辐照后测量组织凝固体积并观察光电镜下组织学及细胞超微结构改变。 结果A组与B组组织凝固体积分别为（0．07±0．02）cm^3和（0．21±0．06）cm^3（P＜0．05）。光镜下两组辐照区肝组织未见凝固性坏死，B组可见部分细胞膜及胞核破坏。电镜下两组辐照区细胞内均未见完整细胞器，均呈现不可逆凝固性坏死，A组辐照区细胞结构较B组清楚。 结论超声造影剂增加HIFU焦域体积并进一步破坏细胞结构，从而增强HIFU消融作用。     

超声造影联合血清学在卵巢癌早期筛查中的应用研究

目的 探讨超声造影指标联合血清学糖类抗原125 (CA125)、癌胚抗原(CEA)、人附睾分泌蛋白4(HE4)在卵巢癌早期筛查中的应用价值.方法 选取卵巢占位性病变患者105例,均行超声造影检查和血清CA125、CEA、HE4检查,分析超声造影联合血清CA125、CEA、HE4对卵巢癌的诊断效能.结果 相比良性组,卵巢...