人肝癌裸鼠皮下移植瘤早期血液供应模式的定量研究

目的 定量评估不同时间点人肝癌裸鼠皮下移植瘤内血液供应模式的变化。方法 将1×10⁷/mL的MHCC97-H细胞悬液同一时间接种于40只裸鼠（0.2 mL/鼠）的左侧腹股沟皮下,分别于种瘤后第2、3、4、5周取瘤行HE染色和免疫组化染色（CD34和CD34/PAS双染色）,定量分析血管参数,包括微血管面积（microvascular area,MVA）、微血管密度（microvessel density,MVD）、血管生成拟态（vasculogenic mimicry,VM）,评估肿瘤内血管供应模式的变化。结果 随着肿瘤生长时间的延长,MVA先减小后增大,第3周肿瘤MVA小于第2周[（13 720.8±2 375.6）μm² vs.（28 795.5±3 412.7）μm²,P=0.013],第4周肿瘤MVA大于第3周[（29 221.3±3 958.5）μm² vs.（13 720.8±2 375.6）μm²,P=0.025];VM百分比呈明显升高趋势,第4周肿瘤VM百分比高于第2周（84.2%±15.4% vs.50.1%±14.6%,P=0.015）。结论 在人肝癌裸鼠皮下移植瘤新生血管形成的早期阶段,随着肿瘤生长时间的延长,VM逐渐成为肿瘤的主要血液供应模式。     

光学相干断层扫描血管造影在眼底微血管定量分析中的研究进展

光学相干断层扫描血管造影通过连续探测同一位置的血管内红细胞运动,生成三维血流信息,获取高分辨率的眼底血管图像。分频幅去相关血流成像演算技术,减少了因眼球轴向运动和组织运动产生的噪点及伪影,优化了信噪比,使得对毛细血管网的检测更具有连贯性。光学相干断层扫描血管造影目前已应用于糖尿病性视网膜病变、年龄相关性黄斑变性、视网膜血管阻塞、青光眼、中心性浆液性脉络膜病变等疾病的诊疗中,具有广阔的临床应用及科研前景。本文就光学相干断层扫描血管造影在眼底微血管定量分析中的应用作综合性论述。     

Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.Angiogenesis plays a central role in many diseases, including age-related macular degeneration (AMD), a leading cause of blindness. Advanced AMD exists in two forms, “atrophic” and “neovascular,” which are defined by the absence or presence of choroidal neovascularization (CNV), respectively (1). Neovascular AMD is characterized by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina (1). These vessels generally are immature in nature and leak fluid below or within the retina (2). Although growth factors are thought to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. The current standard of care for individuals with neovascular AMD is based on the targeting of VEGF, which promotes both angiogenesis and vascular permeability (3). However, although VEGF-targeted therapy attenuates angiogenesis and vascular permeability, it does not lead to complete vascular regression or disease resolution (3).The ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. The ω-6 LCPUFA, arachidonic acid (AA), and its cytochrome P450 (CYP)-generated metabolites (epoxyeicosatrienoic acids, EETs) recently have attracted much attention as a result of increasing evidence that they play a role in cancer as well as in cardiovascular disease (4–9). EETs are part of the VEGF-activated signaling cascade leading to angiogenesis (10) and promote tumor growth and metastasis (11). The major dietary ω-3 LCPUFAs are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are highly enriched in the central nervous system including the retina (12). The ω-3 LCPUFAs have antithrombotic, antiangiogenic, and anti-inflammatory properties, and they compete with ω-6 LCPUFAs as substrates for synthesis of downstream metabolites by CYP enzymes, cyclooxygenases (COX), and lipoxygenases (LOX) (6, 13–15). Moreover, dietary enrichment with ω-3 LCPUFAs has been shown to protect against pathological angiogenesis-associated cancer and retinopathy (2, 16–19). Of the three main pathways (COX, LOX, and CYP) involved in eicosanoid biosynthesis, the lipid mediators derived from the CYP branch are the most susceptible to changes in dietary fatty acid composition (20–23). The ω-3 double bond that distinguishes DHA and EPA from their ω-6 counterparts provides a preferred epoxidation site for specific CYP family members (20, 22). In fact, most CYP isoforms can metabolize EPA and DHA with significantly higher catalytic efficiency than AA, making them uniquely susceptible to variations in the availability of these lipids (19–22). CYP epoxygenases target the ω-3 double bond, resulting in an accumulation of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) derived from EPA and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from DHA (20, 22). Very recently, it was recognized that19,20-EDP inhibits angiogenesis, tumor growth, and metastasis (24). Thus, it appears that the CYP–epoxygenase pathway has the capacity to produce proangiogenic metabolites from ω-6 LCPUFAs (10, 11) and antiangiogenic metabolites from ω-3 LCPUFAs (24). This unique feature of the CYP enzymes may provide a previously unidentified mechanistic link between the ω-6/ω-3 ratio of dietary LCPUFAs and pathological angiogenesis; however, their roles in ocular angiogenesis have been largely unexplored to date.We now show that dietary enrichment with ω-3 LCPUFAs suppresses CNV, vascular leakage, and immune cell recruitment to the lesion site in a mouse model of laser-induced CNV. We characterized the CYP-dependent pathway by which dietary ω-3 LCPUFAs promote resolution of choroidal neovessels in this model and identified CYP-generated metabolites 17,18-EEQ and 19,20-EDP as mediators of disease resolution. Furthermore, we show that expression of adhesion molecules at the CNV site was down-regulated in association with inhibition of leukocyte recruitment in mice receiving ω-3 LCPUFAs.     

Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis

Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2–induced lymphangiogenesis. Intriguingly, the VEGFR-3–mediated signaling was required for the lymphatic tip cell formation in both FGF-2– and VEGF-C–induced lymphangiogenesis. Consequently, a VEGFR-3–specific neutralizing antibody markedly inhibited FGF-2–induced lymphangiogenesis. Thus, the VEGFR-3–induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2–stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2– and VEGF-C–induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.     

IL-18: a new player in immunotherapy for age-related macular degeneration?

Recent evidence suggests that the pro-inflammatory cytokine IL-18 may have utility as an anti-angiogenic agent in the eye. Numerous laboratories, including our own have demonstrated the ability of murine IL-18 to prevent neovascularization in the retina, choroid and cornea in pathological scenarios. Here, we summarize the potential use of IL-18 as an immunotherapy for wet age-related macular degeneration treatment, describing past and recent findings pertaining to its biological function in the eye.     

IMI Pathologic Myopia

Pathologic myopia is a major cause of visual impairment worldwide. Pathologic myopia is distinctly different from high myopia. High myopia is a high degree of myopic refractive error, whereas pathologic myopia is defined by a presence of typical complications in the fundus (posterior staphyloma or myopic maculopathy equal to or more serious than diffuse choroidal atrophy). Pathologic myopia often occurs in eyes with high myopia, however its complications especially posterior staphyloma can also occur in eyes without high myopia.Owing to a recent advance in ocular imaging, an objective and accurate diagnosis of pathologic myopia has become possible. Especially, optical coherence tomography has revealed novel lesions like dome-shaped macula and myopic traction maculopathy. Wide-field optical coherence tomography has succeeded in visualizing the entire extent of large staphylomas. The effectiveness of new therapies for complications have been shown, such as anti-VEGF therapies for myopic macular neovascularization and vitreoretinal surgery for myopic traction maculopathy.Myopia, especially childhood myopia, has been increasing rapidly in the world. In parallel with an increase in myopia, the prevalence of high myopia has also been increasing. However, it remains unclear whether or not pathologic myopia will increase in parallel with an increase of myopia itself. In addition, it has remained unclear whether genes responsible for pathologic myopia are the same as those for myopia in general, or whether pathologic myopia is genetically different from other myopia.     

Ocular manifestations in phakomatosis pigmentovascularis: Current concepts on pathogenesis,diagnosis, and management

Phakomatosis pigmentovascularis is a rare congenital multisystemic disease with variable manifestations where a vascular malformation of the skin is associated with a pigmentary nevus. Ocular involvement includes glaucoma, choroidal hemangioma, and pigmentary alterations that predispose to uveal melanoma. Diagnosis is made on clinical grounds, although recent advances in molecular genetics have better clarified the etiopathogenesis of the condition. The advent of improved imaging techniques such as enhanced depth imaging spectral domain optical coherence tomography has provided new insight into the ocular alterations, enabling better follow-up of patients. We review the ophthalmic manifestations of the disease with an update on etiopathogenesis and current management strategies.     

高度近视合并脉络膜脱离型视网膜脱离预后相关因素分析

目的 分析高度近视合并脉络膜脱离型孔源性视网膜脱离（RRD-CD） 患者的预后相关因素。设计 回顾性病例系列。研究对象 2004-2018年北京同仁医院高度近视合并RRD-CD患者占836例。方法 回顾北京同仁医院住院HIS系统,收集高度近视合并RRD-CD手术治疗患者临床资料。随访6个月视网膜复位为复位组,发生视网膜再脱离为未复位组。采用Logistic回归法分析视网膜脱离复发的危险因素。主要指标 手术成功率及复发危险因素。结果 共纳入高度近视合并RRD-CD患者836例,平均年龄（56.51±12.14）岁;男性518例（61.9%）,右眼发病434例 （51.9%）。视网膜脱离未复位为22.7%,与视网膜复位患者相比,未复位患者年龄较轻,术前视力、眼轴、晶状体状态、视网膜裂孔、增生性玻璃体视网膜病变（PVR）等级及手术方式等差异均有统计学意义,其中年龄〔优势比（OR）=0.972,95%可信区间（95%CI）,0.967~0.989〕,术前视力光感（OR=1.898,95%CI为1.297~2.777）,人工晶状体眼（OR=1.860,95%CI为1.255~2.758）,眼轴>30 mm（OR=1.718,95%CI为1.240~2.379）,巨大视网膜裂孔（OR=2.464,95%CI为1.495~4.063）及PVR D级（OR=1.551,95%CI为1.046~2.300）为视网膜脱离未复位的危险因素。结论 高度近视合并RRD-CD患者男性比例大,中年发病、超高度近视、人工晶状体眼、巨大视网膜裂孔及PVD D级患者首次手术成功率低,视网膜脱离易复发。（眼科,2021,30： 42-46）     

原发性闭角型青光眼脉络膜厚度的变化

目的:探讨原发性急性闭角型青光眼(APACG)、原发性慢性闭角型青光眼(CPACG)脉络膜厚度(CT)的变化及相关因素。方法:回顾性研究。选取APACG患者35例43眼,CPACG患者26例46眼和正常对照组46例81眼参与这项研究。EDI-OCT用于测量和比较APACG、CPACG及正常对照组黄斑中心凹下、距黄斑中心凹2mm鼻侧、颞侧、上方、下方的CT,分别标记为黄斑中心凹下脉络膜厚度(SFCT),鼻2mm(N 2mm)、颞2mm(T 2mm)、上2mm(S 2mm)、下2mm(I 2mm)。进行线性回归分析探讨CT的相关因素。使用Logistic回归模型分析CT与APACG、CPACG的关系。结果:APACG,CPACG和正常对照组在所有位点的CT均无差异(P>0.05)。所有位点的CT与眼轴长度(AL)呈负相关。N 2mm、I 2mm还与年龄、前房深度(ACD)呈负相关,SFCT与年龄、AL呈负相关(P<0.05)。多因素Logistic回归分析表明,S 2mm与APACG存在相关性(P=0.029),OR值和95%的置信区间为0.975(0.953,0.997)。各位点CT与CPACG无相关性(P>0.05)。结论:年龄、AL、ACD是CT的相关因素。S 2mm的变薄与APACG相关。然而,CPACG与各位点CT不存在相关性。     

玻璃体腔注射康柏西普治疗高度近视黄斑脉络膜新生血管的疗效

目的：探究玻璃体腔注射康柏西普治疗高度近视黄斑脉络膜新生血管(CNV)的疗效。

方法：回顾性选取2017-06/2019-12我院眼科收治的因高度近视导致CNV的患者56例56眼作为研究对象,根据治疗方式分为对照组和观察组,对照组28例28眼行玻璃体腔注射雷珠单抗治疗,观察组28例28眼行玻璃体腔注射康柏西普治疗。末次治疗后随访3mo,记录患者眼压、最佳矫正视力(BCVA)及并发症发生情况,采用光学相干断层扫描(OCT)测定黄斑中心凹视网膜厚度(CMT),采用OCT仪水平线性扫描测量CNV面积。

结果：治疗后两组患者BCVA均较治疗前改善,且观察组BCVA优于对照组(均P<0.05)。治疗后3mo两组患者眼压、CNV面积及CMT均较治疗前降低,且观察组改善情况优于对照组(均P<0.05)。随访期间,观察组并发症发生率(4%)低于对照组(18%)。

结论：玻璃体腔注射康柏西普治疗高度近视CNV疗效优于雷珠单抗,可有效改善BCVA,降低CMT,减少术后并发症,提高临床疗效。