BACKGROUND & AIMS: :Laminin 5/laminin 332 (LN332) is an adhesion substrate for epithelial cells. After secretion of LN332, a regulated cleavage occurs at the carboxy-terminus of its alpha3 subunit, which releases a tandem of two globular modules named LG4/5. We show that the presence of the LG4/5 domain in precursor LN332 decreases its integrin-mediated cell adhesion properties in comparison with mature LN332. Whereas cell adhesion to the recombinant LG4/5 fragment relies solely on the heparan sulfate proteoglycan (HSPG) receptor syndecan-1, we reveal that both syndecan-1 and the alpha3beta1 integrin bind to precursor LN332. We further demonstrate that syndecan-1 mediated cell adhesion to the LG4/5 fragment and pre-LN332 allows the formation of fascin-containing protrusions, depending on the GTPases Rac and Cdc42 activation. Reducing syndecan-1 expression in normal keratinocytes prevents cell protrusions on pre-LN332 with subsequent failure of the peripheral localization of the alpha3beta1 integrin. We finally show that cell migration on pre-LN332 requires syndecan-1. Therefore, the LG4/5 domain in precursor LN332 appears to trigger intracellular signaling events, which participate in keratinocyte motility.

背景与目标： 层粘连蛋白5/层粘连蛋白332 (LN332) 是上皮细胞的粘附底物。LN332分泌后，在其 α3亚基的羧基末端发生受调节的裂解，该裂解释放出两个名为LG4/5的球状模块的串联。我们表明，与成熟的LN332相比，前体LN332中LG4/5结构域的存在降低了其整联蛋白介导的细胞粘附特性。尽管细胞对重组LG4/5片段的粘附仅依赖于硫酸乙酰肝素蛋白聚糖 (HSPG) 受体syndecan-1，但我们揭示了syndecan-1和 α3beta1整联蛋白均与前体ln332结合。我们进一步证明，syndecan-1介导的细胞粘附到LG4/5片段和pre-LN332允许形成含fascin的突起，这取决于GTPases Rac和Cdc42的激活。降低正常角质形成细胞中的syndecan-1表达可防止pre-LN332上的细胞突起，随后 α3β1整联蛋白的外周定位失败。我们最后证明pre-LN332上的细胞迁移需要syndecan-1。因此，前体LN332中的LG4/5结构域似乎触发细胞内信号传导事件，参与角质形成细胞的运动。

BACKGROUND & AIMS: :Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine phosphorylation in rat common carotid arteries, and siRNA-mediated down-regulation of its levels substantially attenuated BI-induced smooth muscle cell migration and proliferation, resulting in reduced neointima formation. Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, is involved in vascular wall remodeling. Our findings also show that protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation of vascular wall remodeling. Of note, we also observed that CCR2-Gi/o-Fyn signaling mediates MCP1-induced p115 RhoGEF and Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for MCP1-induced HASMC migration and proliferation in vitro and for injury-induced neointima formation in vivo by modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling.

背景与目标： : 尽管对Rho蛋白参与血管疾病的发病机理进行了很好的研究，但对其上游调节剂Rho鸟嘌呤核苷酸交换因子 (rhoiefs) 的作用知之甚少。在这里，我们试图鉴定参与单核细胞趋化蛋白1 (MCP1) 诱导的血管壁重塑的RhoGEFs。我们发现，在测试的RhoGEFs中，MCP1诱导人主动脉平滑肌细胞 (HASMCs) 中p115 RhoGEF的酪氨酸磷酸化，但不诱导PDZ RhoGEF或与白血病相关的RhoGEF的酪氨酸磷酸化。此外，p115 rhoge抑制抑制了MCP1-induced HASMC的迁移和增殖。与这些观察结果一致，球囊损伤 (BI) 在大鼠颈总动脉中诱导了p115 RhoGEF酪氨酸磷酸化，而siRNA介导的其水平下调大大减弱了BI诱导的平滑肌细胞迁移和增殖，从而减少了新内膜的形成。此外，p115 RhoGEF水平的耗竭也消除了MCP1或BI诱导的Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导，正如我们先前报道的那样，这与血管壁重塑有关。我们的发现还表明，Rac1-cyclin D1/CDK6下游和p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号轴CDK4-PAK1上游的蛋白激酶N1 (PKN1) 参与了血管壁重塑的调节。值得注意的是，我们还观察到CCR2-Gi/o-Fyn信号介导MCP1-induced p115 rhoge和rac1gtpase激活。这些发现表明，p115 RhoGEF对于MCP1-induced HASMC在体外迁移和增殖以及通过调节Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导在体内损伤诱导的新内膜形成至关重要。

BACKGROUND & AIMS: :Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1α in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1α by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1α but rescued when eliminating homeodomain-interacting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase-2-hypoxia-inducible factor-1α pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1α in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma.

背景与目标： 缺氧通过激活关键转录因子缺氧诱导因子-1在肝细胞癌的进展和转移中起关键作用。这项研究旨在确定低氧诱导因子-1α 在肝细胞癌中失调的新机制。我们发现，组蛋白去乙酰化酶5 (一种在肝细胞癌中高表达的组蛋白去乙酰化酶) 在缺氧而非常氧条件下加强了肝细胞癌细胞的迁移和侵袭。此外，组蛋白脱乙酰基酶5通过沉默同源结构域相互作用的蛋白激酶2表达来诱导缺氧诱导因子1α 的转录，这也依赖于缺氧。然后，低氧诱导因子-1α 的敲除降低了间充质标志物N-钙粘蛋白和波形蛋白以及基质金属蛋白酶MMP7和MMP9的表达; 然而，上皮标志物E-钙粘蛋白增加。表型实验表明，组蛋白去乙酰化酶5或缺氧诱导因子-1α 的敲除损害了肝癌细胞的迁移和侵袭，但在消除肝癌细胞中的同源结构域相互作用蛋白激酶-2时得以挽救，这表明组蛋白去乙酰化酶5-同源多蛋白相互作用蛋白kinase-2-hypoxia-inducible因子-1α 途径在缺氧诱导的转移中起关键作用。最后，临床分析证实了组蛋白去乙酰化酶5与低氧诱导因子-1α 在肝细胞癌标本中的正相关，并且对于高水平组蛋白去乙酰化酶5和低氧诱导因子-1α 的患者预后相对较差。总之，我们的发现证明了肝细胞癌中组蛋白去乙酰化酶5和缺氧诱导因子1之间串扰的新机制。

BACKGROUND & AIMS: :Phenomenological parameters from a mathematical model of cell motility are used to quantitatively characterize chemosensory migration responses of rat alveolar macrophages migrating to C5a in the linear under-agarose assay, simultaneously at the levels of both single cells and cell populations. This model provides theoretical relationships between single-cell and cell-population motility parameters. Our experiments offer a critical test of these theoretical linking relationships, by comparison of results obtained at the cell population level to results obtained at the single-cell level. Random motility of a cell population is characterized by the random motility coefficient, mu (analogous to a particle diffusion coefficient), whereas single-cell random motility is described by cell speed, s, and persistence time, P (related to the period of time that a cell moves in one direction before changing direction). Population chemotaxis is quantified by the chemotactic sensitivity, chi 0, which provides a measure of the minimum attractant gradient necessary to elicit a specified chemotactic response. Single-cell chemotaxis is characterized by the chemotactic index, CI, which ranges from 0 for purely random motility to 1 for perfectly directed motility. Measurements of cell number versus migration distance were analyzed in conjunction with the phenomenological model to determine the population parameters while paths of individual cells in the same experiment were analyzed in order to determine the single-cell parameters. The parameter mu shows a biphasic dependence on C5a concentration with a maximum of 1.9 x 10(-8) cm2/sec at 10(-11) M C5a and relative minima of 0.86 x 10(-8) cm2/sec at 10(-7) M C5a and 1.1 x 10(-8) cm2/sec in the absence of Ca; s and P remain fairly constant with C5a concentration, with s ranging from 2.1 to 2.5 microns/min and P varying from 22 to 32 min. chi 0 is equal to 1.0 x 10(-6) cm/receptor for all C5a concentrations tested, corresponding to 60% correct orientation for a difference of 500 bound C5a receptors across a 20 microns cell length. The maximum CI measured was 0.2. Values for the population parameters mu and chi 0 were calculated from single-cell parameter values using the aforementioned theoretical linking relationships. The values of mu and chi 0 calculated from single-cell parameters agreed with values of mu and chi 0 determined independently from population migrations, over the full range of C5a concentrations, confirming the validity of the linking equations. Experimental confirmation of such relationships between single-cell and cell-population parameters has not previously been reported.

背景与目标： : 来自细胞运动数学模型的现象学参数用于定量表征在线性下琼脂糖测定中同时在单细胞和细胞群体水平上迁移到C5a的大鼠肺泡巨噬细胞的化学感觉迁移反应。该模型提供了单细胞和细胞群体运动参数之间的理论关系。通过将在细胞群体水平上获得的结果与在单细胞水平上获得的结果进行比较，我们的实验为这些理论联系关系提供了严格的测试。细胞群的随机运动的特征是随机运动系数mu (类似于粒子扩散系数)，而单细胞随机运动则由细胞速度，s和持续时间描述，P (与单元格在改变方向之前沿一个方向移动的时间段有关)。群体趋化性通过趋化敏感性chi 0来量化，chi 0提供了引起指定趋化反应所需的最小引诱剂梯度的量度。单细胞趋化性的特征是趋化指数CI，其范围从纯随机运动的0到完全定向运动的1。结合现象学模型分析了细胞数量与迁移距离的测量结果，以确定种群参数，同时分析了同一实验中单个细胞的路径，以确定单细胞参数。参数mu显示了对C5a浓度的双相依赖性，在10(-11) M C5a时最大值为1.9 × 10(-8) cm2/秒，在10(-7) M C5a和1.1 × 10(-10) 相对最小值为0.86 × 10(-8) cm2/秒。8) 在没有Ca的情况下cm2/sec; s和P在C5a浓度下保持相当恒定，s的范围为2.1至2.5微米/分钟，P的变化范围为22至32分钟。对于所有测试的C5a浓度，chi 0等于1.0x10(-6) cm/受体，对应于跨越20微米细胞长度的500结合C5a受体的差异的60% 正确取向。测量的最大CI为0.2。使用上述理论链接关系，根据单细胞参数值计算种群参数mu和chi 0的值。在整个C5a浓度范围内，由单细胞参数计算出的mu和chi 0的值与独立于种群迁移而确定的mu和chi 0的值一致，从而证实了链接方程的有效性。以前尚未报道过单细胞和细胞群体参数之间这种关系的实验证实。

BACKGROUND & AIMS: :Gastrulation is a dynamic tissue-remodeling process occurring during early development and fundamental to the later organogenesis. It involves both chemical signals and physical factors. Although much is known about the molecular pathways involved, the roles of physical forces in regulating cellular behavior and tissue remodeling during gastrulation have just begun to be explored. Here, we characterized the force generated by the leading edge mesoderm (LEM) that migrates preceding axial mesoderm (AM), and investigated the contribution of LEM during Xenopus gastrulation. First, we constructed an assay system using micro-needle which could measure physical forces generated by the anterior migration of LEM, and estimated the absolute magnitude of the force to be 20-80nN. Second, laser ablation experiments showed that LEM could affect the force distribution in the AM (i.e. LEM adds stretch force on axial mesoderm along anterior-posterior axis). Third, migrating LEM was found to be necessary for the proper gastrulation cell movements and the establishment of organized notochord structure; a reduction of LEM migratory activity resulted in the disruption of mediolateral cell orientation and convergence in AM. Finally, we found that LEM migration cooperates with Wnt/PCP to form proper notochord. These results suggest that the force generated by the directional migration of LEM is transmitted to AM and assists the tissue organization of notochord in vivo independently of the regulation by Wnt/PCP. We propose that the LEM may have a mechanical role in aiding the AM elongation through the rearrangement of force distribution in the dorsal marginal zone.

背景与目标： : 胃形成是一个动态的组织重塑过程，发生在早期发育过程中，是后期器官发生的基础。它涉及化学信号和物理因素。尽管人们对所涉及的分子途径了解很多，但在胃形成过程中，物理力在调节细胞行为和组织重塑中的作用才刚刚开始探索。在这里，我们表征了在轴向中胚层 (AM) 之前迁移的前缘中胚层 (LEM) 产生的力，并研究了LEM在非洲爪蟾胃形成过程中的贡献。首先，我们使用微针构建了一个测定系统，该系统可以测量由LEM的前迁移产生的物理力，并估计该力的绝对大小为20-80nn。其次，激光消融实验表明，LEM可以影响AM中的力分布 (即LEM沿前后轴在轴向中胚层上增加拉伸力)。第三，发现迁移LEM对于适当的胃形成细胞运动和建立有组织的脊索结构是必要的; LEM迁移活动的减少导致AM中上外侧细胞取向和会聚的破坏。最后，我们发现LEM迁移与Wnt/PCP合作形成适当的脊索。这些结果表明，由LEM的定向迁移产生的力传递到AM，并独立于Wnt/PCP的调节而有助于体内脊索的组织组织。我们建议，LEM可能具有机械作用，可通过重新排列背侧边缘区的力分布来帮助AM伸长。

BACKGROUND & AIMS: OBJECTIVE:To evaluate the effect of scleral buckling surgery on the treatment of hypotony caused by choroidal holes and suprachoroidal silicone oil (SO) migration following surgical procedures for open globe injuries. DESIGN:Retrospective, consecutive, interventional case series. PARTICIPANTS:Ten eyes of 10 patients with hypotony caused by choroidal holes with suprachoroidal SO migration and choroidal detachment after vitrectomy for open globe injuries between October 2009 and December 2010. METHODS:All cases clinically diagnosed as hypotony caused by choroidal holes with suprachoroidal SO migration and choroidal detachment were identified. Those eyes with retinal detachment, ciliary body damage, ciliary body fibrosis, or cyclodialysis cleft were excluded. Scleral buckling with or without suprachoroidal SO drainage was performed. RESULTS:The mean preoperative intraocular pressure (IOP) was 6.7 ± 1.4 mm Hg (5.3-9.0 mm Hg). The mean final follow-up IOP was 12.2 ± 4.7 mm Hg (7.0-21.0 mm Hg; p = 0.005). In 7 eyes, the IOP increased to ≥10 mm Hg, whereas 3 eyes showed no significant IOP elevations. The choroidal hole was closed, and the range of choroidal detachment was significantly reduced in those 7 eyes. Although the choroidal hole was not fully closed in 3 eyes, the choroidal detachment area was less extensive, and the IOP was stable at approximately 7 mm Hg. CONCLUSION:Scleral buckling surgery combined with suprachoroidal SO drainage is an effective way to manage hypotony caused by choroidal holes and suprachoroidal SO migration in a SO-filled eye after vitrectomy for open globe injuries.

背景与目标：

BACKGROUND & AIMS: :This study is part of the Promoting Aging Migrants' Capabilities programme that applied person-centred group meetings and one individual home visit to prolong independence in daily activities among people ≥70 years who had migrated to Sweden from Finland or the Western Balkan region. With the purpose to understand programme outcomes, the study aimed to explore the participants' everyday experiences of using health-promoting messages exchanged during the programme. Using a grounded theory approach, 12 persons aged 70-83 years were interviewed six months to one year after their participation in the programme. The participants experienced how using health-promoting messages was a dynamic process of how to make decisions on taking action to satisfy health-related needs of oneself or others immediately or deferring action. Five sub-processes were also identified: gaining inner strength, meeting challenges in available resources, being attentive to what is worth knowing, approaching health risks, and identifying opportunities to advocate for others. The results suggest that the programme could develop personal skills to support older people who have migrated to overcome health-related challenges. They further demonstrate the importance of supporting their health literacy before personal resources hinder action, and call for research on programmes to overcome environmental barriers to health.

背景与目标： : 这项研究是 “促进老龄移民能力” 计划的一部分，该计划采用以人为中心的小组会议和一次个人家访，以延长从芬兰或西巴尔干地区移民到瑞典的70岁以上人群的日常活动独立性。为了了解计划的结果，该研究旨在探索参与者在计划中使用健康促进信息的日常经验。采用扎根理论的方法，对12名年龄在70-83岁的人参加该计划六个月至一年后进行了采访。参与者体验了如何使用促进健康的信息是一个动态的过程，如何决定立即采取行动以满足自己或他人的健康相关需求或推迟采取行动。还确定了五个子过程: 获得内在力量，应对可用资源的挑战，关注值得了解的内容，应对健康风险以及确定为他人辩护的机会。结果表明，该计划可以发展个人技能，以支持为克服健康相关挑战而移民的老年人。他们进一步证明了在个人资源阻碍行动之前支持其健康素养的重要性，并呼吁研究克服环境对健康的障碍的方案。

BACKGROUND & AIMS: :Activin receptor-like kinase 1 (ALK1) is an endothelial-specific type I receptor of the TGFbeta receptor family that is implicated in angiogenesis and in the pathogenesis of the vascular disease, hereditary hemorrhagic telangiectasia (HHT). In the absence of a specific ligand, ALK1 cellular functions have been mainly studied through the use of a constitutively active form of this receptor (ALK1ca) and are still debated. We previously reported that ALK1ca inhibits proliferation and migration of human endothelial cells suggesting that ALK1 plays an important role in the maturation phase of angiogenesis (Lamouille et al., 2002, Blood 100: 4495-4501). In the present work, we further analyzed the role of ALK1 in the migration of human dermal microvascular endothelial cell (HMVEC-d) and observed that silencing endogenous ALK1 expression with siRNAs accelerates endothelial cell migration in the wound assay. Further, we demonstrate that ALK1-induced inhibition of migration is Smad-independent. Using a panel of kinase inhibitors, we found that HMVEC-d wound closure was completely inhibited by a JNK inhibitor and to a lower degree by an ERK kinase inhibitor. Further, HMVEC-d wounding induced activation of both JNK and ERK, and these were inhibited by ALK1ca expression. Taken together, these results support a significant role for ALK1 as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect.

背景与目标： : 激活素受体样激酶1 (ALK1) 是TGFbeta受体家族的内皮特异性I型受体，与血管生成和血管疾病的发病机理有关，遗传性出血性毛细血管扩张 (HHT)。在没有特定配体的情况下，主要通过使用该受体的组成型活性形式 (ALK1ca) 来研究ALK1细胞功能，并且仍在争论中。我们先前报道ALK1ca抑制人内皮细胞的增殖和迁移，这表明ALK1在血管生成的成熟期中起重要作用 (Lamouille等人，2002，血液100: 4495-4501)。在目前的工作中，我们进一步分析了ALK1在人真皮微血管内皮细胞 (hmvec-d) 迁移中的作用，并观察到用sirna沉默内源性ALK1表达会加速伤口检测中的内皮细胞迁移。此外，我们证明了ALK1-induced对迁移的抑制是不依赖Smad的。使用一组激酶抑制剂，我们发现hmvec-d伤口闭合被JNK抑制剂完全抑制，而被ERK激酶抑制剂抑制的程度较低。此外，HMVEC-d损伤诱导JNK和ERK的激活，并且这些激活被ALK1ca表达抑制。总之，这些结果支持ALK1作为内皮细胞迁移的负调节剂的重要作用，并暗示JNK和ERK作为这种作用的介体。

BACKGROUND & AIMS: :Colon cancer is among the leading causes of cancer death in North America. CD44, an adhesion and antiapoptotic molecule is overexpressed in colon cancer. Cofilin is involved in the directional motility of cells. In the present study, we looked at how CD44 might modulate cell migration in human colon cancer via cofilin. We used a human colon cancer cell line, HT29, which expresses CD44, HT29 where CD44 expression was knocked down by siRNA, SW620, a human colon cancer cell line which does not express CD44, stably transfected exons of CD44 in SW620 cells and the colon from CD44 knockout and wild-type mouse. Western blot analysis of siRNA CD44 lysates showed increased level of AKT phosphorylation and decreased level of cofilin expression. Similar results were also observed with SW620 cells and CD44 knockout mouse colon lysates. Experiments using the AKT phosphorylation inhibitor LY294002 indicate that AKT phosphorylation downregulates cofilin. Immunoprecipitation studies showed CD44 complex formation with Lyn, providing an essential link between CD44 and AKT phosphorylation. LY294002 also stabilized Lyn from phosphorylated AKT, suggesting an interaction between Lyn and AKT phosphorylation. Immunocytochemistry showed that cofilin and Lyn expression were downregulated in siRNA CD44 cells and CD44 knockout mouse colon. siRNA CD44 cells had significantly less migration compared to HT29 vector. Given the well-defined roles of CD44, phosphorylated AKT in apoptosis and cancer, these results indicate that CD44-induced cell migration is dependent on its complex formation with Lyn and its consequent regulation of AKT phosphorylation and cofilin expression.

背景与目标： : 结肠癌是北美癌症死亡的主要原因之一。CD44是一种粘附和抗凋亡分子，在结肠癌中过度表达。Cofilin参与细胞的定向运动。在本研究中，我们研究了CD44如何通过cofilin调节人结肠癌中的细胞迁移。我们使用了表达CD44，HT29的人结肠癌细胞系HT29，其中CD44表达被不表达CD44的人结肠癌细胞系siRNA SW620下调，SW620细胞和结肠中CD44的稳定转染外显子来自CD44基因敲除和野生型小鼠。siRNA CD44裂解物的Western印迹分析显示AKT磷酸化水平升高，cofilin表达水平降低。SW620细胞和CD44敲除小鼠结肠裂解物也观察到类似的结果。使用AKT磷酸化抑制剂LY294002的实验表明，AKT磷酸化下调了cofilin。免疫沉淀研究表明，与Lyn形成CD44复合物，在CD44和AKT磷酸化之间提供了重要的联系。LY294002还使Lyn从磷酸化的AKT中稳定下来，表明Lyn和AKT磷酸化之间存在相互作用。免疫细胞化学显示cofilin和Lyn在siRNA CD44细胞和CD44基因敲除小鼠结肠中的表达下调。与HT29载体相比，siRNA CD44细胞的迁移明显减少。鉴于CD44，磷酸化的AKT在细胞凋亡和癌症中的明确定义的作用，这些结果表明CD44-induced细胞迁移取决于其与Lyn的复合物形成及其对AKT磷酸化和cofilin表达的调节。

BACKGROUND & AIMS: :A standardized microculture system has been developed to assess the ability of lymphocytes to secrete leukocyte migration inhibitory factor (LMIF) in response to the nonspecific mitogen concanavalin(Con A). LMIF-rich supernates collected from stimulated lymphocytes cultured in plastic microtiter plates are assayed by pulse exposure of purified human granulocytes and inhibition of their migration in agarose medium. LMIF activity in this system is suppressed by the protein synthesis inhibitor puromycin, but not by inhibition of lymphocyte proliferation by irradiation. It is demonstrated that normal lymphocytes stimulated with mitogen elaborate LMIF activity, while lymphocytes from malignant lymphoma patients are frequently unable to produce it. Thus, mitogen-induced mediator production may be a useful parameter in further characterization of primary and secondary immunodeficiencies.

背景与目标： : 已开发出一种标准化的微培养系统，以评估淋巴细胞响应非特异性有丝分裂原伴刀豆球蛋白 (Con A) 分泌白细胞迁移抑制因子 (LMIF) 的能力。通过脉冲暴露纯化的人粒细胞并抑制其在琼脂糖培养基中的迁移，测定从在塑料微量滴定板中培养的受刺激淋巴细胞中收集的富含LMIF的上清液。该系统中的LMIF活性被蛋白质合成抑制剂嘌呤霉素抑制，但不能被辐射抑制淋巴细胞增殖。已证明，有丝分裂原刺激的正常淋巴细胞具有丰富的LMIF活性，而恶性淋巴瘤患者的淋巴细胞通常无法产生LMIF活性。因此，有丝分裂原诱导的介体产生可能是进一步表征原发性和继发性免疫缺陷的有用参数。

BACKGROUND & AIMS: 1. The effect of the selective type 4 phosphodiesterase (PDE 4) inhibitor rolipram on human eosinophil activation and migration mediated by eotaxin was investigated. 2. Studies were performed with human freshly isolated eosinophils from peripheral blood of healthy donors by a magnetic cell separation (MACS) technique to a purity > 99%. To test the effect of rolipram, eosinophils were stimulated with recombinant human eotaxin and the cell surface activation markers CD11b and L-selectin were analysed by flow cytometry. Furthermore, eotaxin mediated eosinophil migration was measured in a transendothelial chemotaxis assay. 3. Our results indicate that rolipram inhibited eotaxin-induced CD11b up-regulation up to 60.6 +/- 7.6% at the highest tested dose (10 microM), whereas transendothelial chemotaxis was partially inhibited reaching a plateau of approx. 30% at a rolipram concentration of 0.1 microM. 4. We conclude that the selective PDE 4 inhibitor rolipram decreases eotaxin mediated eosinophil activation, an observation that may contribute to elucidate the mechanism by which PDE 4 inhibitors reduce antigen-induced eosinophil infiltration in different animal models of allergic inflammation.

背景与目标： 1.研究了选择性4型磷酸二酯酶 (PDE 4) 抑制剂罗利普兰对eotaxin介导的人嗜酸性粒细胞活化和迁移的影响。2.研究是通过磁性细胞分离 (MACS) 技术从健康供体的外周血中分离的人新鲜嗜酸性粒细胞进行的，其纯度> 99%。为了测试罗利普兰的作用，用重组人嗜酸性粒细胞趋化因子刺激嗜酸性粒细胞，并通过流式细胞术分析细胞表面活化标记物CD11b和L-选择素。此外，在跨内皮趋化试验中测量了eotaxin介导的嗜酸性粒细胞迁移。3.我们的结果表明，在最高测试剂量 (10微米) 下，罗利普兰抑制eotaxin诱导的CD11b上调高达60.6 +/- 7.6%，而内皮细胞的趋化性被部分抑制，达到约。在0.1微米的罗利普拉姆浓度下30%。4.我们得出的结论是，选择性PDE 4抑制剂rolipram降低了eotaxin介导的嗜酸性粒细胞活化，这一观察结果可能有助于阐明PDE 4抑制剂在不同的过敏性炎症动物模型中减少抗原诱导的嗜酸性粒细胞浸润的机制。

BACKGROUND & AIMS: :In order to compare the risk of gynaecologic cancer among foreign-born women to the risk among those born in Sweden and to elucidate risk of cancer in relation to age at migration and duration of residence, we followed a cohort of 5.3 million women between 1969 and 2004 in Sweden. Through linkage with the national cancer register, we estimated cancer risk as rate ratios (RRs) with 95% confidence intervals (CIs) using Poisson regression. We reported RRs adjusted for age, calendar year of follow-up and years of education. Overall, 18,247 cases of cervical, 35,290 cases of endometrial and 32,227 cases of ovarian cancers occurred during 117 million person-years of follow-up. We found that adjusted RRs of all the three cancers were lower or the same among foreign-born women compared to those born in Sweden. As for cervical cancer, women aged 35-49 years born in Poland and Bosnia and women aged 50 years or more born in South America showed an increased risk, which was related to increasing age at migration. The risk was lowest among women born in Iran, Iraq, Organisation for Economic Cooperation & Development (OECD) and Finland, and highest among women born in Bosnia and Eastern Europe during their first 5 years since immigration. RRs for endometrial and ovarian cancers did not vary by duration of residence or by age at migration. Health care providers should be aware of the higher risk of cervical cancer among immigrants from high-risk areas, especially among those who immigrate at older ages. On the other hand, protective factors for ovarian and endometrial cancers seem to be retained upon migration.

背景与目标： : 为了比较外国出生妇女与瑞典出生妇女的妇科癌症风险，并阐明与迁移年龄和居住时间有关的癌症风险，我们对530万名1969年和2004名瑞典妇女进行了随访。通过与国家癌症登记册的联系，我们使用泊松回归用95% 置信区间 (CIs) 估计癌症风险as率比 (RRs)。我们报告了根据年龄，随访日历年和受教育年限进行调整的RRs。总体而言，在1.17亿人年的随访中发生了18,247例宫颈癌，35,290例子宫内膜癌和32,227例卵巢癌。我们发现，与在瑞典出生的女性相比，在外国出生的女性中，所有三种癌症的调整后的RRs均较低或相同。至于宫颈癌，在波兰和波斯尼亚出生的35-49岁妇女和在南美出生的50岁或50岁以上妇女的风险增加，这与移民年龄的增加有关。在伊朗，伊拉克，经济合作与发展组织 (OECD) 和芬兰出生的妇女中，风险最低，在移民后的头5年中，在波斯尼亚和东欧出生的妇女中风险最高。子宫内膜癌和卵巢癌的RRs没有随居住时间或迁移年龄而变化。卫生保健提供者应意识到，来自高风险地区的移民中，尤其是在年龄较大的移民中，患宫颈癌的风险更高。另一方面，卵巢癌和子宫内膜癌的保护因素似乎在迁移后保留。

BACKGROUND & AIMS: :Cell migration and axon guidance require proper regulation of the actin cytoskeleton in response to extracellular guidance cues. Rho/Rac small GTPases are essential regulators of actin remodeling. Caenorhabditis elegans CED-10 is a Rac1 homolog that is required for various cellular morphological changes and migration events and is under the control of several guidance signaling pathways. There is still considerable uncertainty regarding events following the activation of guidance receptors by extracellular signals and the regulation of actin dynamics based on spatiotemporally restricted Rac activity. Here we show that the VPS9 domain protein RIN-1 acts as a novel effector for CED-10 in C. elegans. The orthologous mammalian Rin1 protein has previously been identified as an effector for Ras GTPase and is now known to function as a guanine nucleotide exchange factor for Rab5 GTPase. We found that RIN-1 specifically binds to the GTP-bound form of CED-10 and that mutations in rin-1 cause significant defects in migration and axon guidance of restricted neuronal cell types including AVM and HSN neurons, in contrast to the various defects observed in ced-10 mutants. Our analyses place RIN-1 in the Slit-Robo genetic pathway that regulates repulsive signaling for dorsoventral axon guidance. In rin-1 mutants, actin accumulated on both the ventral and dorsal sides of the developing HSN neuron, in contrast to its ventral accumulation in wild type. These results strongly suggest that RIN-1 acts as an effector for CED-10/Rac1 and regulates actin remodeling in response to restricted guidance cues.

背景与目标： : 细胞迁移和轴突引导需要对肌动蛋白细胞骨架进行适当的调节，以响应细胞外引导提示。Rho/Rac小GTPases是肌动蛋白重塑的重要调节剂。秀丽隐杆线虫CED-10是Rac1同源物，是各种细胞形态变化和迁移事件所必需的，并且受多种引导信号通路的控制。关于细胞外信号激活引导受体以及基于时空限制的Rac活性调节肌动蛋白动力学之后的事件，仍然存在相当大的不确定性。在这里，我们显示了VPS9结构域蛋白RIN-1作为秀丽隐杆线虫CED-10的新效应子。直系同源哺乳动物Rin1蛋白先前已被鉴定为Ras GTPase的效应子，现在已知可作为Rab5 GTPase的鸟嘌呤核苷酸交换因子。我们发现RIN-1与GTP结合形式的CED-10特异性结合，并且rin-1中的突变导致包括AVM和HSN神经元在内的受限神经元细胞类型的迁移和轴突引导的显著缺陷，与在ced-10突变体中观察到的各种缺陷相反。我们的分析将RIN-1置于Slit-Robo遗传途径中，该途径调节背腹轴突引导的排斥信号。在rin-1突变体中，肌动蛋白在发育中的HSN神经元的腹侧和背侧都积累，与野生型的腹侧积累相反。这些结果强烈表明，RIN-1充当CED-10/Rac1的效应器，并响应于受限的引导线索调节肌动蛋白重塑。

BACKGROUND & AIMS: :Elevated plasma concentrations of Lp(a) [lipoprotein(a)] are an emerging risk factor for atherothrombotic disease. Apo(a) [apolipoprotein(a)], the unique glycoprotein component of Lp(a), contains tandem repeats of a plasminogen kringle (K) IV-like domain. In the light of recent studies suggesting that apo(a)/Lp(a) affects endothelial function, we evaluated the effects of apo(a)/Lp(a) on growth and migration of cultured HUVECs (human umbilical-vein endothelial cells). Two full-length r-apo(a) [recombinant apo(a)] variants (12K and 17K), as well as Lp(a), were able to stimulate HUVEC growth and migration to a comparable extent; 17K r-apo(a) also decreased the levels of total and active transforming growth factor-beta secreted by these cells. Using additional r-apo(a) variants corresponding to deletions and/or site-directed mutants of various kringle domains in the molecule, we were able to determine that the observed effects of full-length r-apo(a) on HUVECs were dependent on the presence of a functional lysine-binding site(s) in the apo(a) molecule. With respect to signalling events elicited by apo(a) in HUVECs, we found that 17K treatment of the cells increased the phosphorylation level of FAK (focal adhesion kinase) and MAPKs (mitogen-activated protein kinases), including ERK (extracellular-signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase). In addition, we showed that LM609, the function-blocking antibody to integrin alphaVbeta3, abrogated the effects of 17K r-apo(a) and Lp(a) on HUVECs. Taken together, the results of the present study suggest that the apo(a) component of Lp(a) signals through integrin alphaVbeta3 to activate endothelial cells.

背景与目标： : Lp(a) [脂蛋白 (a)] 的血浆浓度升高是动脉粥样硬化血栓形成疾病的新兴危险因素。载脂蛋白 (a) [载脂蛋白 (a)] 是Lp(a) 的独特糖蛋白成分，包含纤溶酶原kringle (K) IV样结构域的串联重复序列。鉴于最近的研究表明apo(a)/Lp(a) 影响内皮功能，我们评估了apo(a)/Lp(a) 对培养的HUVECs (人脐静脉内皮细胞) 生长和迁移的影响。两个全长r-apo(a) [重组apo(a)] 变体 (12k和17K) 以及Lp(a) 能够在相当程度上刺激HUVEC的生长和迁移; 17K r-apo(a) 也降低了这些细胞分泌的总和活性转化生长因子-β 的水平。使用对应于分子中各种kringle结构域的缺失和/或定点突变体的其他r-apo(a) 变体，我们能够确定观察到的全长r-apo(a) 对huvec的影响取决于apo(a) 分子中功能性赖氨酸结合位点的存在。关于huvec中apo(a) 引起的信号事件，我们发现细胞的17k处理增加了FAK (粘着斑激酶) 和mapk (丝裂原活化蛋白激酶) 的磷酸化水平，包括ERK (细胞外信号调节激酶)，p38和JNK (c 6月N端激酶)。此外，我们显示LM609 (整合素alphaVbeta3的功能阻断抗体) 消除了17K r-apo(a) 和Lp(a) 对huvec的影响。总之，本研究的结果表明，Lp(a) 的apo(a) 成分通过整合素 αvbeta3发出信号以激活内皮细胞。

BACKGROUND & AIMS: OBJECTIVE:To describe the risk factors, clinical course, and complications of migration of a dexamethasone (DEX) intravitreal implant (OZURDEX; Allergan, Inc., Irvine, CA) into the anterior chamber and subsequent management strategies. DESIGN:Retrospective, observational case series. PARTICIPANTS:Fifteen patients had 18 episodes of migration of the DEX implant into the anterior chamber. METHODS:The medical records of 15 patients with spontaneous migration of a DEX implant were retrospectively reviewed. MAIN OUTCOME MEASURES:Migration of the DEX implant into the anterior chamber. RESULTS:Migration of a DEX intravitreal implant into the anterior chamber occurred in 6 patients who were aphakic, 4 patients with an anterior chamber intraocular lens, 2 patients with a scleral-fixated posterior chamber intraocular lens (PCIOL), 2 patients with a PCIOL, and 1 patient with an iris-fixated PCIOL. All 15 patients had prior pars plana vitrectomy, and 14 patients (93%) had no lens capsule. The average interval from DEX implant injection to detection of the implant migration into the anterior chamber was 13 days (range, 5-44 days). In 14 patients, corneal edema developed. Among those eyes undergoing surgical removal of the implant, earlier intervention reduced the likelihood of permanent corneal edema (0.5 days [from diagnosis of migration to surgical removal of the implant] vs. 5.5 days; P = 0.04). Aspiration was necessary to remove the implant in 6 patients. Among the 14 patients with corneal edema, the corneal edema did not resolve in 10 patients (71%), 6 (43%) of whom required corneal transplantation. CONCLUSIONS:Absence of lens capsule and prior vitrectomy are risk factors for migration of the DEX implant into the anterior chamber. Early removal of the implant may be necessary to minimize the risk of chronic corneal edema.

背景与目标：