The Role of VEGF family in angiogenesis, tumor growth and metastasis

Tumor growth is dependent on angiogenesis, and cells in tumor tissues produce various angiogenic factors to induce neovascularization. Among tumor-derived angiogenic factors, members of the vascular endothelial growth factor (VEGF) family are most frequently and highly expressed in various solid tumors. VEGF-A, the prototype of VEGF, is the most powerful pro-angiogenic factor that binds to VEGF receptor-1 (VEGFR-1, also called FMSRelated Tyrosine Kinase-1/Flt-1) and VEGFR-2 (also called Kinase Insert Domain Receptor/KDR or Fetal Liver Kinase -1/Flk-1). While the VEGFR-2-transduced angiogenic signals, pathways, and functions are well characterized, the VEGFR-1-mediated functions are poorly understood. The angiogenic functions of placental growth factor (PlGF), which is a specific VEGFR-1-binding ligand, remain controversial. The role of VEGF-B in tumor angiogenesis is still unclear. In addition, the two other VEGF family members, VEGF-C and VEGF-D are the major lymphangiogenic factors that contribute to lymphatic metastasis. The work contained in this thesis aimed to study the role of VEGF family members in angiogenesis, tumor growth and metastasis. Our work shows that PlGF exhibits a duality in modulation of angiogenesis and tumor growth in a VEGF-A-dependent manner. This is noted when the tumor cell-derived PlGF sensitizes the tumor to the anti-angiogenic and anti-tumor effects of anti-VEGF drugs. We also noted that anti-VEGF treatment induces various vascular alterations in mouse healthy tissues. Additionally, we revealed the collaborative interaction between FGF-2 and VEGF-C in promotion of lymphangiogenesis and metastasis. In paper I, using two independent tumor models, we show that PlGF modulated tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism in either a positive or a negative manner. In the VEGF-A positive model, PlGF inhibited tumor growth and angiogenesis, leading to normalized tumor vasculature with dilated vessel lumens, infrequent vascular branches and increased perivascular cell coverage. Surprisingly, in the VEGF-A negative model, overexpression of PlGF resulted in the opposite phenotype to that seen in the VEGF-A positive model, namely accelerated tumor growth rates and abundant chaotic tumor vessels. Our data uncovered the molecular mechanisms underlying the complex interplay between PlGF and VEGF-A. These findings have conceptual implications for anti-angiogenic cancer therapy. In paper II, we show that tumors from humans and mice with high levels of expression of PlGF were hypersensitive to anti-VEGF-A and anti-VEGFR-2 therapies. We then validated this finding with a loss-of-function experiment using PLGF shRNA in a human choriocarcinoma cell line. Down-regulation of PlGF significantly accelerated tumor growth rate and led to resistance to anti-VEGF drugs. We also show that VEGFR-2 and VEGFR-1 neutralizing antibodies displayed opposing effects on tumor growth and angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and sensitizes treatment effect of anti-VEGF drugs in VEGF-A positive tumors, PlGF level in VEGF-A positive tumor may potentially be a predictive marker of anti-VEGF cancer therapy. In paper III, we investigated vascular alteration in various organs after systemic treatment with anti-VEGF-A, anti-VEGFR-1 and anti-VEGFR-2 neutralizing antibodies. This study provides functional and structural mechanisms for anti-VEGF drug-induced adverse effects in patients. In paper IV, we looked into the role of fibroblast growth factor-2 (FGF-2) and VEGF-C on angiogenesis, lymphangiogenesis and tumor metastasis. The results showed that FGF-2 and VEGF-C could both separately and collaboratively promote angiogenesis and lymphangiogenesis in the cornea of the mouse and in the mouse tumor tissue, resulting in pulmonary and lymph node metastases in animal models. By blocking VEGFR-3 and FGF receptor-1 (FGFR-1), we also revealed the fact that VEGFR-3-induced lymphatic endothelial cell (LEC) tip formation is a necessity for FGF-2-FGFR-1 signaling stimulated lymphangiogenesis. This study suggests that combined targeting of FGF-2 and VEGF-C might be an effective approach for cancer therapy and prevention of metastasis

Optimized Hierarchical Power Oscillations Control for Distributed Generation Under Unbalanced Conditions

Control structures have critical influences on converter-interfaced distributed generations (DG) under unbalanced conditions. Most of previous works focus on suppressing active power oscillations and ripples of DC bus voltage. In this paper, the relationship between amplitudes of the active power oscillations and the reactive power oscillations are firstly deduced and the hierarchical control of DG is proposed to reduce power oscillations. The hierarchical control consists of primary and secondary levels. Current references are generated in primary control level and the active power oscillations can be suppressed by a dual current controller. Secondary control reduces the active power and reactive power oscillations simultaneously by optimal model aiming for minimum amplitudes of oscillations. Simulation results show that the proposed secondary control with less injecting negative-sequence current than traditional control methods can effectively limit both active power and reactive power oscillations.Comment: Accepted by Applied Energ

Silica sulfuric acid: a versatile and reusable heterogeneous catalyst for the synthesis of N-acyl carbamates and oxazolidinones under solvent-free conditions

Silica sulfuric acid catalyzes efficiently the reaction of carbamates and oxazolidinones with anhydrides under solvent-free conditions. All the reactions were done at room temperature and the N-acyl carbamates and oxazolidinones were obtained with high yields and purity via an easy work-up procedure. This method is attractive and is in a close agreement with green chemistry.KEY WORDS: N-Acyl carbamates, N-Acyl oxazolidinones, Silica sulfuric acid, Solvent-free Bull. Chem. Soc. Ethiop. 2011, 25(1), 151-155

DODA: Data-oriented Sim-to-Real Domain Adaptation for 3D Indoor Semantic Segmentation

Deep learning approaches achieve prominent success in 3D semantic segmentation. However, collecting densely annotated real-world 3D datasets is extremely time-consuming and expensive. Training models on synthetic data and generalizing on real-world scenarios becomes an appealing alternative, but unfortunately suffers from notorious domain shifts. In this work, we propose a Data-Oriented Domain Adaptation (DODA) framework to mitigate pattern and context gaps caused by different sensing mechanisms and layout placements across domains. Our DODA encompasses virtual scan simulation to imitate real-world point cloud patterns and tail-aware cuboid mixing to alleviate the interior context gap with a cuboid-based intermediate domain. The first unsupervised sim-to-real adaptation benchmark on 3D indoor semantic segmentation is also built on 3D-FRONT, ScanNet and S3DIS along with 7 popular Unsupervised Domain Adaptation (UDA) methods. Our DODA surpasses existing UDA approaches by over 13% on both 3D-FRONT $\rightarrow$ ScanNet and 3D-FRONT $\rightarrow$ S3DIS. Code will be available

Explorar el poder predictivo del compromiso laboral y la resiliencia de los profesores de EFL en su desarrollo profesional

The complexities and constant changes of trends in teaching the English language demand teachers to work on their pedagogical knowledge and skills continuously. These are best obtainable in professional development programs. However, the role of teacher emotions in such programs has remained unaddressed. To bridge this gap, this study examined the predicating role of second language (L2) teachers’ work engagement and buoyancy in their professional development. A total of 348 Chinese teachers participated in a survey with three online questionnaires. The results of structural equation modeling (SEM) and regression illustrated that both teacher work engagement and buoyancy could predict L2 teachers’ professional development. In particular, it was found that about 68% and 61% of changes in TPD could be predicted by work engagement and buoyancy, respectively. The study is momentous for L2 teaching and teacher education by calling for the integration of emotions into TPD and pedagogy.Las complejidades y los constantes cambios en las tendencias de enseñanza del idioma inglés exigen que los profesores trabajen continuamente en su conocimiento pedagógico y habilidades. Estas mejoras se obtienen mejor a través de programas de desarrollo profesional. Sin embargo, el papel de las emociones de los profesores en dichos programas ha quedado sin abordar. Para abordar esta brecha, este estudio investigó el papel predictivo del compromiso laboral y la resiliencia de los profesores de segunda lengua (L2) en el desarrollo profesional. Un total de 348 profesores chinos participaron en tres encuestas en línea. Los resultados del modelo de ecuaciones estructurales (SEM) y los análisis de regresión indicaron que tanto la dedicación laboral como la resiliencia pueden predecir el desarrollo profesional de los profesores de L2. Específicamente, el estudio descubrió que aproximadamente el 68% y el 61% de las variaciones en el desarrollo profesional de los profesores pueden ser respectivamente predichas por el compromiso laboral y la resiliencia. Este estudio es transcendental para la enseñanza de L2 y la formación de profesores, ya que aboga por la integración de las emociones en el desarrollo profesional y la pedagogía de los profesores